Dissertations / Theses: 'PARP inhibitory'

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Block, Katherine M. "Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcription." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/194826.

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Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.

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Kumpan, Katerina. "Structure-activity studies on inhibitors of the tankyrases." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619223.

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Tankyrases-1 and -2 (TNKS-1 and -2) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily, which modify and regulate target proteins by addition of multiple (ADP-ribose) units from the substrate NAD+. TNKS-1 and -2 have many cellular roles, including regulation of elongation of telomeres, activation of nuclear mitotic apparatus protein (NuMA) in mitosis and regulation of the Wnt signalling pathway. This makes the tankyrases attractive new targets for design and development of new anti-cancer drugs. 2-(4-Trifluoromethylphenyl)-7,8-dihydro-3H-thiopyranopyrimidin-4-one (XAV939) was one of the few active inhibitors of tankyrases reported until 2013. The aim of this project was to explore the structure-activity relationships towards enhancing potency and selectivity by replacing the saturated sulfur-containing ring with saturated and unsaturated nitrogen heterocycles and by varying the aromatic side-chain. Firstly, ascorbate-modified Sonogashira couplings of bromocyanopyridines and a variety of 4-substituted arylethynes, followed by acidic cyclisation and conversion of the lactone into the lactam, gave differently substituted arylnaphthyridinones. The alternative route used transition-metal-free reaction of bromopyridinecarboxylic acids with symmetrical β-diketones. 7-Phenyl-1,6-naphthyridin-5-one and 7-(4-methylphenyl)-1,6-naphthyridin-5-one were converted to the N1-oxides. Alkylation at 1-N gave 7-aryl-1-methyl-5-oxo-5,6-dihydro-1,6-naphthyridin-1-ium iodides and subsequent reduction gave saturated target 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Other target compounds included pyridopyrimidinones, which were prepared from the corresponding bromopyridinecarboxylic acids by a copper-catalysed reaction with 4-substituted benzamidines. Target tetrahydropyridopyrimidinones, however, were obtained from condensation of 1-benzyl-4-oxopiperidine-3-carboxylic esters with substituted benzamidines. All compounds were evaluated in vitro for inhibition of the catalytic activity of TNKS-2. The best compounds were investigated further, including in vitro TNKS-1 and PARP-1 inhibition and anti-proliferative studies on HT29 and FEK4 cell lines. Notably, 1-methyl-7-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one and 1-methyl-7-(4-methoxyphenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one showed 50% inhibition of TNKS-2 at 1.5 nM and 1.1 nM, respectively, showing also high selectivity (IC50 against PARP-1: 4.8 μM and 3.4 μM, respectively). This high potency and selectivity point to potential for development towards therapeutic use in cancer. A patent covering these discoveries has been filed.

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Castroviejo, Bermejo Marta. "RAD51 as functional biomarker to select tumors for PARP inhibitor treatment." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667273.

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Los inhibidores de la enzima Poly (ADP-ribosa) polimerasa (PARPi) son efectivos en el tratamiento de cánceres que presentan defectos en la reparación del ADN por recombinación homóloga (HRR), incluyendo aquellos con mutaciones en BRCA1 y BRCA2 (BRCA1/2). Se han descrito distintos mecanismos de resistencia a PARPi en tumores con mutaciones germinales en BRCA1/2 (gBRCA), y existen otros tumores sin mutaciones en BRCA1/2 (no-BRCA) que responden a PARPi. Existe la necesidad de desarrollar un biomarcador robusto para una mejor selección de tumores deficientes en HRR y extender el uso de PARPi a nuevas indicaciones, así como estudiar terapias en combinación que mejoren la eficacia en la clínica. En este trabajo se evaluó la actividad del PARPi olaparib en xenoimplantes de tumores derivados de pacientes (PDX, patient derived tumor xenografts) con cáncer de mama u ovario, tanto gBRCA como no-gBRCA. Se estudiaron los mecanismos de resistencia y sensibilidad a PARPi in vivo, así como la utilidad de una inmunofluorescencia para detectar focos nucleares de RAD51 como biomarcador de HRR y respuesta a PARPi, tanto en PDXs como en muestras clínicas. Además, se investigó la actividad antitumoral del inhibidor de WEE1 AZD1775 y del inhibidor de ATM AZD0156 en monoterapia y combinación con PARPi. Se investigaron los mecanismos de acción de estas terapias utilizando distintos marcadores de estrés replicativo. Entre los modelos PDX gBRCA resistentes a PARPi no se encontraron mutaciones secundarias en BRCA1/2 pero sí la formación de focos nucleares de BRCA1, en concordancia con la expresión de proteínas BRCA1 hipomórficas. En tres PDX resistentes a PARPi se identificó la pérdida de 53BP1 y FAM35A como mecanismo de resistencia. La única característica común a todos los PDXs resistentes a PARPi, ya sea resistencia primaria o adquirida, fue la capacidad de formación de focos nucleares de la proteína RAD51. De acuerdo con estos resultados, la ausencia de focos de RAD51 se asoció con respuesta clínica a PARPi en muestras de pacientes. Cuando se estudiaron los mecanismos de sensibilidad a PARPi en la colección de PDXs no-gBRCA, se observó la presencia de hipermetilación del promotor de BRCA1 y alteraciones en otros genes relacionados con HRR en modelos sensibles a PARPi. Sin embargo, de nuevo la única característica común a todos los PDXs respondedores fue la ausencia de focos nucleares de RAD51. El ensayo de RAD51 se pudo realizar en muestras no tratadas y mostró ser altamente discriminativo entre sensibilidad y resistencia a PARPi, superando la capacidad predictiva del test genético myChoice® HRD de Myriad. En muestras clínicas de rutina procedentes de pacientes con síndrome de cáncer de mama y ovario hereditario, todos los tumores relacionados con mutaciones en PALB2 se clasificaron como deficientes en HRR. Finalmente, se demostró que la resistencia a la terapia con PARPi en tumores con alteraciones en BRCA1 puede revertirse combinando estos agentes con un inhibidor de WEE1 o de ATM, y en ambas estrategias se reportó una mayor inducción de estrés replicativo en PDX sensibles a la combinación. Los resultados de esta tesis permiten concluir que los tumores gBRCA logran la resistencia a PARPi mediante diferentes mecanismos que restauran HRR y puede detectarse por la formación de focos nucleares de RAD51. Este ensayo funcional permite identificar tumores no-BRCA sensibles a PARPi y representa un biomarcador prometedor para mejorar la selección de pacientes y ampliar la población candidata a recibir esta terapia. Los resultados también impulsan el desarrollo clínico de estrategias terapéuticas que combinen los PARPi con inhibidores de WEE1 y ATM, destacando la inducción de estrés replicativo como principal mecanismo de acción de estos fármacos.
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective anticancer drugs in cancers with defective homologous recombination DNA repair (HRR), including cancers with mutations in BRCA1 and BRCA2 (BRCA1/2), which also display enhanced sensitivity to DNA damaging chemotherapy such as platinum salts. Several mechanisms of PARPi resistance have been described in tumors with germline mutations in BRCA1/2 (gBRCA) and there are also other tumors with wild type BRCA1/2 (non-BRCA) that benefit from PARPi treatment. Therefore, there is a need to develop robust biomarkers to better select HRR- deficient tumors and extend the use of PARP inhibition in new indications, as well as identify PARPi-resistant tumors and study combination treatment options that enhance clinical efficacy and utility of PARPi. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from patients with breast or ovarian cancer, both with and without gBRCA mutation, exhibiting differential response to PARPi. We studied the in vivo mechanisms of PARPi resistance and sensitivity in these models and tested the formation of RAD51 nuclear foci by immunofluorescence as biomarker of HRR functionality and PARPi response in PDXs and routine clinical samples. We also tested the antitumor activity of the WEE1i AZD1775 and the ATMi AZD0156 as single agent and in combination with PARPi in PDXs. The measurement of replication stress biomarkers was assessed to study the mechanisms of action of these treatment strategies. Within the gBRCA PDXs panel, no BRCA1/2 secondary mutations were found in the PARPi resistant models. BRCA1 nuclear foci were detected in six out of ten PARPi-resistant PDXs, in keeping with expression of hypomorphic BRCA1 isoforms. Loss of 53BP1 and FAM35A were identified in three PDXs, one of which concomitantly expressed an hypomorphic BRCA1 protein. The common feature in all PDXs with primary or acquired PARPi resistance was the formation of RAD51 nuclear foci. Consistently, lack of RAD51 foci was always associated with clinical response to PARPi in patients treated with these agents. When studying the mechanisms of PARPi sensitivity in the non-gBRCA PDX cohort, BRCA1 promoter hypermethylation and alterations in HRR-related genes were found in PARPi- sensitive models. Again, the unique common feature in all PDXs that exhibited tumor regression upon PARPi treatment is the absence of RAD51 nuclear foci. The RAD51 assay could be performed in untreated samples and was highly discriminative of PARPi sensitivity versus PARPi resistance in different PDX cohorts and outperformed the Myriad’s myChoice® HRD genomic test. In routine clinical samples from patients with hereditary breast and ovarian cancer (HBOC) syndrome, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. In PDXs, PARPi resistance in BRCA1-altered tumors could be reverted upon combination of PARPi with WEE1 or ATM inhibitors and both combination strategies resulted in exacerbated induction of replication stress (RS) in combination- sensitive PDXs. With the results obtained in this thesis, it can be concluded that gBRCA tumors achieve PARPi resistance by several mechanisms that restore HRR function, all detected by the presence of RAD51 nuclear foci. This functional assay also enables the identification of PARPi-sensitive non-gBRCA tumors independently of the mechanisms of HRR-deficiency, thereby being a promising biomarker to better select patients for PARP inhibition and broaden the population who may benefit from this therapy. Our study also supports the clinical development of PARPi combinations such as those with WEE1 and ATM inhibitors and highlighted the induction of RS as the major mechanisms of action of these drugs.

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Geraets, Liesbeth. "Dietary PARP-1 inhibitors as anti-inflammatory compounds." Maastricht : Maastricht : Universitaire Pers ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=14252.

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Smar, Michael William. "Part 1: Reversible and irreversible inhibitors of aldose reductase as probes of the inhibitor binding site. Part 2: Synthesis of permanently charged and permanently uncharged dopamine agonists /." The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487597424138323.

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Almeida, Gilberto Serrano de. "Pre-clinical imaging evaluation of the PARP inhibitor rucaparib." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2033.

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Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA-binding enzyme involved in DNA repair by the base-excision pathway. The inhibition of PARP1 is being investigated as a cancer treatment. Rucaparib (CO338) is a potent PARP 31 inhibitor currently in Phase II clinical development. In this thesis P in vivo MR Spectroscopy (MRS) and Dynamic Contrast Enhanced (DCE) MRI were used to study acute effects of rucaparib on energy metabolism and tumour vasculature. 1 31 18 18 Ex vivo H and P-MRS, and in vivo [ F]FLT and [ F]FDG-PET, were used to study effects of treatment with rucaparib on tumour metabolism and proliferation. A2780 and SW620 tumours implanted in mice were scanned in a horizontal Varian 7T MR system. Two i.v. injections of the MRI contrast agent gadoteridol were given 90 minutes apart with dynamic phosphorus MRS acquired following the injection of rucaparib, temozolomide or both drugs in combination. The 18 18 same tumours were evaluated by [ F]FLT- and [ F]FDG-PET after 5 daily treatments with rucaparib, temozolomide or the combination, and the livers of PARP1 knock out (KO) and wild type (WT) mice treated in a similar manner 1 31 were analysed by ex vivo H and P-MRS. Tumour uptake of gadoteridol changed significantly after treatment with hydralazine and higher doses of rucaparib in SW620 tumours, and following 31 hydralazine and 1mg/Kg of rucaparib in A2780 tumours. P-MRS studies revealed an increase in the inorganic phosphate (Pi) to β-NTP ratio, consistent with impairment of tumour energy metabolism following hydralazine treatment. 18 [ F]FLT-PET demonstrated a significant reduction in the SUV values in the 18 rucaparib/temozolomide combination group in SW620 tumours, and [ F]FDG- PET revealed a non-significant reduction in tumour metabolism in A2780 1 tumours. H ex vivo MRS demonstrated an increase in the liver NAD concentrations after treatment with rucaparib, but a decrease following the treatment with temozolomide, regardless of the PARP1 status. Together, these pre-clinical imaging studies have shown that MR can be used 18 to investigate the acute anti-vascular effects of rucaparib, that [ F]FLT-PET predicted subsequent changes in tumour volume following combined rucaparib 1 and temozolomide treatment, and that ex vivo H-MRS can be used in mechanistic studies of PARP inhibition. Both MRI/MRS and PET are potential pharmacodynamic and surrogate response imaging biomarkers for PARP inhibitors.

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Davies, Glyn Daniel. "Inhibitor studies on para-aminobenzoic acid synthase." Thesis, University of Cambridge, 2003. https://www.repository.cam.ac.uk/handle/1810/265461.

