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1
Ptchelintsev, Dmitri Stanislav. "Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168.
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Allen, Serena. "The Combined Neuropharmacology and Toxicology of Major 'Bath Salts' Constituents MDPV, Mephedrone, and Methylone." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3431.
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The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the present dissertation aimed to address this limitation and characterize the acute and chronic effects of combined synthetic cathinone exposure on dopaminergic tone in mesolimbic and nigrostriatal brain regions. To accomplish this, male Swiss-Webster mice were administered MDPV, mephedrone, and methylone, individually or concomitantly, 1 time or 7 times over the course of two weeks and the corresponding effects of each treatment on mesolimbic and nigrostriatal brain tissue levels of dopamine (DA) and DA metabolites were analyzed using a high performance liquid chromatography – electrochemical detection (HPLC-ECD) assay. Additionally, motor-stimulant activity was evaluated after both dosing regimens using locomotor activity assays, while immunoblot and immunostaining techniques were used to evaluate the chronic effects of co-synthetic cathinone exposure on tissue levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and glial fibrillary acidic protein (GFAP). Results from these studies provide evidence of a significant pharmacological interaction among major bath salt constituents, MDPV, mephedrone, and methylone. This was observed acutely as enhanced DA responses and chronically as functional toxicity at the DA synapse. Furthermore, such interactions may contribute to the deleterious effects reported by bath salt users. Together, these findings have shown that the composition of bath salts preparations can significantly influence their psychostimulant and toxic effects, substantiating the importance of modeling bath salts as drug mixtures.
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Stice, Szabina A. "Speciation, Metabolism, Toxicity, and Protein-binding of Different Arsenic Species in Human Cells." FIU Digital Commons, 2014. http://digitalcommons.fiu.edu/etd/1203.
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Despite of its known toxicity and potential to cause cancer, arsenic has been proven to be a very important tool for the treatment of various refractory neoplasms. One of the promising arsenic-containing chemotherapeutic agents in clinical trials is Darinaparsin (dimethylarsinous glutathione, DMAIII(GS)). In order to understand its toxicity and therapeutic efficacy, the metabolism of Darinaparsin in human cancer cells was evaluated. With the aim of detecting all potential intermediates and final products of the biotransformation of Darinaparsin and other arsenicals, an analytical method employing high performance liquid chromatography inductively coupled mass spectrometry (HPLC-ICP-MS) was developed. This method was shown to be capable of separating and detecting fourteen human arsenic metabolites in one chromatographic run. The developed analytical technique was used to evaluate the metabolism of Darinaparsin in human cancer cells. The major metabolites of Darinaparsin were identified as dimethylarsinic acid (DMAV), DMAIII(GS), and dimethylarsinothioyl glutathione (DMMTAV(GS)). Moreover, the method was employed to study the conditions and mechanisms of formation of thiol-containing arsenic metabolites from DMAIII(GS) and DMAV as the mechanisms of formation of these important As species were unknown. The arsenic sulfur compounds studied included but were not limited to the newly discovered human arsenic metabolite DMMTAV(GS) and the unusually highly toxic dimethylmonothioarsinic acid (DMMTAV). It was found that these species may form from hydrogen sulfide produced in enzymatic reactions or by utilizing the sulfur present in protein persulfides. Possible pathways of thiolated arsenical formation were proposed and supporting data for their existence provided. In addition to known mechanism of arsenic toxicity such as protein-binding and reactive oxygen formation, it was proposed that the utilization of thiols from protein persulfides during the formation of thiolated arsenicals may be an additional mechanism of toxicity. The toxicities of DMAV(GS), DMMTAV, and DMMTAV(GS) were evaluated in cancer cells, and the ability of these cells to take the compounds up were compared. When assessing the toxicity by exposing multiple myeloma cells to arsenicals externally, DMMTAV(GS) was much less toxic than DMAIII(GS) and DMMTAV, probably as a result of its very limited uptake (less than 10% and 16% of DMAIII(GS) and DMMTAV respectively).
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Rafael, Venson. "Hollow-fibre liquid-phase microextraction : investigation into the potential use in clinical and forensic toxicology." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8697/.