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Para-aminobenzoic acid (PABA) synthase is a three-subunit enzyme system that catalyses the conversion of chorismic acid top-aminobenzoic acid in plants and microorganisms. P ABA is then incorporated into folic acid an essential nutrient for mammals and utilised in the transfer of one-carbon units. For this reason it is a potential target for herbicidal and antibiotic development. A glutamine amidotransferase and ADC synthase form a heterodimeric complex and carry out the amino substitution reaction to yield 4-amino-4-deoxychorismate (ADC). A separate subunit, ADC lyase, then carries out the elimination of pyruvate to yield P ABA. My research describes a number of advances in the purification and assay system used and the organic synthesis of inhibitors of ADC synthase. The purification and characterisation was carried out of newly cloned 6-His tagged PABA synthase enzymes from E. coli. engineered to overexpress these proteins. The assay system used was refined and substrate kinetic data obtained. Results were compared to 'wild-type' enzyme and data obtained when the assay system has ammonium in place of glutamine and glutamine amidotransferase. The crystal structures of 'wild-type' ADC synthase and ADC Lyase enzymes are only recently available in the literature. Inhibition data for compounds synthesised was obtained initially via a fluorescence screen and then to greater accuracy via a continuous UV assay. My inhibitor studies revealed a close structural analogue of 4-amino-4- deoxychorismate, 4-amino-3-[1-carboxyethoxy] benzoate as the best inhibitor (ea. 20 ?M) of P ABA synthase so far. The synthesis of a number of aromatic compounds to act as m1m1cs of ADC was accomplished. An aromatic nitro group was reduced to give an amine using tin(II) chloride and hydrogenation reactions. Other forms of nitrogen protection using carbamates and bissilyl protection were also utilised. The formation of an enol pyruvyl group was accomplished in an original manner using lithium diisopropylamine to deprotonate a proton alpha to an ester. This was followed by selenation and elimination/oxidation to form the required methylene group as an a,,B-unsaturated ester. Alternative methods, involving a rhodium catalysed hydroxy insertion followed by either a Wadsworth-Horner-Emmons modified Wittig reaction with formaldehyde or alkylation with Eschermosers' Salt, were also carried out. Further synthesis of ADC and chorismate analogues was performed using the aza-Cope and oxy-Cope rearrangements of oxygen-alkylated hydroxybenzoates and N-alkylated aromatic amines. The organic synthesis of an inhibitor containing vinyl fluoride functionality has been the focus of previous studies. The biosynthesis of 6-fluorochorismate led to the discovery that this species was an irreversible inhibitor of the P ABA synthase system. Synthesis of a vinyl fluoride was achieved via a vinyl triflate and vinyl trialkylstannane utilising a lithium cuprate reagent. Fluorination was carried out using XeF2 in the presence of a catalytic amount of Ag(OTf). The mild conditions achieved form a foundation for the synthesis of more complex 6-fluorochorismate analogues. Further synthesis was carried out to try to synthesise a Michael acceptor for an enzyme active-site nucleophile based on a proposed mechanism for the irreversible inhibitor. Dianion alkylation chemistry using �sodium hydride followed by n-BuLi was used to control regioselectivity in the alkylation of a cyclic ,8-ketoester. In a one-pot synthesis, selenyl elimination/oxidation of the alkylated cyclic ,8-ketoester was used to form an extended delocalised system with the potential to act as a Michael acceptor.

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Verástegui, Pereira Karina Meliza. "Utilidad del Cociente Inhibitorio en la interpretación del antibiograma para Enterobacterias aisladas de Urocultivos en pacientes ambulatorios, Hospital Nacional Docente Madre Niño (HONADOMANI) “San Bartolomé” Febrero - Diciembre 2014 Lima-Perú." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2015. https://hdl.handle.net/20.500.12672/4391.

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Introducción: La interpretación del antibiograma por la CLSI tiende a brindarnos cierta información para elegir mejor el antimicrobiano capaz de inhibir o disminuir el crecimiento bacteriano, sin embargo existe una falta de concordancia de la prueba de susceptibilidad in vitro de un patógeno aislado del tracto urinario con la respuesta de la eficacia clínica o selección del antibacteriano. Objetivo: Determinar la utilidad del cociente inhibitorio en la interpretación del Antibiograma realizadas para enterobacterias aisladas de urocultivos positivos de pacientes ambulatorios. (...) Resultados: Fueron analizados 223 urocultivos positivos a enterobacterias en pacientes ambulatorios. El principal uropatógenos aislado fue Escherichia coli (86.5%). Se obtuvo una interpretación de respuesta terapéutica favorable por el cociente inhibitorio en todos los casos de cepas categorizadas como sensible a Fluoroquinolonas, Betalactámico y aminoglucósidos. La cepas que fueron categorizadas como intermedio, se obtuvo en todas ellas una interpretación de respuesta terapéutica favorable por cociente inhibitorio con una frecuencia para cada antibiótico probado de: Ampicilina (5), Ceftriaxone (3), Gentamicina (4); y Ciprofloxacino (5); a excepción de la Amikacina que presentó un caso de cepa intermedio con una interpretación de respuesta terapéutica no favorable por CI. Por otro lado, se mostró que la cepas como intermedios para cefalotina por la interpretación convencional se obtuvo una interpretación de una respuesta terapéutica favorable con el CI en el 100%(52) de los hallados con un IC95% (-6.9% a 6.9%). Para los casos de cepas categorizadas como “resistente”, se observó un porcentaje de ellas interpretadas con una respuesta terapéutica favorable por el CI de 29.5% (13/44) para ceftriaxone, de 27.5% (11/40) para Gentamicina, 12.4% (11/89) para ciprofloxacino, y 8.1% (6/74) para cefalotina. Se comparó la interpretación de sensibilidad para cepas de E.coli y cepas con presencia de BLEE, entre las dos interpretaciones. Para el primer caso, solo se observó para cefalotina con 58(30%) de cepas más sensible, interpretadas como respuesta terapéutica favorable significativo con un IC 95% (20.3% a 39.0%) dadas por el cociente inhibitorio. Para el segundo caso, de cepas E.coli productoras de BLEE mostró una diferencia significativa, a favor cepas interpretadas con respuesta terapéutica favorable por el CI para Ceftriaxone con 9(26.5%) con un IC95% (10.1% a 42.8%). Conclusiones: El uso del cociente inhibitorio en la interpretación del antibiograma nos podría dar mayores alternativas en la elección terapéutica siempre que dichos resultados sean valorados a través de un seguimiento del paciente por el médico, siendo así se disminuiría con ello los casos de resistencia, el uso de antibióticos de amplio espectro, que además pueden ser costosos, y poder modificar la dosis, etc.
--- Introduction: The interpretation by the CLSI antimicrobial susceptibility tends to provide certain information to better choose the antimicrobial capable of inhibiting or reducing bacterial growth, but there is a mismatch of in vitro susceptibility testing of isolated urinary tract pathogen the response of the clinical efficacy of antibacterial or selection. Objective: To determine the usefulness of the inhibitory quotient in the interpretation of Antibiogram made for enterobacteria isolated from urine cultures from outpatients. (...) Results: There were 223 positive enterobacteriaceae in outpatient urine cultures. The main uropathogens isolated was Escherichia coli (86.5%). An interpretation of favorable therapeutic response by the inhibitory quotient in all cases categorized as sensitive strains Fluoroquinolones, Betalactam and aminoglycoside was obtained. The strains were categorized as intermediate, an interpretation favorable therapeutic response was obtained for all inhibitory quotient with a frequency for each antibiotic tested: Ampicillin (5), Ceftriaxone (3), gentamicin (4); and Ciprofloxacin (5); Amikacin except that presented a case intermediate strain with an interpretation of therapeutic response CI unfavorable. Furthermore, it was shown that the strains as intermediates for the conventional interpretation cephalothin an interpretation of a positive therapeutic response with CI in 100% (52) of those found with a 95% CI (-6.9% to 6.9% was obtained). For cases of strains categorized as resistan, a percentage of them performed with a favorable therapeutic response by the CI 29.5% (13/44) for ceftriaxone, 27.5% (11/40) for gentamicin, 12.4% was observed (11/89) to ciprofloxacin and 8.1% (6/74) to cephalothin. The interpretation of sensitivity for E. coli strains and strains with BLEE presence between the two interpretations were compared. In the first case, only it observed for cephalothin 58 (30%) of more sensitive strains interpreted as significant favorable therapeutic response with 95% (20.3% to 39.0%) given by the inhibitory quotient. For the second case of E.coli BLEE producing strains it showed a significant difference in favor strains with favorable therapeutic response interpreted by the CI to Ceftriaxone 9 (26.5%) with a 95% (10.1% to 42.8%). Conclusions: The use of inhibitory quotient in the interpretation of susceptibility could give us more alternatives in the therapeutic choice provided that such results are assessed through monitoring of the patient by the physician, and still be diminished thereby cases of resistance, use of broad-spectrum antibiotics, which can also be expensive, and modify the dose, etc. Keywords: inhibitory ratio, maximum concentration of antimicrobial susceptibility, minimum inhibitory concentration, pharmacodynamics, pharmacokinetics.
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Ordway, Gregory A., Attila Szebeni, Liza J. Hernandez, Jessica D. Crawford, Katalin Szebeni, Michelle J. Chandley, Katherine C. Burgess, Corwin Miller, Erol Bakkalbasi, and Russell W. Brown. "Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2768.

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Many patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors.

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Fraser, Rebecca Dawn. "Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction : Part II structure-activity relationship for a series of glycosidase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/30508.

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Yamamoto, Masaru. "Synthesis and oxidation studies of sulfur containing inhibitors for human leukocyte elastase : (2) synthesis of cyclic peptide analogs for tissue factor pathway inhibitor (TFPI) : Part 2 synthesis and evaluation of aziridinecarboxylic acid analogs as a new family of cysteine proteinase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/25953.

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Löser, Dana A. "Investigating the mechanisms by which PARP inhibitors increase sensitivity to DNA damaging agents." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505912.

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Damage induced by ionising radiation (IR) is mainly repaired by classical non homologous end joining (D-NHEJ), but a small subset of DSBs is repaired with slow kinetics in an ATM (Ataxia telangiectasia mutated) and Artemis dependent manner. In addition, a PARP-1 dependent NHEJ backup pathway (B-NHEJ) was described, which is thought to function in the absence of D-NHEJ. Using ATM, Artemis or DNA ligase IV deficient mouse embryonic fibroblasts (MEFs) as a model system, the effect of the potent and specific PARP-1/-2 inhibitor KU-0059436 upon clonogenic survival after various types of damage that induce different spectra of SSBs and DSBs was measured. In Artemis or ATM deficient MEFs no sensitising effect of KU-0059436 was detected after neocarzinostatin (NCS) treatment; however PARP inhibition increased sensitivity to IR and methylmethane sulphonate (MMS) markedly. In these cell lines no specific single strand break repair (SSBR) defect was observed, and radio-sensitisation by KU-0059436 was replication dependent. Furthermore PARP inhibition led to increased formation of DSBs, an effect which was augmented in Artemis deficient cells. PARP inhibition in DNA ligase IV deficient cells led to increased sensitivity after damage induction to all agents. However, radiosensitisation by KU-0059436 was replication independent. Results show that PARP inhibition increases the dependence on Artemis and ATM after SSB induction, which is consistent with a model whereby DSBs that arise from SSBs during DNA replication in the presence of a PARP inhibitor require ATM and Artemis for their repair. In cells deficient for DNA ligase IV, PARP inhibition causes additional replication independent sensitisation both by abrogating B-NHEJ and promoting accumulation of replication independent DSBs.

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Jewett, Benjamin E., Merry N. Miller, Libby A. Ligon, Zachary Carter, Ibrahim Mohammad, and Gregory A. Ordway. "Rapid and Temporary Improvement of Depression and Anxiety Observed Following Niraparib Administration: A Case Report." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etsu-works/8592.

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Background: Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. Case presentation: A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. Conclusions: This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.

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Mauricio, Anna Theresa. "Heterocyclic alpha-aminoalkylphosphonate diphenyl esters as inhibitors of serine proteases : Part II: Basic alpha-aminoalkylphosphonate diphenyl esters as inhibitors of cathepsin G." Diss., Georgia Institute of Technology, 1996. http://hdl.handle.net/1853/27157.

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Liu, Tao. "Part 1 Synthesis of a potent histone deacetylase inhibitor; Part 2 Studies towards a stabilized helix-turn-helix peptide." Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/26019.

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The first part of this work describes the synthesis of a new histone deacetylase (HDAC) inhibitor (HDI). HDAC enzymes modify core histones, influence nucleosome structure and change gene transcription by removing the acetyl groups from lysine residues on proteins. HDIs are showing exciting potential as a new class of drugs for cancer and a variety of other diseases. A new HDAC inhibitor based on the hydroxamic acid motif has been synthesized. Two characteristic structural features were incorporated into the design of the novel inhibitor. A cyclic peptide mimetic of known structure was fused to a hydroxamic acid moiety through an aliphatic chain. The HDAC inhibitor provided significant inhibitory activity against HDACs with an IC50 value of 46 Â± 15 nM, and against HDAC8 with an IC50 value of 208 Â± 20 nM. The potent HDAC inhibitory activity of the HDAC inhibitor demonstrates the importance of the rim recognition region in the design of HDIs. The hydrophobic cyclic turn mimic allows the formation of a tight complex between HDI and HDAC enzymes. The second part of this work is to synthesize secondary structure mimics and incorporate them into the helix-turn-helix (HTH) motif. One of the important methods to study the conformation of the biologically active peptides is to incorporate the rigid peptidomimetics into the relevant peptides. Important information can be obtained from the study of conformationally constrained peptides. HTH proteins are well characterized and found in many organisms from prokaryotes to eukaryotes. The relatively small size, simple structure, and significance in stabilizing tertiary structures make the HTH peptide an attractive target to mimic. Both a Gly HTH turn mimic and a Ser HTH turn mimic were synthesized using stereoselective hydrogenation and macrocyclization starting from unnatural amino acids in a yield of 33% and 14%, respectively. The synthesis of Fmoc protected HTH turn mimics allowed incorporation into HTH peptides using Fmoc chemistry on solid phase. The incorporation of the HTH turn mimics into the peptides proved to be challenging, either by sequential elongation or by segment condensation. Alternative peptide synthesis strategies were employed in attempts to solve the problems.
Ph. D.

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Ordway, Gregory A., W. D. Gill, J. B. Coleman, Hui Wang-Heaton, and Russell W. Brown. "Anti-Inflammatory PARP Inhibitor Demonstrates Antidepressant Activity in Animal Model of Treatment Resistant Depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/8643.