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Hollow-fibre liquid-phase microextraction (HF-LPME) was introduced in 1999 as a miniaturised version of liquid-liquid extraction (LLE) in order to reduce the consumption of organic solvents and offer an environmentally-friendly approach to extraction procedures. Since then, several studies have been published in the field of forensic and clinical toxicology applying the technique to a broad range of analytes; however more studies are necessary regarding its applicability to bioanalyses. The principle of HF-LPME is the extraction of analytes across a thin supported liquid membrane within the walls of a hollow fibre from a donor phase (DP) into an acceptor phase (AP). It is an extraction technique that encompasses several parameters that require optimisation for an efficient method; this is most effectively achieved by utilising a design of experiment (DoE) approach rather than the conventional one-factor-at-a-time (OFAT) approach. The main aim of this work is to further investigate the applicability of HF-LPME to the fields of forensic and clinical toxicology by developing and validating methods to extract various drugs from different biological matrices. Complex matrices, such as whole blood, are commonly used in forensic toxicology. Considering that not many studies have been performed on the application of HF-LPME to whole blood (only 10 up to the present day), this is an aspect that requires further investigation. For this, a fast, accurate and precise 3-phase HF-LPME method followed by LC-MS/MS analysis was developed and validated to simultaneously quantify 5 NBOMe drugs in human whole blood. NBOMe drugs are a group of substances part of the so-called “novel psychoactive substances” (NPS); drugs that have been emerging with increasing frequency over the last few years. NBOMes are associated to deaths as the causa mortis, and due to their high potency, these drugs are normally abused in micrograms. For that reason, the HF-LPME method developed had to present high sensitivity (LOD of pg/mL). The aim of the second part of this project was to challenge HF-LPME further by developing and validating methods to assess the potential application of HF-LPME in multi-drug analyses. Urine was selected as biological matrix, and the group of chosen analytes were 14 anti-hypertensive drugs and their metabolites with very different physical-chemical properties. HF-LPME has never been applied to such a broad spectrum of substances in previous bioanalytical studies. These drugs were divided into two groups (acidic and basic/neutral), and a total of four extraction methods (two for each group of analytes) were developed and optimised using chemometrics (DoE) then analysed by LC-MS/MS. Two of these methods were liquid-liquid extraction (LLE) methods that were developed and validated to be used as reference to which the two HF-LPME methods were compared. The LLE methods were sensitive, accurate, precise, and valid for application to real case samples. The HF-LPME methods presented some limitations due to the lack of isotopically-labelled analogues of each specific analyte as internal standards (IS); for non-exhaustive methods the use of these IS should be adopted as standard practise. Real urine samples from genuine patients were extracted using all 4 methods followed by LC-MS/MS analysis. By applying the methods to real case samples, it was possible to define that the HF-LPME methods were suitable for qualitative screening of urine to determine the level of compliance of patients under anti-hypertensive pharmacotherapy. However, for quantification of the drugs applying HF-LPME, further development is required to incorporate the use of isotopically labelled analogues. This study proved that HF-LPME is a potential asset not only for forensic but also for clinical toxicology. It can be a very powerful tool which, mainly due to its green-chemistry approach and pre-concentration capabilities, which allows direct injection into the analytical instrument, could potentially become a more used technique in the future. However, the analyst should be careful when developing HF-LPME methods, to bear in mind its limitations so that methods that are fit-for-purpose can be developed.
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Mishra, Murli. "EXPLORATION OF THE SRX-PRX AXIS AS A SMALL-MOLECULE TARGET." UKnowledge, 2016. http://uknowledge.uky.edu/toxicology_etds/14.