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Background: Major depressive disorder is associated with elevated levels of DNA oxidation, DNA damage, and gene expression of DNA repair enzymes including poly (ADP-ribose) polymerase-1 (PARP1). Elevated PARP1 activity is directly linked to neuroinflammation and PARP inhibitors are anti-inflammatory and neuroprotective. We previously showed that PARP inhibitors produce antidepressant-like effects equivalent to fluoxetine in rodent models. Here, we examined whether the PARP inhibitor 3-aminobenzamide (3AB) is effective in a rat model of treatment-resistant depression. Methods: Treatment-resistant depression was modeled with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily chronic unpredictable stress (CUS) for 28 days. Anhedonia and helplessness were indexed with sucrose preference and forced swim tests, respectively, in 5 groups of rats (n¼6-8 rats/group) including unstressed, CUS, and CUS+LPS rats treated with saline, and CUS+LPS rats treated with either 3AB or fluoxetine. Results: Anhedonia induced by CUS+LPS was significantly attenuated by 3AB (p¼0.01), while fluoxetine failed to do so. Likewise, 3AB was superior to fluoxetine in reducing helplessness, where latency to immobility times were significantly lower in CUS+LPS rats treated with fluoxetine (p¼0.001) compared to unstressed rats, but not significantly different for 3AB-treated CUS+LPS rats. Conclusions: The PARP inhibitor 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the TRD rat model. PARP is linked to neuroinflammation through release of microglia-activating factors including poly (ADP-ribose) and HMGB1, and through NF-kB activation, pathways under investigation by our lab. PARP inhibitors are currently used clinically to facilitate cytotoxicity of DNA-damaging anti-cancer treatments. Further research could implicate re-purposing non-cytotoxic PARP inhibitors for treatment-resistant depression.

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Raithel, Kerstin. "Effekt von S-Lost in HaCaT-Zellkulturen : Induktion der Apoptose und Effekt eines PARP-Inhibitors /." München, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254372.

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Alkhateeb, Hebah, Gregory A. Ordway, W. Drew Gill, Joshua B. Coleman, Hui Wang-Heaton, Russell W. Brown, Michelle Chandley, et al. "PARP1 inhibition produces unique antidepressant effects in an animal model of treatment-resistant depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/49.

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Major depressive disorder (MDD) is a prevalent and enervating mental illness affecting millions globally. Unfortunately, a significant proportion of patients do not receive clinical benefit from existing antidepressant medications. The limited effectiveness of currently available antidepressant drugs emphasizes the need to identify more effective medications for individuals who are treatment-resistant. We have previously reported abnormally elevated poly (ADP-ribose) polymerase-1 (PARP1) gene expression levels in the postmortem brain from MDD brain donors. PARP1 is a DNA damage repair enzyme that is also linked to neuroinflammation through multiple biochemical pathways. PARP1 upregulation in MDD could indicate a role for this enzyme in the etiopathology of MDD, particularly as it relates to neuroinflammation. In fact, we have shown that drugs that inhibit PARP1 produce antidepressant-like properties in two different rodent behavioral models that mimic depressed mood in humans. In the present study, we utilized a unique rodent behavioral model that produces depressive-like behavior by combining psychological stress with stimulation of inflammation. Depressive behavior produced by this experimental paradigm is not reversed by the prototypical antidepressant fluoxetine. This treatment-resistant depression was elicited by treating rats with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily exposure to chronic unpredictable stress (CUS) for 28 days. Depressive behaviors were measured with sucrose preference and forced swim tests in 5 treatment groups (n=6-8 rats per group) including unstressed rats, CUS rats, CUS+LPS rats, and CUS+LPS rats treated with either the PARP1 inhibitor 3-aminobenzamide (3AB) or the antidepressant fluoxetine. We evaluated the role of neuroinflammation in this model by measuring the amount of microglial activation in several brain regions in rats from all treatment groups. Microglia activation was measured by quantifying the relative amount of expression of the microglia marker protein, IBA1, using an anti-IBA1 antibody. 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the treatment-resistant rat model. IBA1-immunoreactivity levels were elevated in brains from CUS and CUS+LPS rats, although there was no evidence that LPS increased IBA1-immunoreactivity above levels found in CUS rats that did not receive LPS. Levels of IBA1-immunoreactivity in the brains from rats treated with either fluoxetine or 3AB trended lower as compared to the CUS and CUS+LPS groups, although this effect did not reach statistical significance. The lack of significant differences is likely related to small sample sizes; experiments are underway to increase the sample sizes of each group. The findings provide further support for the potential of PARP1 inhibitors in treating MDD and suggest that these drugs may be more effective, or more broadly effective than standard antidepressants.

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Maier, Christian. "Auswirkungen des PARP-1 Inhibitors INO-1001 auf Ischämie-Reperfusionsbedingte Organschädigungen nach thorakalem Aortencrossclamping am Schwein." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-64137.

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Grüger, Thomas. "Die Rolle von Topoisomerase IV als Zielstruktur für Inhibitoren in E. coli sowie die Transkriptionskontrolle ihrer Strukturgene parC und parE." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973153601.

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Coleman, Joshua B., Wesley Drew Gill, Allee C. Maxwell, and Russell W. Brown. "Analysis of a Poly(ADP-ribose) Polymerase (PARP) Inhibitor in a Treatment-resistant Depression Model in the Rat." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/53.

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Over 16 million people in the US suffer from major depressive disorder (MDD) each year. Approximately 1/3rd of MDD patients (~5 million) obtain only partial remission or no benefit after trials with multiple drugs or drug combinations. Recently, Ordway and colleagues have reportedelevated levels of DNA oxidation and upregulated gene expression of the base excision repair enzyme poly(ADP-ribose) polymerase-1 (PARP1) in postmortem brain from donors who had MDD at the time of death, as compared to age-matched psychiatrically normal control donors. This study was designed to test whether an inhibitor of PARP, 3-aminobenzamide (3-AB), may be effective to alleviate depressive-like behaviors in a rodent model of treatment-resistant depression. Male rats were ip administered lipopolysaccharide (LPS;100ug/kg) daily for 28 days, and administered a chronic unpredictable stressor on each day. All rats were also administered saline, 3-AB (40 mg/kg), or the serotonin-reuptake inhibitor (SSRI) fluoxetine (trade name: Prozac; 10 mg/kg) on each day, approximately 30 min after LPS treatment. During the 28 day period of LPS treatment, animals were behaviorally tested 5 times on sucrose preference (a test of anhedonia). At the end of the 28 day period, rats were behaviorally tested on a test of acute stress, the Porsolt swim test. Results revealed that 3-AB alleviated anhedonia and the response to acute stress in the Porsolt swim test superior to the fluoxetine group, demonstrating the utility of a PARP inhibitor to alleviate depressive-like behavior in this model. In addition, fluoxetine produced a loss of weight which recovered over days, but not to control levels, and 3-AB did not produce this effect. This study shows that PARP inhibitors may be effective in treatment-resistant depression.

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Muyaid, Lara. "Synthesis of an intermediate as part of synthetic route of a SGLT1 inhibitor." Thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-449945.

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23

Hryshko, Patrick, Zac Johnson, and Nicki Scovis. "Appropriateness of Repeated Clinical Alerts to Add Angiotensin Converting Enzyme Inhibitor Therapy in Diabetic Patients with Medicare Part D Coverage." The University of Arizona, 2014. http://hdl.handle.net/10150/614189.

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Class of 2014 Abstract
Specific Aims: To identify reasons that an angiotensin converting enzyme inhibitor (ACEi) would not be indicated in diabetic patients with repeated clinical alerts to add ACEi therapy for preservation of renal function and/or hypertension. In addition, to identify if these repeated clinical alerts to add ACEi therapy are appropriate. Methods: Eligible patient charts were reviewed by researchers using a data dictionary to complete a standardized spreadsheet with patient demographic information (age, gender, and location), type of diabetes mellitus, evidence indicative of comorbid hypertension, action taken by pharmacist in response to clinical alert (letter sent to patient and letter sent to prescriber), and rationale of that action. This data, along with SOAP notes of patient interactions, was used by researchers to classify the repeated clinical alert as appropriate or inappropriate. Main Results: There were a total of 200 charts reviewed (male n = 61 (30.5%), female n = 139 (69.5%), mean age = 70 ± 11 years). Reasons for not contacting patients again include previous failure or adverse drug reaction (n = 62, 31.0%), patient did not meet call script requirements (n = 55, 27.5%), patient did not have diabetes or hypertension (n = 20, 10.0%), potential drug-disease interaction (n = 17, 8.5%), overlapping or previously addressed alerts (1.9%), or documentation was provided for “other” reasons (n = 43, 21.5%). The previous failure or adverse drug reaction rationale was appropriate in 32 of 62 repeated clinical alerts (52%; χ2= 10.15). The patient did not have diabetes or hypertension rationale was appropriate in 11 of 20 repeated clinical alerts (55%, χ2= 2.72). The potential drug-disease interaction rationale was appropriate in 3 of 17 repeated clinical alerts (8%, χ2= 9.89). The patient did not meet call script requirements rationale was appropriate in 31 of 55 repeated clinical alerts (56%, χ2= 6.91). The overlapping or previous alerts rationale was appropriate in 2 of 3 repeated clinical alerts (67%, χ2= 0.18). The “other” rationale were appropriate in 22 of 43 repeated clinical alerts (51%, χ2= 7.21) Overall, retrigger alerts were considered appropriate 50.5% of the time compared to the predicted value of 90% (χ2= 347 > critical value = 3.84 for p = 0.05 Conclusion: There are multiple reasons pharmacists do not recommend initiating ACEi therapy in patients with diabetes. Although the Medication Management Center (MMC) has rationale of these reasons documented after individual patient interactions, there are still several reasons why a retrigger alert would be appropriate despite that rationale. In addition, retrigger alerts were not considered appropriate as frequently as expected.

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Drew, Yvette Claire. "The potential of the PARP-1 inhibitor, AGO14699, in human cancers defective in homologous recombination DNA repair." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1551.

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The aims of this study were to undertake the first comprehensive in vitro, in vivo and clinical investigation into the effects of the PARP-1 inhibitor, AG014699, in human cancers defective in homologous recombination (HR) DNA double strand break (DSB) repair. HR deficient cells were 9-fold more sensitive to AG014699 than HR proficient cells (mean LC50 = 3.26 μM vs. 29.68; P < 0.0001), confirming the theory of synthetic lethality. BRCA1 methylated UACC3199 breast cancer cells were also sensitive to AG014699 with mean LC50 significantly lower than the HR proficient cells (7.6 μM vs. 29.68; P = 0.002). AG014699 inhibited PARP activity by > 95% and induced DNA DSBs in all 11 cell lines studied. Evidence of HR (by Rad51 foci) was observed only in cells with functional BRCA1/2. A prolonged schedule of AG014699 (10 mg/kg daily for five days of a seven-day cycle for six cycles) more effectively delayed the growth of BRCA2 mutated xenografts than a ten day AG014699 schedule (tumour growth delay (TGD) = 27.5 vs. 12.5 days; P = 0.02). AG014699 significantly delayed UACC3199 tumour growth compared to untreated controls (mean time to relative tumour volume 5 = 35.8 vs. 25.2 days; P = 0.05); confirming in vitro findings that BRCA1 methylated cancer cells are sensitive to PARP inhibition. Clinical trial data from 38 patients demonstrated that AG014699 is non-toxic and efficacious with a clinical benefit rate of 34%. Higher baseline PARP-1 activity was associated with response to AG014699. The major findings of these studies are: the confirmation of the selective cytotoxicity of PARP inhibitors in BRCA mutated cancers; the results in UACC3199 cells which suggest that cancers with other HR defects could benefit from single agent PARP inhibitors, and finally the concept that length of exposure to (not just degree of) PARP inhibition is important for single agent anti-tumour activity. Furthermore, these data have formed the basis for a major amendment to the clinical trial; the result of which is eagerly awaited.

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Lu, Hang. "The synthesis and structure-activity relationship study of azo dye related HIV replication inhibitors : Part 2: Plant isolation of signalling pathways inhibitors as anti-cancer agents." Diss., Georgia Institute of Technology, 1994. http://hdl.handle.net/1853/27436.

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Kohl, Vanessa [Verfasser], and Alice [Akademischer Betreuer] Fabarius. "Synthetische Letalität von PARP- und APE1-Inhibitoren bei hämatologischen Neoplasien / Vanessa Kohl ; Betreuer: Alice Fabarius." Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1237750598/34.

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Efraim, Priscilla 1978. "Estudo para minimizar as perdas de flavonoides durante a fermentação de sementes de cacau para produção de chocolate." [s.n.], 2004. http://repositorio.unicamp.br/jspui/handle/REPOSIP/255238.