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Lung cancer is a leading cause of cancer-related mortality irrespective of gender. The Sulfiredoxin (Srx) and Peroxiredoxin (Prx) are a group of thiol-based antioxidant proteins that plays an essential role in non-small cell lung cancer. Understanding the molecular characteristics of the Srx-Prx interaction may help design the strategies for future development of therapeutic tools. Based on existing literature and preliminary data from our lab, we hypothesized that the Srx plays a critical role in lung carcinogenesis and targeting the Srx-Prx axis or Srx alone may facilitate future development of targeted therapeutics for prevention and treatment of lung cancer. First, we demonstrated the oncogenic role of Srx in urethane-induced lung carcinogenesis in genetically modified FVB mice. The Srx-null mice showed resistance to urethane-induced lung cancer. Second, we demonstrated the Srx and Prx sites important for Srx-Prx interaction. The orientation of this arm is demonstrated to cause some steric hindrance for the Srx-Prx interaction as it substantially reduces the rate of association between Srx and Prx. Finally, we carried out virtual screening to identify molecules that can successfully target Srx-Prx interaction. Multiple in-silico filters were used to minimize the number of chemicals to be tested. We identified ISO1 as an inhibitor of the Srx-Prx interaction. KD value for Srx-ISO1 interaction is calculated to be 42 nM. Together, these data helps to identify an inhibitor (ISO1) of the Srx-Prx interaction that can be further pursued to be developed as a chemotherapeutic tool.
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Lai, Kuei-Hung. "Studies on anti-leukemic terpenoids from medicinal mushrooms and marine sponges with ChemGPS-NP-based targets investigation of lead compounds." Doctoral thesis, Uppsala universitet, Avdelningen för farmakognosi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-317554.
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This thesis investigates the anti-leukemic activity of terpenoids isolated from medicinal mushrooms and marine sponges, as well as their possible targets and mechanisms of action. In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms Antrodia cinnamomea, Ganoderma lucidum, and Poria cocos, which have been used in folk medicine for centuries and also developed into several contemporary marketed products. We isolated the major and characteristic triterpenoids from these mushrooms, together with six new lanostanoids (II-1–II-6). The anti-leukemic activity of the isolates was evaluated in vitro using MTT proliferative assay and seven of them exhibited potential anti-leukemic effect. The active lead compounds were further subjected to computational analyses utilizing the ChemGPS-NP tool. We established a database for the anti-leukemic relevant chemical space of triterpenoids isolated from these three medicinal mushrooms, which could be used as a reference database for further research on anti-leukemic triterpenoids. Our results indicated that the anti-leukemic effect of the active lead compounds was mediated not only through topoisomerases inhibition but also through inhibiting DNA polymerases. The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of Carteriospongia sp. led to the isolation of two new scalarane-type sesterterpenoids (III-1 and III-2) and one known tetraprenyltoluquinol-related metabolite (III-3). All isolates exhibit an apoptotic mechanism of action against Molt 4 cells, found to be mediated through the disruption of the mitochondrial membrane potential (MMP) and inhibition of topoisomerase IIα expression. Detailed investigation of the apoptotic mechanism of action using molecular docking analysis revealed that compound III-1 might target Hsp90 protein. The apoptotic-inducing effect of III-3 was supported by in vivo experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control. In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge Luffariella sp.. Manoalide has been studied as a potential anti-inflammatory agent for the last thirty years with more than 200 publications and 40 patents. However, the configurations at positions 24 and 25 were never revealed. In the current study, ten manoalide-type sesterterpenoids (IV-1–IV-10) were isolated from Luffariella sp. and their stereoisomers at positions 24 and 25 were identified and separated for the first time. The configuration at positions 24 and 25 showed to have a significant effect on the anti-leukemic activity of manoalide derivatives, with the 24R,25S-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound IV-7 against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound IV-7 also inhibited activity against both human topoisomerases, I and II. The in vivo experiment further supported the anti-leukemic effect of IV-7 with a 66.11% tumor volume suppression compared to the control.
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Eckenrode, Joseph Michael. "DEVELOPMENT OF MITHRAMYCIN ANALOGUES WITH IMPROVED EFFICACY AND REDUCED TOXICITY FOR TREATMENT OF ETS-DEPENDENT TUMORS IN EWING SARCOMA AND PROSTATE CANCER." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacy_etds/107.
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Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor of ubiquitous SP1 transcription factor, likely inducing non-specific toxicity. In collaboration with two medicinal chemistry groups, two semi-synthetic efforts were implemented to develop novel analogues of MTM. The first effort utilized the biosynthetic product mithramycin SA (MTMSA) to modify C3-side chain. The second effort utilized an oxime linker directly formed on MTM’s C3-side chain (MTM-oxime; MTMox). Here I present the pharmacological assessment of over 75 novel MTM analogues towards selectively targeting oncogenic ETS transcription factors, like EWS-FLI1, over ubiquitous transcription factors, like SP1.