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Orientadores: Nelson Horacio Pezoa Garcia, Denise Calil Pereira Jardim
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos
Made available in DSpace on 2018-08-03T19:14:01Z (GMT). No. of bitstreams: 1 Efraim_Priscilla_M.pdf: 836235 bytes, checksum: 197b6ebcb7737d4d06c3ba707d63337d (MD5) Previous issue date: 2004
Resumo: As sementes de cacau (Theobroma cacao L.) da variedade Forastero são extremamente ricas em compostos fenólicos, que representam em média 15 a 20% de seu peso seco e desengordurado, sendo que 60% pertencem à classe dos flavonóides, compostos apontados atualmente como responsáveis pela prevenção de doenças coronárias, diminuição do colesterol sérico, auxiliadores do sistema imunológico, entre outros. Durante a etapa de fermentação, são perdidos, em média, 70% dos flavonóides devido a importantes reações bioquímicas que ocorrem principalmente pela diminuição do pH, aumento de temperatura (45-50°C) e atuação de certas enzimas presentes no fruto ou produzidas pelos microrganismos que participam desta etapa. Tais reações são, em parte, responsáveis pela redução do amargor e da adstringência melhorando assim o desenvolvimento do sabor do chocolate. Desta forma, o presente trabalho visou modificar a etapa de fermentação de sementes de cacau para a produção de chocolate rico em flavonóides sem prejudicar seu sabor. Para isso, procurou-se inibir as enzimas que são possivelmente as principais responsáveis pela perda dos flavonóides através da adição de inibidores químicos (bissulfito de sódio e sulfato cúprico) na etapa de fermentação. Foram realizados sete experimentos distintos: ensaios A e G (fermentações convencionais com duração de 7 e 3 dias respectivamente); ensaios B, C e F (fermentações por 7 dias, modificadas com adição de 5mg, 10mg e 5mg de bissulfito de sódio/100g de massa de sementes com polpa após 48hs, 48hs e 120hs respectivamente e ensaios D e E (fermentações por 7 dias modificadas com adição de 5mg e 10mg de sulfato de cobre/100g de massa de sementes com polpa após 48 horas do início respectivamente). Os resultados indicaram que, de uma forma geral, todos os tratamentos propostos mantiveram maior teor de compostos fenólicos em relação à fermentação convencional (ensaio A). Quanto aos compostos fenólicos totais, o ensaio D apresentou a maior retenção (62,70%) desde o início da fermentação ao término da secagem, enquanto que no ensaio A foram retidos 36,38% destes compostos. Em relação aos flavan-3-óis e procianidinas, observou-se maior retenção, para monômeros, nos ensaios D (34,27%) e G (33,72%); para dímeros, nos ensaios D (21,83%) e G (21,78%); para trímeros, nos ensaios C (22,85%), D (22,37%) e F (22,38); para quatrâmeros, nos ensaios C (25,84%), D (24,77%) e F (27,21) e para pentâmeros, nos ensaios C (35,24%), D (34,45%) e F (34,16). Observou-se que a maior perda dos compostos fenólicos estudados ocorreu entre o término da fermentação e a secagem. Verificou-se que o residual de Cobre remanescente da adição feita durante a fermentação (ensaios D e E) nos liquors e nos chocolates produzidos foi de 0,23 e 0,36mg de cobre/100g de liquor (ensaios D e E respectivamente) e 0,025 e 0,036mg de cobre/100g de chocolate (ensaios D e E respectivamente), todos valores consideravelmente inferiores ao Limite Máximo Tolerado (LMT) definido pela Agência Nacional de Vigilância Sanitária (ANVISA), correspondente a 3,0mg de cobre/100g de amostra. Os chocolates produzidos a partir dos ensaios B, C, D e E mostraram aceitabilidade sensorial igual ou melhor ao convencional (A), enquanto que os produzidos a partir dos ensaios F e G apresentaram aceitabilidade mediana e incertezas com relação a intenção de compra
Abstract: Cocoa seeds (Theobroma cacao L.) from the Forastero variety are very rich in phenolic compounds which represent 15-20% of the defatted dry weight. The principal compounds are (+)-catechin, (-)-epicatechin and 60% of procyanidins that belong to the flavonoid class. These compounds are currently been considered responsible for coronary heart disease prevention, lowering the serum cholesterol and helping the immunological system. During the fermentation, 70% of the total phenolic compounds are lost in important biochemical reactions accelerated by the reduction in pH, temperature increase (45-50°C) and action of some enzymes, present in the fruit or produced by the microorganism growing at this stage. These reactions contribute to a reduction in bitterness and astringency, improving the flavor of the chocolate. The objective of this work was to modify the fermentation stage of cocoa seeds to produce flavonoid-rich chocolates without prejudicing its flavor. This was done by the inactivation of enzymes probably responsible for flavonoid degradation, through the addition of chemical inhibitors (sodium bissulfite and cupric sulphate) during the fermentation stage. Seven experiments were carried out: Experiments A and G (conventional fermentations during 7 and 3 days respectively); experiments B, C and F (modified fermentations during 7 days, with the addition of 5mg, 10mg and 5mg of sodium bissulfite/100g of cocoa seeds with pulp after 48hs, 48hs and 120hs since the beginning of fermentation respectively) and experiments D and E (modified fermentations during 7 days, with the addiction of 5mg and 10mg of cupric sulphate/100g of cocoa seeds with the pulp after 48hs and 120hs since the beginning of fermentation respectively). The results showed that all the treatments proposed maintained higher quantities of phenolic compounds as compared with the conventional experiment (A). Considering the total phenolics, experiment D showed the highest retention (62,70%) from the beginning of the fermentation up to the end of the drying stage, while in the experiment A, the retention was 36,38%. Considering the flavan-3-ols and procyanidins, a higher retention of monomers was observed in experiments D (34,27%) and G (33,72%); of dimers in experments D (21,83%) and G (21,78%); of trimers in experiments C (22,85%), D (22,37%) and F (22,38); of tetramers in experiments C (25,84%), D (24,77%) and F (27,21) and of pentamers in experiments C (35,24%), D (34,45%) and F (34,16). It was observed that the greatest loss of the phenolic compounds studied occurred between the end of fermentation and the beginning of the drying stage. It was shown that the copper residue in the liquor and chocolate remaining from the addition during fermentation (experiments D and E) was 0,23 and 0,36mg of copper/100g of liquor (experiments D and E respectively) and 0,025 e 0,036mg of copper /100g of chocolate (experiments D and E respectively). These values are below the Maximum Tolerated Limit (MTL) defined by ANVISA for this metal (3,0mg/100g). The chocolates B, C, D and E showed equal or better sensory acceptance as compared with conventional (A), and F and G chocolates which showed average sensory acceptance and uncertainty with respect to buying intention
Mestrado
Mestre em Tecnologia de Alimentos

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Guillot, Clément. "Potentiel des inhibiteurs de poly(ADP-ribose) polymérases seuls ou en combinaison avec la radiothérapie comme nouvelle option thérapeutique pour le carcinome hépatocellulaire." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10281.

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Le carcinome hépatocellulaire est l'un des cancers les plus fréquents et des plus sévères à travers le monde. Le diagnostic est souvent tardif et les traitements curatifs ne peuvent être proposés qu'à un nombre limité de patients. Les technologies modernes ont permis le développement de nouvelles méthodes de radiothérapie qui montrent aujourd'hui de bons résultats. Par ailleurs, bien que des déficiences dans les voies de réparation de l'ADN soient associées à une instabilité génomique et une susceptibilité au cancer, une inhibition de ces voies sensibilise les cellules cancéreuses à la chimiothérapie et à la radiothérapie. Dans ce contexte, les inhibiteurs de poly(ADP-ribose) polymérases (PARP) ont déjà montré des résultats prometteurs dans des études pré-cliniques et sont en cours d'évaluation clinique pour de nombreux cancers. Ce travail de thèse a consisté en l'évaluation du potentiel des inhibiteurs de PARP en combinaison avec la radiothérapie comme nouvelle option thérapeutique pour le carcinome hépatocellulaire. La première étape de ce travail a été de caractériser les profils d'expression et d'activité de plusieurs membres de la famille PARP dans des cellules cancéreuses du foie et des hépatocytes primaires humains ainsi que dans des tissus hépatiques. En second lieu, nous avons étudié le potentiel de l'inhibiteur de PARP ABT-888 seul et en combinaison à des radiations ionisantes in vitro. Le traitement par l'inhibiteur de PARP ABT-888 en agent seul a montré une sensibilité variable des différentes lignées cellulaires étudiées à cette drogue. Afin de comprendre la sensibilité variable des cellules cancéreuses hépatiques à l'ABT-888, nous avons analysé leur capacité de réparation des dommages à l'ADN et avons observé des capacités différentes entre les lignées cellulaires. Finalement, nous avons pu montrer que l'ABT-888 sensibilise les cellules cancéreuses hépatiques aux radiations ionisantes. Ce travail de recherche a permis de montrer que les inhibiteurs de PARP ont un fort potentiel pour améliorer les méthodes de radiothérapie utilisées dans la prise en charge du carcinome hépatocellulaire
Hepatocellular carcinoma is the third cause of cancer related death. Due its often late diagnosis and advanced stage, a limited number of patients can benefit from curative treatments. There is thus a constant need for new treatment strategies for patients with hepatocellular carcinoma. Targeting DNA repair pathways to sensitize tumor cells to chemoor radiotherapeutic treatments is now a common strategy under investigation for cancer treatment with inhibitors of poly(ADP-ribose) polymerases (PARP) showing great potential. The aim of this work was to evaluate the potential of PARP inhibitors alone and in combination with radiation therapy as a new strategy for the treatment of hepatocellular carcinoma. We first analyzed the expression and activity of different PARP genes in a panel of liver cancer cell lines and primary human hepatocytes as well as their DNA repair capacity and assess the impact of PARP inhibitors alone and in combination with ionizing radiation in these models on cell survival. A large range in expression of PARP family members, PARP activity and sensitivity to ABT-888 in the panel of liver cells was observed as well as differential excision/synthesis repair capacity. Finally, we showed that ABT-888 sensitizes liver cancer cells to the cell killing effects of ionizing radiation. PARP inhibitors show great potential for improving radiation therapy strategies used in the management of hepatocellular carcinoma

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Cherry, K. E. "The poly (ADP-ribose) polymerase (PARP) inhibitors AG14361 and AG014699 : mechanisms of action and implications for clinical application." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546027.

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30

Chabanon, Roman. "Exploiting DNA Repair Vulnerabilities to Modulate Anti-Cancer Immunity : a Study of the Immunological Potential of PARP inhibitors." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS007.

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Les inhibiteurs de poly(ADP-ribose) polymérase (PARPi) ciblent sélectivement les cellules porteuses de défauts des voies de réparation de l’ADN tels que les mutations de BRCA1/2 et les défauts d’ERCC1. Sur le plan clinique, plusieurs PARPi ont été approuvés pour le traitement des cancers BRCA-mutés ou platine-sensibles du sein et de l’ovaire, et des essais cliniques sont en cours pour évaluer l’efficacité des PARPi dans le cancer bronchique non-à-petites cellules (CBNPC) platine-sensible. Alors que les PARPi ont un fort potentiel thérapeutique dans les cancers comportant des défauts de réparation de l’ADN, de plus en plus d’essais cliniques évaluent également l’efficacité de ces médicaments en combinaison avec les « inhibiteurs d’immune checkpoints » (ICI) dans diverses populations de patients. Dans ce contexte, il est essentiel de mieux comprendre comment les PARPi modulent la réponse immunitaire anti-tumorale, et d’étudier le potentiel immunologique inhérent de ces médicaments.Dans cette étude, nous avons établi que les cellules de CBNPC déficientes en ERCC1 expriment fortement la signature interféron (IFN) de type I, et que les tumeurs de CBNPC ayant une faible expression d’ERCC1 ont un infiltrat lymphocytaire renforcé. En utilisant des lignées cellulaires isogéniques et des xénogreffes dérivées de patients, nous avons montré que plusieurs PARPi, notamment l’olaparib et le rucaparib, ont des propriétés immunomodulatrices dans les modèles de CBNPC ERCC1-déficients et de cancers du sein triple-négatifs (CSTN) BRCA1-mutés. D’un point de vue mécanistique, les PARPi génèrent des fragments d’ADN cytoplasmiques ayant les caractéristiques de micronoyaux ; ceux-ci activent la voie cGAS/STING et déclenchent une réponse IFN de type I, associée à la sécrétion de la cytokine CCL5. De manière importante, ces effets sont largement diminués dans les cellules de CSTN BRCA1-révertantes et les cellules de CBNPC ré-exprimant ERCC1, ce qui suggère que les défauts de réparation de l’ADN amplifient les phénotypes immunitaires associés au traitement par PARPi. En outre, ces effets sont totalement abrogés dans les cellules de CSTN PARP1-neutralisées, ce qui confirme que les phénotypes observés dépendent d’un effet spécifique des PARPi sur leur cible.Au-delà de leur potentiel d’activation d’une immunité spécifique des cellules cancéreuses via cGAS/STING et la signalisation IFN de type I, nous avons également constaté que les PARPi potentialisent les effets inducteurs de l‘IFN de type II sur l’expression de PD-L1 dans des lignées cellulaires et cellules tumorales fraîches de patients CBNPC, surtout en présence de défauts d’ERCC1. De plus, nous avons montré que certains PARPi, utilisés à des concentrations létales, activent de manière indépendante les éléments moléculaires clés de la mort cellulaire immunogénique, dont l’exposition de la calréticuline à la surface des cellules cancéreuses, la sécrétion d’ATP et le relargage d’HMGB1 en grandes quantités dans le milieu extracellulaire.Dans l’ensemble, ces données précliniques suggèrent que les PARPi ont des propriétés immunomodulatrices intrinsèques qui participent à l’activation de réponses immunitaires anti-tumorales ; ce potentiel pourrait être exploité cliniquement en combinaison avec les ICI dans des populations adéquatement sélectionnées au plan moléculaire
Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as BRCA1/2 mutations or ERCC1 defects. Clinically, several PARPi are currently approved for the treatment of BRCA-mutant or platinum-sensitive advanced ovarian and breast cancers, and ongoing clinical trials are investigating the efficacy of PARPi in platinum-sensitive Non-Small Cell Lung Cancer (NSCLC). While PARPi constitute potent targeted therapies for the treatment of DNA repair-deficient malignancies, an increasing number of clinical trials are also evaluating their efficacy in combination with immune checkpoint inhibitor (ICI) in various populations. In this context, it is of critical importance to better understand how PARPi might modulate immune responses against cancer, and to investigate the inherent immunological potential of these agents.In this study, we show that ERCC1-defective NSCLC cells exhibit an enhanced type I interferon (IFN) transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration in human NSCLC tumours. Using isogenic cell lines and patient-derived xenografts, we further demonstrate that several clinical PARPi, including olaparib and rucaparib, display cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-mutant triple-negative breast cancer (TNBC) models. Mechanistically, PARPi generate cytoplasmic chromatin fragments with micronuclei characteristics; this activates the cGAS/STING pathway and elicits downstream type I IFN signalling and CCL5 secretion. Importantly, these effects are suppressed in BRCA1-reverted TNBC cells and ERCC1-rescued NSCLC cells, suggesting that DNA repair defects exacerbate the innate immunity-related phenotypes triggered by PARPi. Similarly, these effects are totally abrogated in PARP1-null TNBC cells, supporting the on-target effect of PARPi in mediating such phenotypes. Besides this potential to activate tumour cell-autonomous immunity through cGAS/STING and type I IFN signalling, we also observed that PARPi synergize with type II IFN to induce PD-L1 expression in NSCLC cell lines and fresh patient tumour cells, especially in the ERCC1-deficient setting. Moreover, we show that lethal concentrations of some PARPi independently activate the key damage-associated molecular patterns dictating the immunogenicity of cancer cell death, including calreticulin exposure at the tumour cell surface, ATP secretion and HMGB1 release in the extracellular compartment.Together, these preclinical data suggest that PARPi have intrinsic immunomodulatory properties that activate anti-cancer immune responses; this could be exploited clinically in combination with ICI in appropriately molecularly-selected populations

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Mennucci, Marina Martins. ""Influência de inibidores no comportamento de corrosão de aço CA-50 para armadura de estruturas de concreto"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/85/85134/tde-29052007-161636/.