Methods: Novel MTM analogues were evaluated for selective cytotoxicity against ETS fusion-dependent cell lines. Selectively cytotoxic analogues were evaluated for inhibitory effects on several gene promoters in TC-32 reporter cell lines, a Ewing sarcoma cell line dependent on EWS-FLI1, transfected with luciferase reporter vector. Cloned reporter vectors incorporated NR0B1 (EWS-FLI1 binding), β-actin (SP1 binding) and CMV (non-specific) gene promoters. Furthermore, gene (mRNA) and protein expression changes of EWS-FLI1 and SP1, as well as regulated target genes, namely NR0B1, VEGFA and BCL-2 were evaluated with MTM analogue treatments. The MTM analogues with most selective activity in vitro were administered to mice by intravenous bolus dose for pharmacokinetic analysis. The MTM analogues with highest systemic exposure from each semi-synthetic effort, namely MTMSA-Trp-A10 and MTMox-24, were further evaluated. Metabolic stabilities in whole blood, plasma, and tumor cell matrices, and across multiple species were compared with MTM. Moreover, intrinsic hepatic clearances were estimated using mouse liver microsomes. Tumor and liver distributions were estimated in tumor bearing mice. Additionally, the effect of organic anionic transporter polypeptides (OATP) on distribution of MTM was investigated. Maximum tolerated doses were evaluated for lead MTM analogues, having both selective activities in vitro and high systemic exposure, compared to MTM. Complete blood cell counts and plasma alanine aminotransferase activity were measured to evaluate dose-dependent blood and liver toxicities, respectively. ETS fusion-dependent and non-dependent cell lines were implanted subcutaneously into immunocompromised mice for efficacy studies. Average tumor volumes and survival were tracked for mice receiving treatment, compared to MTM and vehicle treatment.
Results: Evaluation of MTM analogues from both semi-synthetic efforts revealed that conjugation of MTM C3-side chain with tryptophan (Trp) and/or phenylalanine (Phe) improved selective cytotoxicity against ETS fusion-dependent cell lines. This was highlighted by MTMSA-Trp-A2 (also refer to as MTMSA-Phe-Trp) and MTMSA-Trp-A10 (also refer to as MTMSA-Trp-Trp), with selective indices of 19.1 and 15.6, respectively, compared to MTM (1.5). Similarly, MTMox-23 (also refer to as MTMox-Phe-Trp) and MTMox-20 (also refer to as MTMox-Trp) had selectivity indices of 4.6 and 4.5, respectively. These selectively cytotoxic MTM analogues inhibited EWS-FLI1-mediated transcription 10-fold more effectively than both non-specific CMV-mediated and SP1-mediated (via β-actin promoter) transcription in TC-32 reporter cell lines. Moreover, gene (mRNA) and protein expression of EWS-FLI1 and regulated gene, NR0B1, were inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells. Similarly, SP1 and target genes, VEGFA and BCL-2, gene (mRNA) and protein expressions were also inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells.
Conjugation of Trp and/or Phe to C3-side chain of MTM increased systemic exposure in vivo. Most impressively, the addition of two Trp residues, namely MTMSA-Trp-A10 and MTMox-24 (also refer to as MTMox-Trp-Trp), resulted in systemic exposure increases of 218- and 42-fold, respectively, after intravenous (IV) bolus dose. Metabolically, tryptophan/phenylalanine conjugated MTM analogues are liable to esterase activity on carboxy-methyl functional group. Very rapid de-methylation in biological matrix was observed with MTMox-24, compared to MTMSA-Trp-A10, suggesting a regiospecific effect. However, esterase activity was limited to rodent matrices and demethylation occurred at significantly diminished rates in non-human primate and human plasma. MTM analogues were not susceptible to p450-mediated metabolism, with negligible loss in mouse liver microsome assay compared to verapamil control. MTM (1mg/kg) and MTMox-24 (6mg/kg) were detected in subcutaneously implanted (flank) LL2 tumors and liver homogenates after IV bolus dose. Interestingly, MTMSA-Trp-A10 (2mg/kg) was not. Despite a 3-fold increase in systemic exposure with rifampin oral pretreatment, an OATP inhibitor, exposure of MTM was unaffected in Oatp knockout mouse model. Exposure of MTM in liver tissue was 8.4-fold higher compared to tumor tissue with low tissue clearance. This agrees with the lack of metabolism observed in liver microsomes and may provide a mechanism for clinically observed liver toxicity.
MTMSATrp-A10 had a single maximum tolerated dose (MTD) of 0.75mg/kg, compared to 1mg/kg for MTM, administered by IV bolus. In contrast, MTM-oxime analogues (MTMox-20, -23, -24 and -25) had single maximum tolerated doses of 20 – 25mg/kg. These increased tolerances are the result of additive differences in whole blood stability, cytotoxicity and systemic exposure. At a dose of 0.75mg/kg, administered every 3 days, MTMSA-Trp-A10 did not result in an efficacious result in tumor xenograft studies. These studies remain under further investigation, but the result may indicate high plasma protein binding of MTMSA-Trp-A10 and lack of free fraction available within tumor. The most selective MTM-oxime analogue in vitro, MTMox-23, significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0025, day 16, one-way ANOVA multiple comparisons test) compared to MTM (p=0.1174, day 16) and extending survival for 17 days out of 48 days on study (p=0.0003, Log Rank (Mantel-Cox) single comparison test) with treatment at MTD every 3 days, compared to vehicle. Additionally, the MTM-oxime analogue with highest systemic exposure, MTMox-24, also significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0003, day 21, one-way ANOVA multiple comparisons test) compared to MTM (p=0.032, day 21) and extending survival for 12 days out of 37 days on study (p=0.0004, Log Rank (Mantel-Cox) single comparison test) with treatment, compared to vehicle.
Conclusion: These studies in whole highlight the importance of exposure (pharmacokinetics; PK), toxicity and efficacy (pharmacodynamics; PD) relationships. The cytotoxicity and high systemic exposure of MTMSA-Trp-A10 directly contributes to its lower tolerated dose. However, despite a similar tolerated dose to MTM, systemic exposure remains 163-fold higher at the MTD. High systemic exposure may be attributed to high plasma protein binding, but also reduces the exposure of free MTMSA-Trp-A10 within the tumor tissue, which drives the efficacious response. In contrast, the less cytotoxic and rapidly de-methylated MTM-oxime analogues allow for 25-fold higher tolerances in mice. This unique metabolism and clearance may prevent exposures required to induced systemic blood and liver toxicities induced by MTM. Moreover, at these highly tolerated doses, the initial systemic exposure at MTD is highest among analogues tested, which resulted in an efficacious response with MTMox-23 and MTMox-24 treatment in tumor xenograft models. It remains to be determined if these PK/PD relationships can be reproduced in additional animal models, including human, without inducing toxicity. Nonetheless, these initial studies in mice demonstrate that a more selective, more tolerated analogue of MTM has potential for clinical success in treating ETS fusion-dependent tumors.
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Al-Darraji, Ahmed Hamish Neamah. "AZITHROMYCIN THERAPY REDUCES CARDIAC INFLAMMATION AND MITIGATES ADVERSE CARDIAC REMODELING AFTER MYOCARDIAL INFARCTION." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacol_etds/30.
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Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, polarizes macrophages towards the reparatory phenotype. AZM has an excellent safety profile and has been approved for human use. We hypothesize that AZM reduces inflammation and improves heart function in MI.
Methods and results: In our initial studies, we demonstrated that oral free AZM (160 mg/kg daily for 7 days), initiated 3 days prior to MI, enhances post-MI cardiac recovery as a result of shifting macrophages to the reparatory state. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory and an increase in reparative macrophages, decreasing the pro-inflammatory/reparative macrophage ratio. Macrophage changes were associated with a significant decline in pro- and an increase in anti-inflammatory cytokines. Additionally, AZM treatment was correlated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the reparative phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. We designed this proof of concept study using pre-MI AZM therapy to achieve steady state levels prior to injury. Therefore, in our follow-up studies we targeted inflammatory macrophages using a non-Pegylated liposomal formulation of AZM (Lazm) which has been shown in multiple studies to promote drug efficacy and minimize off-target effects. To test the hypothesis that Lazm is more effective and safer than free AZM, low doses of free/liposomal AZM (10 or 40 mg/kg, administered intravenously) were initiated immediately after MI. We observed that Lazm induces early resolution of the post-MI inflammatory response as evidenced by switching of the activation state of monocytes/macrophages towards the reparatory phenotype. Neutrophils were substantially decreased, particularly pro-inflammatory neutrophils. Cytokine profiles were also shifted to the anti-inflammatory status with Lazm therapy. Taken together, AZM treatment resulted in a significant shift in macrophage activation towards the reparatory state. The shift in inflammatory state was accompanied by a decrease in apoptosis and infarct size in the injured heart, as well as enhanced angiogenesis and LV functional recovery in our long-term studies. In addition, Lazm was protective against off-target effects of AZM on the heart.