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Neste trabalho, vários tipos de compostos foram testados com o objetivo de avaliar sua potencialidade para uso como inibidores de corrosão de armadura de aço carbono em concreto armado. Os aditivos testados foram benzoato de sódio, benzotriazol, carbonato de ítrio, polietilenoglicol, e hexametilenotetramina. Inicialmente foram realizados ensaios exploratórios para seleção dos candidatos potenciais entre os compostos testados com base na eficiência de inibição determinada por ensaios eletroquímicos, especificamente ensaios de polarização e espectroscopia de impedância eletroquímica. Os ensaios eletroquímicos foram realizados em uma solução sintética composta por 0,01N de hidróxido de sódio (NaOH) mais 0,05N de hidróxido de potássio (KOH), para simular a composição da solução dentro dos poros no concreto. O aditivo que apresentou melhor potencialidade para uso como inibidor de corrosão foi o benzotriazol (BTA). Após eliminação dos compostos que apresentaram potencial de plicação, e seleção do candidato com maior eficiência de inibição no meio de estudo, o efeito da sua concentração na resistência à corrosão foi avaliado. Soluções de nitrito de sódio foram também usadas nas mesmas oncentrações que as adotadas para as de BTA para efeito de comparação. O nitrito de sódio é um inibidor de corrosão já estabelecido para reforços de aço carbono em concreto, mas este tem sido associado com efeitos tóxicos. O benzotriazol (BTA) foi associado com eficiências de inibição sempre superiores às do nitrito de sódio nas mesmas concentrações. Um filme escuro e aderente foi formado na superfície do aço durante períodos longos de imersão no meio alcalino contendo BTA. Os resultados apontaram para o alto potencial de aplicação do BTA como aditivo inibidor da corrosão do aço em estruturas de concreto armado, podendo vir a substituir o nitrito nestas aplicações.
In this work, various compounds were tested to evaluate their potential capability for their use as corrosion inhibitors of carbon steel reinforcement in concretes. The addit ives tested were sodium benzoate, polyethylene glycol, hexamethylenetetramine, benzot riazole and itrium carbonate. Initially, exploratory tests were carried out to select the ones to be used as corrosion inhibitors, based on the inhibit ion ef f iciency determined from elect rochemical tests, specifically polar ization tests and elect rochemical impedance spect roscopy. These tests were carried out in a solut ion composed of 0.01N sodium hydroxide (NaOH) and 0.05N potassium hydroxide (KOH) to simulate the composition of the solution inside the pores in concretes. The additive that presented the most promising potent ial to be used as cor rosion inhibitor was benzot r iazole (BTA). Af ter the elimination of some compounds and selection of the additive with higher corrosion inhibit ion efficiency in the test medium, the effect of its concent ration on the cor rosion inhibition efficiency was evaluated. Sodium nitrite solutions with the same concentrat ions as those solutions with BTA were tested for compar ison reasons. Sodium nitr ite is a well established corrosion inhibitor for carbon steel reinforcement in concretes but it has been related to toxic effects. The BTA was associated to higher corrosion inhibit ion efficiencies than that of sodium nitrite in similar concentrations. A blackish adherent film was formed on the steel surface exposed to BTA solut ions dur ing long periods of immersion in the alkaline medium. The results suggest that BTA is a potential candidate for subst itution of nit rites as corrosion inhibitor of reinforcements in concrete

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32

Chuang, Hsiao-Ching. "Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365.

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Harand, Kristina Marie. "Assessment of Acrolein-induced Toxicity Using In-vitro Modeling to Evaluate the Role of PARP Inhibitors in Reducing Cytotoxicity." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6091.

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Acrolein is an electrophilic α, β-unsaturated aldehyde. Additionally, acrolein is a metabolite of the antineoplastic alkylating agent cyclophosphamide and is implicated in off-target effects, including to bladder hemorrhagic cystitis and cyclophosphamide-induced cardiotoxicity, both of which have led to serious secondary iatrogenic injury during and following chemotherapy. At low concentrations acrolein inhibits cell proliferation without inducing apoptosis, while at high concentrations may result in secondary apoptosis promotion. This investigation assessed the role of the enzyme poly (ADP-ribose) polymerase (PARP) in acrolein induced toxicity using the established toxicological H9c2 (2-1) cardiomyoblast in vitro model. H9c2 (2-1) cells were plated in 24-well plates at 75,000 cells per well three days prior to testing, followed by acrolein dosing at concentrations between 10 µM and 1000µM for either 30 or 55 minutes. PARP activity was quantitatively measured in total cell lysates using a biotin-avidin-conjugated horseradish peroxidase-TMB reporter system in a 96-well microplate formate. The lowest effective dose of toxicity at 30 minute dosing was found at 25 μM (PARP Activity 1.65-fold control) which returned to baseline at 100 μM; concentrations at or above 250 μM results in significant PARP activity reductions (≤ 0.46-fold control). Biomarkers were further characterized for cytotoxicity (AST presence), and viability (MTT reduction) in order to facilitate mechanistic characterization of PARP-mediated acrolein cardiotoxicity. Investigation of a PARP inhibitor was assessed to explore the intervention for acrolein induced cardiac tissue damage.

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Barbosa, Marta Cristina Fornelos. "Sistema Nervoso Central: planeamento químico-farmacológico para obtenção de um novo alvo terapêutico para a doença de Parkinson." Master's thesis, [s.n.], 2012. http://hdl.handle.net/10284/3205.

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Trabalho apresentado à Universidade Fernando Pessoa como parte integrante dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
O presente trabalho pretende seguir uma linha de investigação pré-laboral, mas de enorme potencial devido à possibilidade de apresentar uma significativa redução nos custos aquando do lançamento de uma nova solução terapêutica. O trabalho será desenvolvido na área do sistema nervoso central (SNC) e a doença abordada será a doença de Parkinson. No decorrer deste trabalho irá ser feito uma abordagem ao tratamento farmacológico da DP, e realizado um estudo químico-farmacológico de potenciais novos inibidores da COMT. A Doença de Parkinson (DP) é uma patologia cerebral em que ocorre morte dos neurónios numa zona do cérebro designada de substância negra. É a segunda doença neurodegenerativa mais frequente depois da doença de Alzheimer. This work intends to pursue a line of pre-employment investigation, but with great potential due to the possibility of presenting a significant cost reduction at the launch of a new therapeutic solution. The work will be developed in the area of the central nervous system (CNS) and the disease discussed will be Parkinson's disease. We will make an approach to the pharmacological treatment of PD, and we will conduct a chemical and pharmacological study of potential new COMT inhibitors. Parkinson's disease (PD) is a brain pathology in which occurs neuronal death in an area of the brain called substantia nigra. It is the second most common neurodegenerative disorder after Alzheimer's disease.

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Grivas, Paul Christopher. "The role of poly (ADP-ribose) polymerase-1 inhibitors : prevention of non glutathione-dependent carbon tetrachloride-induced hepatotoxicity." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001953.

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LUCENA, Danielly Vieira de. "Fluidos inibidos para perfuração de folhelhos." Universidade Federal de Campina Grande, 2014. http://dspace.sti.ufcg.edu.br:8080/jspui/handle/riufcg/237.

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Estudar formações geológicas suscetíveis à hidratação se configura como um desafio por se tratar de um fenômeno responsável por cerca de 90% dos problemas relacionados com a perfuração de poços de petróleo, além de se tratar de um tema que pouco se conhece sobre os mecanismos que regem tal fenômeno e ainda, pela escassez de estudos voltados para a análise de diferentes produtos que evitem a ocorrência da problemática (inibidores) da hidratação. Deste modo, este trabalho objetivou o estudo e a avaliação da eficiência de fluidos de perfuração aquosos inibidos e isentos de cloro no controle da hidratação de formações de folhelhos de várias regiões do país. Para isto, foram estudadas treze amostras de folhelhos brasileiros e duas amostras de argilas bentoníticas. Inicialmente, realizou-se a caracterização de todas as amostras com a finalidade de identificar as mais suscetíveis à hidratação. Em seguida, foi realizado o estudo para selecionar a melhor concentração de inibidor para contenção da expansão de argilas reativas e a partir dos resultados foi estabelecida a concentração ótima de inibidor (20g/ 350mL de água). A partir disto, foram desenvolvidos fluidos de perfuração com quatro diferentes inibidores de argila expansiva (sulfato de potássio, acetato de potássio, citrato de potássio e cloreto de potássio) e determinados o pH, a densidade, as propriedades reológicas e de filtração. Foi também determinada a dispersibilidade dos fluidos desenvolvidos. A partir dos resultados, concluiu-se que foram desenvolvidos com êxito fluidos de perfuração que apresentam satisfatórios desempenhos reológicos e de filtração e propriedades inibitivas. Excelentes resultados em relação às taxas de dispersibilidade também foram obtidas. De modo geral, os resultados obtidos indicam que o inibidor citrato de potássio apresentou o melhor controle da reatividade de formações reativas e que o mesmo se constitui em um produto alternativo à substituição dos inibidores comerciais utilizados pela indústria.
To study geological formations susceptible to hydration is a challenge because it is a phenomenon responsible for about 90% of problems associated to the drilling of oil well, in addition it is a topic that deal with mechanisms little known governing this event and also due to the scarcity of the studies focused on the analysis of different products that avoid the occurrence of the hydration problems (inhibitors). In this way, the aim of this work was study the efficiency of the based water inhibited drilling fluids free of chlorine in the control of hydration of shale formation from various regions of the country. For this, it was studied thirteen samples of brazilian shales and two samples of bentonite clays. Firstly, it was done the characterization of the samples with the purpose of identifying the more susceptible to hydration. Then, it was studied the best concentration of the inhibitor to hinder the expansion of reactive clays and from these results it was established the best concentration of inhibitor (20g/350mL of water). After, it was developed drilling fluids with four different inhibitors of expansive clay (potassium phosphate, potassium acetate, potassium citrate and potassium chloride) and estimated the pH, density, rheological and filtration properties of these fluids. It is also estimated the dispersibility of the developed fluids. From the results, it was concluded that the fluids was developed with success and presented satisfactory rheological, filtration and inhibits properties. Excellent results with regard to the rates of dispersibility were also obtained. In general, the results indicated that the inhibitor potassium citrate presented the best control of reactivity of the formation and it constitutes an alternative to substitute the commercial inhibitors used by petroleum industry.

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Brown, Audra Denise. "α-aminoalkylphosphonate di(chlorophenyl) esters as inhibitors of serine proteases : Part II: A kinetic study of the coupling of the hydrolysis product of the N-tosylalanine ester of 5-phenyl-3-hydroxypyrrole to various diazonium salts : Part III: Rates of thrombin acylation and deacylaton upon reaction with low molecular weight acylating agents, carbamylating agents and carbonylati." Thesis, Georgia Institute of Technology, 1994. http://hdl.handle.net/1853/27552.

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38

Tantishaiyakul, Vimon. "Part I. Synthesis of idocatecholamine derivatives as adrenergic stimulants and thromboxane A₂ antagonists ; Part II. Synthesis of irreversible inhibitors of aldose reductase /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487677267730112.

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39

Sulier, Kiaya Minh-Li. "Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases." Thesis, Virginia Tech, 2017. http://hdl.handle.net/10919/86200.

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Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. PARP inhibitors (PARPi) have shown success in clinical trials for the treatment of homologous recombination-deficient cancers. Though proven effective initially, tumors treated with PARPi eventually develop resistance. Combinatorial therapeutics targeting PARP and other pathways that may re-sensitize tumors to PARP inhibition, including PI3K/AKT/mTor pathway, and cell-cycle checkpoints (such as CDKs, CHK, and Wee) are being tested. In this context, the synthetic lethality of cyclin-dependent kinase 1 (CDK1) and PARP1 is known. Evaluation of PARP1 and CDK1 pharmacophores led to the development of the tetrahydro-arylazepinone (TAAP) scaffold as a potential dual PARP1/CDK1 inhibitor. We screened a handful of TAAP analogs against PARP1 in a cell-free assay that identified the low micromolar PARP1 inhibitor 1,2,3,4-tetrahydro-5H-benzo[e][1,4]-diazepin-5-one (TBAP), which served as the lead compound. The analogous 1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]-diazepin-5-one (TPAP) series showed a similar bioactivity profile. Satisfyingly, the N1-benzyl TPAP analogue showed activity in the low nanomolar range. The TAAP series (i.e., 6/7-membered scaffold) unfortunately lacked CDK1 inhibitory activity. Finally, many PARPi's show poor isoform-selectivity. The development of isoform-selective PARPi can clarify the specific function of each PARP isoform and may reduce the adverse side effects shown by PARPi. A handful of TAAP analogs were screened against 13 PARP isoforms, where some compounds demonstrated exquisite PARP1/2 selectivity. Concurrently, we discovered an inhibitor for PARP11, an isoform that lacks any known synthetic ligand. Future directions are suggested towards fine-tuning the structure-activity relationship of TAAP-isoform selective PARPi as well as developing a dual PARP1/CDK1 inhibitor.
Master of Science

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Morel, Daphné. "Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma PBRM1 Deficiency in Cancer is Synthetic Lethal with DNA Repair Inhibitors Exploiting Epigenetic Vulnerabilities in Solid Tumors: Novel Therapeutic Opportunities in the Treatment of SWI/SNF-Defective Cancers Combining Epigenetic Drugs with other Therapies for Solid Tumours — Past Lessons and Future Promise Targeting Chromatin Defects in Selected Solid Tumors Based on Oncogene Addiction, Synthetic Lethality and Epigenetic Antagonism." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL017.

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L’inactivation de polybromo-1 (PBRM1) est un évènement fréquent dans de nombreux cancers. En particulier, les carcinomes rénaux à cellules claires présentent une déficience en PBRM1 dans 40 à 50% des cas. A ce jour, il n’existe pas d’approche de médecine précision connue capable de cibler spécifiquement les cellules tumorales déficientes en PBRM1.Pour identifier des cibles de létalité synthétique associées à la perte de PBRM1, nous avons (i) réalisé un criblage pharmacologique à haut débit évaluant la sensibilité à 167 molécules dans un modèle cellulaire isogénique pour PBRM1, et (ii) étudié l’impact transcriptomique et protéomique de la perte de PBRM1 dans ce même modèle.Nous avons ensuite caractérisé les mécanismes sous-jacents à la relation de létalité synthétique découverte.Nous avons identifié et validé une relation de létalité synthétique existante entre la perte tumorale de PBRM1 et l’inhibition pharmacologique de PARP, pouvant être potentialisée par l’ajout d’un inhibiteur d’ATR.Cette relation de létalité synthétique était caractérisée par un niveau basal élevé de stress cellulaire chez les cellules déficientes en PBRM1, associant anomalies mitotiques, stress transcriptionnel et stress réplicatif – tous ces phénomènes étant exacerbés à l’ajout d’inhibiteurs de PARP, jusqu’à dépasser les capacités cellulaires à maintenir un phénotype compatible avec la survie.Ces observations apportent la preuve de concept préclinique que les inhibiteurs de PARP sont de potentiels candidats thérapeutiques pour cibler spécifiquement les tumeurs déficientes en PBRM1
Polybromo-1 (PBRM1) inactivation occurs in multiple malignancies and is of particular importance in clear cell renal cell carcinomas (ccRCC), as it drives 40 to 50% of cases. Currently, no precision-medicine approach uses PBRM1 deficiency to specifically target tumour cells. To uncover novel synthetic lethal approaches to treat PBRM1-defective cancers, we performed (i) a high-throughput pharmacological screening, evaluating the sensitivity to 167 small molecules in a PBRM1-isogenic cellular model, and the (ii) systematic mapping of the whole transcriptomic and proteomic profiles associated with PBRM1 loss-of-function within this model. We further investigated the mechanism underlying this synthetic lethal relationship.We identified and validated synthetic lethal effects between PBRM1 loss and both PARP and ATR inhibition. Combinatorial use of PARP with ATR inhibitors exerted additive cytotoxic effects in PBRM1-defective tumor cells. These synthetic lethal relationships were characterized by a pre-existing replication stress in PBRM1-deficient cells associated with mitosis and DNA damage repair abnormalities, which were exacerbated upon PARP inhibition selectively in PBRM1-defective cells.These data provide the preclinical basis for evaluating PARP inhibitors as a monotherapy or in combination in patients with PBRM1-deficient ccRCC

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Martini, Viviane Paula. "DETERMINAÇÃO E ESTUDOS DE ESTRUTURAS DE COMPLEXOS ENZIMALIGANTES RELEVANTES À BIOLOGIA DAS PTERIDINAS EM PARASITAS: BASE PARA O DESENVOLVIMENTO RACIONAL DE DROGAS TERAPÊUTICAS CONTRA DOENÇA DO SONO." UNIVERSIDADE ESTADUAL DE PONTA GROSSA, 2007. http://tede2.uepg.br/jspui/handle/prefix/2124.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
The enzymes dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase (PTR) are involved in the pterin/folate dependent metabolism; together they represent an important target for chemotherapy of parasitic leishmanias and trypanosomes. Xray crystallography was used to elucidate accurately the structure of the PTR1 enzyme from Trypanosoma brucei in complex with inhibitors which are analogous to the substrate. The ligands assayed for crystallization were the substrate folate and the inhibitors melamine, 6-thioguanine, WSG1012, WSG1034, WSG3065, WSG3066 and WSG3067. Of these, four yielded crystals with diffraction patterns sufficient for a complete dataset. WSG3065 (later revealing the lack of the ligand), WSG3066 and WSG3067 are three of the several structures presented in this work which came from the cited crystallization assays; added to these are the refined structures complexed with triamterene and cyromazine, proceeded from two other datasets already available. The datasets were processed with the programs Mosflm / Scala and Xds / Xscale, the structures were refined using the programs CNS and Refmac5 and validated with the programs Procheck, Whatcheck, Sfcheck and ValidationPDB. All refined structures belong to the space group P21 with unit cells around a = 79, b = 90, c = 82, b = 115, 4 monomers each of 268 residues per asymmetric unit and complex active sites. Besides the inhibiting ligands (except WSG3065) present in the structure, other ligands were found either near or outside the active site: dithiothreitol, glycerol, ethylene glycol, sodium and acetate ions. Analyses on the ligand positions and corresponding interactions with the protein were carried out to understand modes of inhibition and to guide the design or the discovery of new compounds which are potent, but selective to the parasitic enzyme, inhibitors. Thereby, initial docking studies were performed aiming at identifying new molecules or lead compounds with inhibitory capabilities.
As enzimas dihidrofolato redutase-timidilato sintase (DHFR-TS) e pteridina redutase (PTR) estão envolvidas no metabolismo pterina/folato dependente; juntas, representam um importante alvo para a quimioterapia de leishmanias e tripanossomas parasitas. A Cristalografia por Raios X foi utilizada para elucidar acuradamente a estrutura da enzima PTR1 de Trypanosoma brucei complexada com inibidores que são análogos ao substrato. Os ligantes ensaiados para cristalização foram o substrato folato e os inibidores melamina, 6-tioguanina, WSG1012, WSG1034, WSG3065, WSG3066 e WSG3067. Destes, quatro forneceram cristais com padrões de difração suficientes para um conjunto de dados completo. WSG3065 (mais tarde revelando ausência do ligante), WSG3066 e WSG3067 são três das estruturas apresentadas neste trabalho derivadas dos ensaios de cristalização citados; somadas a estas estão as estruturas refinadas dos complexos com triantereno e ciromazina, provenientes de dois outros conjuntos de dados anteriormente disponíveis. Os conjuntos de dados foram processados com os programas Mosflm / Scala e Xds / Xscale, as estruturas refinadas usando-se os programas CNS e Refmac5 e validadas com os programas Procheck, Whatcheck, Sfcheck e ValidationPDB. Todas as estruturas refinadas apresentaram grupo espacial P21 com celas unitárias aproximadas a = 79 = 90, c = 82 , b = 115, 4 monômeros de 268 resíduos cada por unidade assimétrica e sítios ativos complexos. Além dos ligantes inibidores presentes nas estruturas (exceto WSG3065), outros ligantes foram encontrados próximos ou fora do sítio ativo: ditiotreitol, glicerol, etilenoglicol, íons sódio e íons acetato. Análises das posições dos ligantes inibidores e correspondentes interações com a proteína foram realizadas a fim de se entender modos de inibição e, em particular, assistir ao planejamento ou à descoberta de novos compostos que sejam inibidores potentes, mas seletivos, para a enzima parasitária. Assim, estudos iniciais de atracagem (docking) foram realizados visando identificar novas moléculas ou arcabouços com capacidades inibitórias.

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Costa, Thiago Santangelo. "Obtenção do copolímero de acrilonitrila e vinil-tetrazol e sua aplicação como inibidor de corrosão para meio ácido." Universidade do Estado do Rio de Janeiro, 2007. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=2803.

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Polímeros heterocíclicos abrangem uma grande variedade de materiais, desde simples polímeros lineares sintetizados a partir de monômeros do tipo heterocíclicos vinílicos até polímeros altamente funcionalizados e reticulados. Neste trabalho realizou-se a modificação química da poliacrilonitrila com a incorporação de grupos tetrazol em diferentes teores (1%, 2,5%, 5% e 10%). Os copolímeros de acrilonitrila e vinil-tetrazol obtidos foram caracterizados por FTIR e o seu comportamento térmico analisado por DSC e TGA. Os polímeros heterocíclicos foram avaliados como inibidores de corrosão para aço-carbono em meio ácido obtendo-se bons resultados e alcançando, em alguns casos, uma eficiência de inibição média superior a 70%
Heterocyclic polymers enclose a great variety of materials, since simple linear polymers synthesized from monomers of vinyl heterocyclics to polymers highly functionalized and crosslinked. In this work was carried out the chemical modified of polyacrilonitrile with incorporation of tetrazole groups in different quantities (1%, 2,5%, 5% and 10%). The acrilonitrile and vinyl-tetrazole copolymers were characterized by FTIR and its thermal behavior analyzed by DSC and TGA. The heterocyclic polymers were evaluated as corrosion inhibitor to carbon steel in acidic medium. It was obtained good results and in some cases inhibitor efficient average higher than 70% were reached

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Silva, Amanda Alves. "Caracterização bioquímica da Beta-Xilosidase II de Caulobacter crescentus visando a degradação da biomassa lignocelulósica para aplicações biotecnológicas." Universidade Estadual do Oeste do Parana, 2015. http://tede.unioeste.br:8080/tede/handle/tede/5.