Conclusion: This is the first evidence of a novel and clinically-relevant therapeutic strategy to modulate post-MI inflammation. We found that AZM reduces cardiac inflammation and improves adverse cardiac remodeling after infarction via promoting a shift of macrophage activation state. The overarching significance of this work is the modulation of sterile inflammation, which can be a viable therapeutic target in many conditions including stroke and heart attack. Additionally, this is the first study to demonstrate the immune modulation properties of liposomal AZM, which has wide potential therapeutic applications beyond the cardiovascular field. Importantly, liposomal formulation of AZM is protective from its cardiac off-target effects. Our findings strongly support clinical trials using AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.
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He, Qinghao. "The Degradation of Pharmaceutical Pollutants in Wastewater Catalyzed by Chloroperoxidase and the Construction of Chloroperoxidase H105R Mutant." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2540.
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Trace amounts of pharmaceuticals have been detected in water, from nanograms per liter to micrograms per liter, and have a negatively effect in the aquatic environment and an increased potential risk of drug poisoning for human and animals. In order to address the problem, drug degradation catalyzed by chloroperoxidase (CPO) has been investigated. CPO is a heme-containing glycoprotein secreted by the fungus, Caldariomyces fumago, it catalyzes two major types of oxidations, two one-electron oxidations as catalyzed by most peroxidases and two-electron oxidations which are rare for conventional peroxidases.
Five common drugs from a variety of classes which were persistent in the environment have been studied. The metabolites of each drug were identified and the pathways of degradation were proposed. All of them were found to be 100% degradation efficiency in the CPO-H2O2-Cl- system which the catalyzation only required low concentration of CPO (normally nanomolar level) as well as relatively low concentration of H2O2 as cofactor. This degradation method is economic and highly efficient, the results of my experiment extensively support the hypothesis that CPO has a great potential in the environmental application.
A new mutant of CPO has been constructed to investigate the role of histidine 105 in the active site of distal pocket. Histidine 105 was suggested to play an essential role in modulating the chlorination activity by forming hydrogen bond with glutamic acid 183, histidine has been replaced by arginine to generate CPO H105R mutant. The construction and transformation were a success but the protein was expressed as apoenzyme, suggesting the mutagenesis to a larger arginine residue at position105 disturbed the heme incorporation.
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Valadon, Philippe. "Cytochromes P-450 et Activation Metabolique du Noyau Thiophene : exemple de l'acide tiénilique et de ses dérivés." Phd thesis, Université Pierre et Marie Curie - Paris VI, 1992. http://tel.archives-ouvertes.fr/tel-00651961.
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L'acide tiénilique (AT) est un diurétique responsable d'hépatite autoimmunes. Dans le sérum des patients on retrouve des autoanticorps (anti-LKM2) dirigés contre les cytochromes P450 impliquées dans la métabolisation de l'AT et de son isomère (TAI) La première partie concerne la détermination de la nature de l'entité réactive du TAI au moyen d'un piègeage par le mercaptoethanol. Deux sulfoxydes des dihydrothiophène ont été caractérisés qui nous permettent de proposer un sulfoxyde de thiophène. En présence d'un excès de mercaptoethanol, ces deux métabolites de piègeage évoluent en une succession de plusieurs métabolites. Afin de généraliser à l'ensemble des cytochromes P-450 , nous avons mis en évidence ce nouveau métabolisme successivement in vivo chez le rat, in vitro chez l'homme, et dans un système modèle constitué par des microsomes de levures Saccharomyces cerevisiae recombinées exprimant le P-450 IIC9 ou le P450 IIC10. Ces 2 cytochromes P450 possèdent une activité d'oxydation vis à vis de l'AT et du TAI. Dans la deuxième partie de ce travail nous avons fixé l'AT sur de la sérumalbumine de boeuf. La protéine obtenue est immunogène chez le lapin et les anticorps obtenus (anti-ATles métabolites de l'AT et du TAI fixés ) reconnaissent en Elisa de façon covalente sur les protéines microsomales. Ces anticorps seront un outil puissant pour étudier la fixation covalente des métabolites de l'AT .