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Made available in DSpace on 2017-05-12T14:36:23Z (GMT). No. of bitstreams: 1 DISSERTACAO AMANDA ALVES MESTRADO EM CIENCIAS FARMACEUTICAS _UNIOESTE 2015.pdf: 10598736 bytes, checksum: 51f0f3eb83858fee62392b7892930766 (MD5) Previous issue date: 2015-12-07
Lignocellulosic biomass are the raw material most abundant and promising as a natural and renewable resource. These plant materials are complex carbohydrate polymer composed mainly of cellulose, hemicellulose and lignin, which are linked by covalent bonds and can be transformed into value-added products, such as biofuels. The degradation of lignocellulosic material is made mainly from enzymes produced by microorganisms such as filamentous fungi, yeast and bacteria. Ethanol production from agricultural residues, based on the enzymatic hydrolysis, it takes basically four stages: production of enzymes, pretreatment, enzymatic hydrolysis and fermentation. Pretreatment is a work that will break the lignin cellulose complex, reducing the degree of crystallinity of the cellulose and increase the porosity of the material, by increasing the surface area of the biomass. However, pre-treatment products can generate inhibitors which include phenolic and other aromatic, aliphatic acids, aldehydes, furans, inorganic ions. The fermentation and simultaneous saccharification is an important approach for producing cellulosic or ethanol of second generation, where the enzymatic hydrolysis of cellulose and fermentation are simultaneously carried out in the same reactor, in order to obtain ethanol at a high rate and decrease formation of inhibitor compounds. Enzymatic hydrolysis requires, first, that the lignocellulosic biomass is pretreated to increase access to enzymatic attack, so that later the cellulose is broken down by cellulase action. Xylanases include the group of enzymes responsible for the hydrolysis of xylan, the major constituent of hemicellulose. The key enzymes involved in this process are β-1,4-endoxylanase and β-D-xylosidase. Endoxylanase cleave glycosidic linkages of the main chain of xylan releasing xylo-oligosaccharides, which are used by β-xylosidase to produce monomers of xylose. The alfaproteobacteria Caulobacter crescentus is non pathogenic, Gram negative, mainly found in aquatic environments and on many types of soils. This bacterium has about seven genes directly associated with xylan degradation and five of them encoding β-xylosidases. To date, there are only three studies on the β-xylosidase II from C. crescentus. The first characterization of this enzyme showed that it is capable of hydrolyzing substrates such as xylobiose, xylotriose and xilopentose whose optimum pH is 6 and optimum temperature is 55°C, although it is stable at 50°C, which shows a thermotolerance, indicating strong enough to be used in different biotechnological applications. The stability and reusability of enzymes are of fundamental importance, since they reflect significantly on the cost of the final product, and one way to achieve this is with the immobilization of enzymes, consisting of confinement thereof in a matrix or support, which can be inert polymers or inorganic materials, so that its catalytic activity is retained and the enzyme can be used repeatedly and continuously. In the present report, it was found that the β-xylosidase II (CcXynB2) of Caulobacter crescentus increased by 62% of its activity in 5 mM KCl probably as a consequence of a positive role of K+ ions. CCxynB2 was measured against various compounds described as inhibitors of hydrolysis and fermentation of lignocellulosic biomass and showed 61% more tolerant incubation with ethanol (200 mM) at 37 °C for 48 h in the absence of alcohol. The specific activities of CcXynB2 were evaluated in the presence of 10mM phenol or galacturonic acid, 100 mM hydroxymethylfurfural or ferulic acid, 1 mM acetic acid, 200 mM arabinose, glucose or xylose and it was found that were equal (100%) or much higher than the values obtained in the total absence of these compounds after 48 h. When the inhibitors were used in combination, the CcXynB2 retained 67% of its initial activity after testing at 37°C during 48 h. The enzymatic hydrolysis of hemicellulose from corncob was conducted with CcXynB2 alone or in synergism with xylanase and commercial β-glycosidase, which were more efficient in performed the saccharification of hemicellulose from 37-50 °C. The immobilized CcXynB2 in mobile phase resin led to a protective effect of specific activity, which was proportionally parallel to decreased temperatures (60 to -20°C). The data presented here indicate that CcXynB2 is promising and has potential to work in simultaneous saccharification and fermentation processes for cellulosic ethanol production. To our knowledge, is the first time that similar results are reported in the literature to bacterial β-xylosidases. Thus, this work contribute positively by providing essential information to improve the use of β-xylosidase II of Caulobacter crescentus.
Biomassas lignocelulósicas constituem a matéria-prima mais abundante e promissora como recurso natural e renovável. Esses materiais vegetais são polímeros de carboidratos complexos compostos basicamente por celulose, hemicelulose e lignina, que estão unidos entre si por ligações covalentes e podem ser convertidos em produtos de valor agregado, como os biocombustíveis. A degradação dos materiais lignocelulósicos é feita a partir de enzimas produzidas principalmente por micro-organismos como fungos filamentosos, leveduras e bactérias. Para obter etanol a partir de resíduos agroindustriais, baseando-se na hidrólise enzimática, são necessárias, basicamente, quatro etapas: produção de enzimas, pré-tratamento, hidrólise enzimática e fermentação. O pré-tratamento é o processo que irá dissociar o complexo lignina-celulose, reduzir o grau de cristalinidade da celulose e aumentar a porosidade dos materiais, através do aumento da área superficial da biomassa. No entanto, o pré-tratamento pode gerar produtos inibidores, que incluem compostos fenólicos e outros aromáticos, ácidos alifáticos, aldeídos, furanos, íons inorgânicos. A fermentação e sacarificação simultânea é uma estratégia importante para a produção de etanol celulósico ou de segunda geração, onde a hidrólise enzimática da celulose e a fermentação são desenvolvidas simultaneamente no mesmo reator, com o intuito de obter etanol em altas taxas e diminuir a formação de compostos inibidores. A hidrólise enzimática necessita, primeiramente, que a biomassa lignocelulósica seja pré-tratada para aumentar o acesso ao ataque enzimático, para que posteriormente a celulose seja quebrada pela ação de celulases. As xilanases compreendem o grupo de enzimas responsáveis pela hidrólise do xilano, principal constituinte da hemicelulose. As principais enzimas envolvidas nesse processo são β-1,4-endoxilanase e a β-D-xilosidase. Endoxilanases clivam as ligações glicosídicas da cadeia principal do xilano liberando xilo-oligossacarídeos, que são utilizados pelas β-xilosidases para liberar xilose. A alfaproteobactéria Caulobacter crescentus é não patogênica, Gram negativa, encontrada principalmente em ambientes aquáticos e em muitos tipos de solos. Essa bactéria apresenta cerca de sete genes envolvidos diretamente na degradação do xilano, sendo que cinco deles codificam para β-xilosidases. Até o momento, existem apenas três trabalhos sobre a β-xilosidase II de C. crescentus. A primeira caracterização da enzima mostrou que esta é capaz de hidrolisar substratos como xilobiose, xilotriose e xilopentose, cujo pH ótimo é 6 e temperatura ótima é 55ºC, embora seja mais estável em 50ºC, o que demonstra uma modesta termotolerância, indicando ser suficientemente resistente para diferentes aplicações biotecnológicas. A estabilidade e a possibilidade de reutilização de enzimas são de fundamental importância, pois refletem significativamente no custo do produto final, e uma forma de conseguir isso é com a imobilização de enzimas, que consiste no confinamento da mesma em uma matriz ou suporte, que podem ser polímeros inertes ou materiais inorgânicos, de modo que sua atividade catalítica fique retida e a enzima possa ser usada repetidamente e continuamente. No presente trabalho, verificou-se que a β-xilosidase II (CcXynB2) de Caulobacter crescentus aumentou 62% da sua atividade em 5 mM de KCl provavelmente em consequência de um papel positivo dos íons K+. CcXynB2 foi avaliada frente a diferentes compostos descritos como inibidores do processo de hidrólise e fermentação da biomassa lignocelulósica e mostrou-se 61% mais tolerante a incubação com etanol (200 mM) a atividades específicas da CcXynB2 foram avaliadas na presença de 10 mM fenol ou ácido galacturônico, 100 mM de hidroximetilfurfural ou ácido ferúlico, 1 mM de ácido acético, 200 mM de arabinose, glicose ou xilose, e verificou-se que foram iguais (100%) ou muito superiores aos valores obtidos na ausência total destes compostos após 48 h. Quando os inibidores foram usados em associação, a CcXynB2 reteve 67% da sua atividade inicial após 48 h de ensaio a 37ºC. A hidrólise enzimática da hemicelulose de sabugo de milho foi conduzida com CcXynB2 isoladamente ou em sinergismo com xilanase e β-glicosidase comerciais, as quais foram mais eficientes em sacarificar a hemicelulose entre 37-50ºC. A imobilização da CcXynB2 em resina de fase móvel levou a um efeito protetor da atividade específica, que ocorreu de forma paralela à diminuição de temperatura (60 a -20ºC). Os dados apresentados aqui indicam que a CcXynB2 é promissora e possui potencial para atuar em processos de sacarificação e fermentação simultânea para produção de etanol celulósico. Segundo nosso conhecimento, é a primeira vez que resultados similares são relatados na literatura para β-xilosidases bacterianas. Dessa forma, este trabalho pode contribuir positivamente, fornecendo informações fundamentais para aprimorar o uso da β-xilosidase II de Caulobacter crescentus

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44

Cartwright, Luke. "The potential of poly (ADP-ribose) polymerase (PARP) inhibitors to improve plant growth and yield : novel crop protection agents under stressed conditions." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/19289/.

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Chemical inhibition of the activity of poly (ADP-ribose) polymerases (PARPs) is associated with enhanced stress tolerance and growth in response to a broad range of abiotic plant stressors. This led to the suggestion that PARP inhibitors might have application in future crop protection strategies. However, the vast majority of studies to date have involved short-term, in vitro assays which are not representative of the conditions crop plants experience in the field. This work aimed to quantify the impact of chemical PARP inhibitor application on photosynthesis, growth and yield in planta, under well-watered and droughted conditions. In Chapter 2, a protocol for the quantification of the impact of drought stress on photosynthesis was developed, mainly using chlorophyll fluorescence imaging. In Chapter 3, the impacts of PARP inhibitors on photosynthesis, growth and survival in response to drought were measured. PARP inhibitors enhanced survival to severe stress but there was a cost associated with application under well-watered and moderate drought conditions. Chlorophyll fluorescence and growth measurements indicated that PARP inhibitors also had a damaging effect. Results from Chapter 4 suggested that PARP and PSII inhibitors had broadly negative impacts on yield. There was a strong relationship between growth (maximum plant object sum area) and yield under stress, which enabled the effects that compounds had on yield to be predicted approximately 40 days earlier than measuring at harvest. By fitting a model to the growth data it was possible to predict the impacts even earlier still. In Chapter 5, application of a PARP inhibitor reduced stomatal conductance but did not alter opening/closing kinetics, indicating the compound had an anti-transpirant effect. The enhanced stress tolerance of PARP-deficient plants likely protected against severe drought. However, a trade-off arises because of the costs associated with application under more moderate conditions. If PARP inhibitors are to be used in agriculture the cost/benefit balance will have to be carefully considered.

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Salwiński, Aleksander. "Development of novel mass spectrometry-based approaches for searching for low-mass tyrosinase inhibitors in complex mixtures." Thesis, Orléans, 2014. http://www.theses.fr/2014ORLE2013/document.

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Ce manuscrit de thèse présente le développement de méthodes basées sur la spectrométrie de masse consacrées à la recherche d'inhibiteurs d'enzymes en milieux complexes, tels que les extraits de plantes. L’enzyme Tyrosinase a été utilisé comme principale cible biologique du fait de son implication dans les processus d’hyperpigmentation cutanée. De ce fait, la recherche d’inhibiteurs de cette enzyme, présente un grand intérêt pour l'industrie cosmétique. La première partie de ce manuscrit décrit la mise en place de la chromatographie d'affinité frontale (FAC), permettant d’obtenir le classement simultané des inhibiteurs présent dans un mélange complexe en fonction de leurs affinités avec la cible biologique. Deux capillaires hydrophiles de phase monolithiques ont été évalués afin de réduire au maximum les interactions non spécifiques indésirables entre les analytes et le support solide d’immobilisation. De plus, nous avons étudié la faisabilité de l’utilisation de phases à base de silice comme support solide d’immobilisation des enzymes dans le cadre de ces analyses par chromatographie d'affinité frontale. La seconde partie du manuscrit de thèse est consacrée au développement et à l’optimisation de l’approche nommée ENALDI-MS (Enzyme-coupled Nanoparticles-Assisted Laser Desorption/Ionisation Mass Spectrometry) permettant d’accéder à une gamme des faibles masses (m/z 500 Da). Elle est déclinée en une première approche dite par ‘extinction d’ions’ (Ion Fading, IF-ENALDI), basée sur l’identification directe de la liaison des inhibiteurs vis-à-vis de l’enzyme sans pré-traitement de l’échantillon végétal. Une seconde déclinaison de l’ENALDI-MS concerne une approche dite par ‘Ion Hunting’ (IH - ENALDI MS), basée sur une méthode de pré-concentration sélective des inhibiteurs présents dans l'échantillon
This thesis report presents the development of mass spectrometry-based methods for searching for inhibitors of enzymes in complex mixtures, such as plant extracts. Tyrosinase enzyme was used as the main biological target for the reason of a significant importance of its inhibitors in the cosmetic industry as the skin whitening agents. The first part of this report describes Frontal Affinity Chromatography (FAC), an approach enabling simultaneous ranking the inhibitors within the complex mixture according to their affinities to the biological target. Two hydrophilic capillary-scale polymer-based bioaffinity stationary phases were evaluated in the context of the presence of undesirable nonspecific interactions between the analyte and the solid immobilisation support. In addition, we explored the usability of two types of silica-based particles as a solid support for enzyme immobilisation for FAC. The second part of the thesis manuscript is devoted to Enzyme-coupled Nanoparticle-Assisted Laser Desorption/Ionisation Mass Spectrometry (ENALDI MS) as a low-mass compatible extension of the Intensity ion Fading MALDI MS (IF-MALDI MS) method for high-throughput screening of the inhibitors in the complex mixtures. Two variations of ENALDI MS were evaluated: 'Ion Fading' (IF-ENALDI MS), based on on-the-spot binding of inhibitors by enzyme molecules and 'Ion Hunting' (IH-ENALDI MS), based on selective pre-concentration of inhibitors present in the sample

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Sanchez, Eduardo Milton Ramos. "Avaliação do modelo de hamster para detecção das alterações lipídicas e cardiotoxicidade associadas à terapia contra o vírus da imunodeficiência humana." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-25032010-153939/.

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Com a introdução de uma nova classe de antiretrovirais integrantes da terapia anti-retroviral altamente ativa (HAART) para o tratamento das infecções pelo vírus da imunodeficiência humana, começaram a ser descritos inúmeros efeitos secundários.Na tentativa de se estabelecer um modelo animal para o estudo destes efeitos buscou-se uma espécie com similaridade no perfil e metabolismo lipídico. Iniciou-se estudo em Mesocricetus auratus. Foram avaliados o perfil lipídico e glicêmico,função hepática e renal, níveis de auto-anticorpos anti ox-LDL, perfil eletrocardiográfico, alterações histopatológicas renais e cardíacas nos animais sob dieta hiperlipídica e normal,tratados com Indinavir, inibidor de protease utilizado na HAART. Observou-se uma diminuição da sobrevida nos animais tratados com indinavir, aumento do nível sérico de triglicérides e glicose, redução de auto-anticorpos anti ox-LDL,aumento do segmento QRS no eletrocardiograma, presença de fibrose renal e cardíaca, hipercelularidade glomerular nos animais tratados com a droga com ou sem dieta hiperlipídica quando comparados com os controles. Concluimos que Mesocricetus auratus se apresenta como um bom modelo para o desvendamento dos mecanismos patológicos observados na HAART.
With the introduction of a new antiretroviral class use, integrants of highly active anti-retroviral therapy (HAART) for the treatment of infections by human immunodeficiency virus, several side effects started to be described.To establish an animal model for the study of these side effects, was chosen specie that have similarities in the lipidic profile and metabolism. A study in Mesocricetus auratus was started. It was evaluated the lipidic and glicemic profile ,hepatic and renal function, the levels of auto-antibodies against ox-LDL, electrocardiographic profile and renal and cardiac histopathological alterations in these animals under hyperlipidic and normal diets,treated with Indinavir, a protease inhibitor used in HAART.It was observed a decrease in the survival rate in the animals treated with Indinavir; an increase of the triglycerides and glucose serum level; reduction of anti ox-LDL auto-antibodies; increased QRS segment in the electrocardiogram; presence of renal and cardiac fibrosis; glomerular hypercellularity in the animals treated with the drug, with or without hyperlipidic diet when compared with the controls. We conclude that the Mesocricetus auratus is a good model for disclosure of the pathological mechanisms generated by HAART.

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Weigert, Verena [Verfasser], Rainer [Akademischer Betreuer] Fietkau, and Luitpold [Gutachter] Distel. "PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts / Verena Weigert ; Gutachter: Luitpold Distel ; Betreuer: Rainer Fietkau." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1231077956/34.

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Rodrigues, Núbia Fernanda Marinho. "Desenvolvimento de sensor bioinspirado em hexapeptídeo de enzima acetilcolinesterase para detecção de pesticidas /." Araraquara, 2018. http://hdl.handle.net/11449/153136.

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Orientador: Hideko Yamanaka
Coorientador: Flávio Santos Damos
Banca: Cecilio Sadao Fugivara
Banca: Eder Tadeu Gomes Cavalheiro
Banca: Carla dos Santos Riccardi
Banca: Silvia Helena Pires Serrano
Resumo: Os pesticidas estão entre os poluentes mais preocupantes, devido à toxicidade e presença significativa no ambiente. A sua toxicidade é baseada na capacidade de inibir irreversivelmente a enzima acetilcolinesterase (AChE) que é chave na transmissão de impulsos nervosos. Este trabalho descreve o desenvolvimento de sensor contendo hexapeptídeo, bioinspirado em enzima acetilcolinesterase, para detecção de pesticidas organofosforados e carbamatos. A sequência peptídica (NH3+ - His - Glu - Trp - Arg - Pro - Ser - COO-) foi imobilizada sobre nanopartículas magnéticas (Fe3O4) previamente sintetizadas, modificadas com quitosana e posteriormente funcionalizadas com 1,12-diaminododecano. As condições experimentais de imobilização do peptídeo foram otimizadas, sendo estas: concentração 5,0 x 10-5 mol L-1 e tempo de incubação de 30 minutos a 25 ºC. O grupo carboxílico presente na sequência peptídica foi ativado com o uso de agentes de acoplamento 1-etil-3-(3-dimetilaminopropil) carbodiimida (EDC) e N-hidróxisuccinimida (NHS). A razão de concentração otimizada de EDC/NHS foi de 18,6/12,5 mmol L-1, respectivamente, e tempo de ativação de 60 minutos. O sinal eletroquímico do peptídeo foi monitorado pelo pico de oxidação da histidina, cujo valor é diminuído ao interagir com o pesticida. O perclorato de sódio (NaClO4) 0,1 mol L-1 pH 7,5 foi selecionado como eletrólito suporte. Os parâmetros da voltametria de onda quadrada foram otimizados (frequência de 100 Hz, amplitude de 90 mV e incremento ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Pesticides are among the most worrying pollutants due to toxicity and significant presence in the environment. Its toxicity is based on the ability to irreversibly inhibit the enzyme acetylcholinesterase (AChE) which is key in the transmission of nerve impulses. This work describes the development of a sensor containing hexapeptide, bioinspiring enzyme acetylcholinesterase, for the detection of organophosphorus pesticides and carbamates. The peptide sequence (NH3+ - His - Glu - Trp - Arg - Pro - Ser - COO-) was immobilized on previously synthesized magnetic nanoparticles (Fe3O4), modified with chitosan and subsequently functionalized with 1,12 - diaminododecane. The experimental conditions of immobilization of the peptide were optimized, being: 5,0 x 10-5 mol L-1 concentration and incubation time of 30 minutes at 25 ºC. The carboxyl group present in the peptide sequence was activated with the use of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) coupling agents. The optimum concentration ratio of EDC / NHS was 18.6 / 12.5 mmol L-1, respectively, and activation time of 60 minutes. The electrochemical signal of the peptide was monitored by the histidine oxidation peak, whose value is decreased when interacting with the pesticide. Sodium perchlorate (NaClO4) 0.1 mol L-1 pH 7.5 was selected as supporting electrolyte. The parameters of the square wave voltammetry were optimized (frequency of 100 Hz, amplitude of 90 mV and increment of sweep of 6 mV) using a matrix of factorial planning. The preconcentration time of the peptide with the pesticide was fixed in 5 minutes. The sensor presented linear response in the studied concentration ranges, with detection limits of 6.0 x 10-11 mol L-1 and 4.0 x 10- 10 mol L- 1 for carbofuran and chlorpyrifos, respectively. The storage in the refrigerator at ± 4 °C allowed 85% stability of the immobilized peptide after a period of...
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Cavallaro, Sergio Henrique. "Avaliação do uso de um sulfossilanol como inibidor de corrosão para aço galvannealed." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/3/3137/tde-06022019-154812/.

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O processo de deposição de uma fina camada de zinco sobre o aço carbono por imersão a quente e posterior tratamento térmico gera como produto o aço galvannealed. O baixo custo do zinco e o fácil processo de aplicação faz com que o maior consumo deste metal seja aplicado na proteção da superfície do aço carbono de um meio agressivo a que ele esteja exposto. Esta camada de zinco não pode ser muito espessa, pois limita a soldabilidade, dificulta o acabamento após pintura e limita a aderência de tintas à superfície. Essa condição da fina espessura da camada de zinco depositada sobre o aço carbono torna necessário o desenvolvimento de revestimentos com espessuras menores, com melhores propriedades de dureza, ductilidade e resistência à corrosão mais elevada. Sendo assim, a superfície de zinco tem de ser pré tratada com a fosfatização e cromatização antes que as tintas possam ser devidamente aplicadas. No entanto, estes processos de pré-tratamento vêm sendo questionados devido à sua toxidade e agressividade ao meio ambiente, levando o seu uso a ser menos frequente por meio do desenvolvimento de novos processos e compostos. Alguns destes compostos estudados são os inibidores de corrosão à base de silanóis, cujo desenvolvimento e aplicação busca a baixa toxicidade, a exigência de serem ecologicamente corretos e a alta eficiência. Quando exposto em meios ácidos, o processo de corrosão para o aço galvannealed pode ser acentuado e dessa maneira, o uso de soluções aquosas de silanos organofuncionais hidrolisados em pH ácido vem sendo promissor como promotores de aderência e como inibidores de corrosão. O número de estudos publicados para o uso de silanóis adicionados diretamente no meio agressivo para a formação de filmes adsorvidos no metal protegendo-o contra a corrosão ainda é baixo, devido seu caráter inovador. Neste estudo, caracterizou-se o uso do sulfossilanol obtido a partir da hidrólise em meio ácido (pH 4,0) do silano NXT (3 - octanoiltio - 1 - propiltrietoxisilano) como inibidor de corrosão para o aço galvannealed, zinco puro e aço carbono em meio ácido (pH 5,0) de NaCl 0,1 mol L-1. Escolheu-se o zinco puro e o aço carbono para estudo pois seus átomos de zinco e ferro são constituintes da liga Fe-Zn do aço galvannealed, de maneira a se observar a adsorção do sulfossilanol em diferentes superfícies. Por meio de técnicas eletroquímicas como a técnica de varredura por eletrodo vibratório (SVET), espectroscopia de impedância eletroquímica (EIE), curvas de polarização, medida da resistência de polarização linear (Rp) foi possível verificar que o sulfossilanol estudado atua como inibidor de corrosão para o aço galvannealed, se mostrando promissor para o zinco. Através deste estudo verificou-se que o inibidor de corrosão em questão atuou principalmente na inibição das regiões ricas em zinco, já que a avaliação isolada dos metais constituintes do aço galvannealed mostrou melhores resultados para o zinco do que para o ferro. A partir disto, estudou-se por meio de técnicas eletroquímicas em meio ácido (pH 5,0) de NaCl 0,1 mol L-1, outro inibidor de corrosão clássico para aço carbono contendo também o enxofre em sua molécula, o 2 - mercaptobenzotiazol (MBT) com o intuito de comparar a eficiência da inibição da corrosão para o aço galvannealed com um inibidor clássico para ferro e o sulfossilanol, já que o aço galvannealed possui áreas ricas em ferro. O estudo evidenciou que tanto o sulfossilanol, como o MBT são bons inibidores para o aço galvannealed, sendo o sulfossilanol um excelente inibidor para zinco e o MBT um excelente inibidor para o ferro.
The process of deposition of a thin layer of zinc on carbon steel by hot immersion and subsequent heat treatment generates as product the galvannealed steel. The low cost of zinc and the easy application process leads to high consumption of this metal for carbon steel surface protection from an aggressive medium. This layer of zinc cannot be too thick because it limits the weldability, hinders the finish after painting and limits the adhesion of paints to the surface. This condition of the thin thickness of the zinc layer deposited on the carbon steel requires the development of coatings having smaller thicknesses with better hardness, ductility and higher corrosion resistance properties. Thus, the zinc surface must be pre-treated with the phosphatization and chromatization before painting. However, these pretreatments processes have been questioned because of their toxicity and aggressiveness to the environment, making their use less frequent with the development of new processes and compounds. Some of these compounds studied are silane-based corrosion inhibitors, whose development and application seek the low toxicity, the requirement of being environmentally correct and the high corrosion inhibition efficiency. When exposed in acidic media, the corrosion process for galvannealed steel can be accentuated and, in this way, the use of aqueous solutions of hydrolyzed organofunctional silanes has been promising as adhesion promoters and as corrosion inhibitors. The number of published studies for the use of sulfur silanol added directly in the aggressive medium for the formation of adsorbed films in the metal protecting it against corrosion is still low due to its novelty. In this study, the use of the sulfur silanol obtained from acid hydrolysis (pH 4.0) of NXT (3-Octanoylthio-1 propyltriethoxysilane) silane as a corrosion inhibitor for galvannealed steel, metallic zinc and carbon steel (pH 5.0) in 0.1 mol L-1 NaCl. Zinc and carbon steel were also chosen for this study because they are constituents of the Fe-Zn alloy phases present in galvannealed steel. By means of electrochemical techniques such as the scanning vibrating electrode (SVET), electrochemical impedance spectroscopy (EIS), polarization curves and linear polarization resistance (Rp) measurements, it was possible to verify that the evaluated sulfur silanol acts as a corrosion inhibitor for galvannealed steel. In this study, it was also verified that the corrosion inhibitor in question acted mainly in the inhibition of zinc rich regions or phases, since the isolated study of the constituent metals of the galvannealed steel showed better results for pure zinc than for iron. From this, it was studied by means of electrochemical techniques in acidic environment (pH 5,0) of 0,1 mol L-1 NaCl, another classic corrosion inhibitor for carbon steel also containing the sulfur in its molecule, 2 - mercaptobenzothiazole (MBT) in order to compare the corrosion inhibition efficiency for galvannealed steel with a classical inhibitor for iron and sulfur silanol, since galvannealed steel has iron rich areas. The study showed that both sulfur silanol and MBT are good inhibitors for galvannealed steel, with sulfur silanol being an excellent inhibitor for zinc and MBT being an excellent inhibitor for iron.

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50

Ramos, Ana Luísa de Queiroz Baddini. "Busca de descritores para modelagem quimiométrica de inibidores de corrosão." Universidade Federal Fluminense, 2005. http://www.bdtd.ndc.uff.br/tde_busca/arquivo.php?codArquivo=303.

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Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro
Este trabalho desenvolve um estudo quantitativo correlacionando a eficiência na inibição de corrosão com propriedades moleculares a partir de três fon-tes diversas. As duas primeiras envolvem constru-ções de modelos matemáticos com os dados experi-mentais obtidos na literatura, enquanto no terceiro os dados experimentais foram fornecidos no curso da tese de doutoramento de S. P. Cardoso (Labo-ratório de Corrosão - COPPE/UFRJ). Empregamos propriedades moleculares quânticas calculadas pelo método AM1 e também alguns descritores associa-dos à contribuição de grupos. A maioria dos mode-los foram obtidos por regressão linear multivariada e as funções resposta utilizadas foram log icorr e ln kads. O primeiro estudo elaborou modelos multiva-riados correlacionando inibição de corrosão no ferro em meio de HCl 5% utilizando piridina, dibenzil-sulfóxido e uma série homóloga de N-óxido de piridi-na como inibidores. O segundo estudo desenvolveu modelos modelos multivariados para a inibição de corrosão do aço N-80 em solução saturada de H2S em cloreto de amônio (pH ~ 4) utilizando 32 molé-culas (aminas alifáticas, imidazolinas e amidoaminas)como potenciais inibidores. Foram utilizados descri-tores quânticos, por contribuições de grupos e produtos de descritores. No terceiro estudo cons-truímos modelos para a inibição de corrosão em três diferentes aços simultaneamente em HCl 15 % p/v utilizando 23 compostos orgânicos (aminas, tiouréia e derivados e álcoois acetilênicos). Além dos des-critores quânticos, por contribuições de grupos e produtos de descritores, empregamos descritores dos aços. Deve-se destacar que esta iniciativa é inédita na literatura, pois os trabalhos prévios jamais estudaram mais de um aço por vez, além de empregar número de compostos muito inferior aquele utilizado em nosso estudo. Neste estudo além da regressão linear multivariada utilizamos o método dos mínimos quadrados parciais (Partial Least Square- PLS).
This work develops a quantitative study correlated to the efficiency in the inhibition of corrosion with molecular properties from three different sources. The two first ones involve the building of mathematical models with experimental data obtained from the literature, while in the third one the experimental data were provided in S. P. Cardosos doctorate course thesis (Corrosion Lab COPPE/UFRJ). We made use of molecular quantum properties calculated by the AM1 method and also some descriptors associated with the contribution of groups. Most of the models were obtained by the multivaried linear regression and the reply functions used were log icorr and ln Kads. The first study elaborated multivaried models correlating iron corrosion inhibition in an HC1 5% medium using pyridine, dibenzyl sulfoxide and a homologue series of pyridine N-oxide as inhibitors. The second study developed multivaried models for the inhibition of the N-80 steel corrosion in an H2S saturated solution in ammonium chloride (pH ~ 4) using 32 molecules (aliphatic amines, imidazolines e amidoamines) as potential inhibitors. In that study quantum descriptors, descriptors by group contributions and products of descriptors were used. In the third study we built models for the corrosion inhibition in three different steels simultaneously in HC1 15% p/v using 23 organic compounds (amines, thiourea and derivatives and acetylenics alcohols). Besides the quantum descriptors, for contributions of groups of descriptors, we made use of steels descriptors. Its important to emphasize that this initiative is unprecedented in the literature, for the previous works never studied more than one steel at a time, besides making use of much inferior number of compounds to that used in our study. In this study besides the multivaried linear regression we used the Partial Least Square method (PLS).

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