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Cao, William Sam. "Characterization and application of human pluripotent stem cell-derived neurons to evaluate the risk of developmental neurotoxicity with antiepileptic drugs in vitro." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/131.
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The risks of damage to the developing nervous system of many chemicals are not known because these studies often require costly and time-consuming multi-generational animal experiments. Pluripotent stem cell-based systems can facilitate developmental neurotoxicity studies because disturbances in nervous system development can be modeled in vitro. In this study, neurons derived from embryonal carcinoma (EC) and induced pluripotent stem (iPS) cells, were first characterized to establish their suitability for developmental neurotoxicity studies. The EC stem cell line, TERA2.cl.SP-12, was differentiated into neurons that expressed voltage-gated sodium and potassium channels as well as ionotropic GABA and glutamate receptors. These cells could also fire action potentials when stimulated electronically. However spontaneous action potentials were not observed. In contrast, pre-differentiated neurons derived from iPS cells fired evoked and spontaneous action potentials. Furthermore, iPS cell-derived neurons also expressed a wide array of functional voltage- and ligand-gated ion channels. Antiepileptic drugs (AEDs) are associated with developmental neurotoxicity. These agents can cause congenital malformations, cognitive deficits and behavioral impairment in children as a result of in utero exposure. The impact of four major AEDs, namely phenobarbital, valproic acid, carbamazepine and lamotrigine, on cell viability, cell cycle and differentiation of TERA2.cl.SP-12 into neurons was studied. All AEDs tested reduced differentiating stem cell viability. Valproic acid and carbamazepine increased apoptosis and reduced cell proliferation. A brief exposure to phenobarbital, valproic acid and lamotrigine at the start of differentiation impaired the subsequent generation of neurons. Additionally, the effect of transient exposure to phenobarbital and carbamazepine on neuronal maturation of iPS-derived neurons was investigated. Exposure to both AEDs resulted in diminished membrane potentials and reduced the proportion of cells that were able to fire action potentials spontaneously in culture. The data from these studies suggest that impairments in proliferation, differentiation and maturation of neurons derived from human stem cells may be sensitive indicators of neurodevelopmental disruption by these drugs that can result from in utero exposure. Furthermore, these findings suggest that the use of human pluripotent stem cells and neurons derived from them can reduce the time, cost and the number of animals used in toxicological research.
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Wang, Yu. "Mechanistic study of aryl hydrocarbon receptor nuclear translocator (ARNT)-mediated signaling." Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/151.
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A novel aryl hydrocarbon receptor nuclear translocator (ARNT)-interacting peptide (Ainpl) was characterized from human liver cDNA library using phage display. Ainpl suppresses hypoxia inducible factor-1a (HIF-1α) signaling pathway through an ARNTdependent manner. HIF-1α is known to be overexpressed in more than 90% of solid tumors, and the inhibition of HIF-1α is proved as an effective approach to suppress tumor growth. ARNT, as the obligatory heterodimeric partner of HIF-1α for downstream gene activation, was used as a bait to screen for Ainpl. Ainpl specifically interacts with the helix-loop-helix (HLH) subdomain of ARNT, but not with HIF-1α. GFP-Ainpl is localized in both cytoplasm and nucleus, and suppresses HIF-1α signaling by two mechanisms: (1) cytoplasmic GFP-Ainp 1 retains ARNT in the cell cytoplasm and (2) nuclear GFP-Ainpl inhibits HIF-1α/ARNT heterodimerization. The suppression of Ainpl on HIF-1α signaling was reversed by introducing ARNT into the cells using transient transfection. We further utilized HIV TAT protein transduction domain to deliver 6His-TAT-Ainpl into three different cancer cell lines (Hep3B, HeLa, MCF-7), and found that 6His-TAT-Ainpl co-localizes with ARNT in the cell nucleus. 6His-TATAinpl can be detected inside the cells after 30 min of transduction, and can reach the maximum level at 2 h. 6His-TAT-Ainp 1 remained detectable in the cells up to 96 h and had a half life of 24 h after transduction. In addition, 6His-TAT-Ainp 1 suppresses HIF-1α downstream genes at both message and protein levels in a dose-dependent manner. Taken together, molecules that target the HIF-1α and ARNT interface can be developed as viable drugs to suppress HIF-1α signaling.
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Rajarathinam, Kayathri. "Nutraceuticals based computational medicinal chemistry." Licentiate thesis, KTH, Teoretisk kemi och biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-122681.
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In recent years, the edible biomedicinal products called nutraceuticals have been becoming more popular among the pharmaceutical industries and the consumers. In the process of developing nutraceuticals, in silico approaches play an important role in structural elucidation, receptor-ligand interactions, drug designing etc., that critically help the laboratory experiments to avoid biological and financial risk. In this thesis, three nutraceuticals possessing antimicrobial and anticancer activities have been studied. Firstly, a tertiary structure was elucidated for a coagulant protein (MO2.1) of Moringa oleifera based on homology modeling and also studied its oligomerization that is believed to interfere with its medicinal properties. Secondly, the antimicrobial efficiency of a limonoid from neem tree called ‘azadirachtin’ was studied with a bacterial (Proteus mirabilis) detoxification agent, glutathione S-transferase, to propose it as a potent drug candidate for urinary tract infections. Thirdly, sequence specific binding activity was analyzed for a plant alkaloid called ‘palmatine’ for the purpose of developing intercalators in cancer therapy. Cumulatively, we have used in silico methods to propose the structure of an antimicrobial peptide and also to understand the interactions between protein and nucleic acids with these nutraceuticals.QC 20130531
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Stamatkin, Christopher W. "PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) AS A THERAPEUTIC TARGET IN NSCLC." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/58.
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Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using isoform-specific inhibitors in a lung cancer model system. Treatment of non-small cell lung cancer (NSCLC) cell lines with PIK3CA, PIK3CB, PIK3CD or PIK3CB/D inhibitors resulted in pharmacokinetic and pharmacodynamic responses that frequently tracked with a specific mutation status. Activation of PIK3CA dictated response to the PIK3CA-specific inhibitor while deletion of PTEN phosphatase indicated response to the PIK3CB inhibitor. The PIK3CD isoform-specific inhibitors lacked efficacy in all NSCLC cell lines tested, however treatment at increased concentrations likely provide concurrent inhibition of both PIK3CB/D isoforms improving activity of either agent alone but did not track with a single biomarker. The observed pharmacodynamic and proliferation responses to isoform-specific inhibitors suggested that PI3K isoforms may functionally compensate for loss of another in certain genetic backgrounds. These studies demonstrate unanticipated cellular responses to PI3K isoform inhibition in NSCLC, suggesting that patient populations with specific mutations can benefit from certain isoform-selective inhibitors, or combinations, allowing for rational and targeted clinical use of these agents.
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Shi, Dong-Fang. "The medicinal chemistry of antitumour benzazoles." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283645.
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Brown, Stacy D., Andy Coop, Paul Trippier, and Eric Walters. "Contemporary Approaches For Teaching Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5251.
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As the profession of pharmacy has transitioned from a chemistry-centered profession to a patient-centered profession, the role of medicinal chemistry in the curriculum has evolved. There is decreased emphasis on memorization of chemical structures, and priority placed on relating these structures to ADME, physical properties, and pharmacodynamics. Simultaneously, the delivery of this content has shifted from traditional lecture format to other styles. Here we discuss some new approaches to teaching medicinal chemistry.
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Brown, Dustin Paul. "TARGET-DIRECTED BIOSYNTHETIC EVOLUTION: REDIRECTING PLANT EVOLUTION TO GENOMICALLY OPTIMIZE A PLANT’S PHARMACOLOGICAL PROFILE." UKnowledge, 2015. http://uknowledge.uky.edu/neurobio_etds/13.
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The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity at this therapeutic target, i.e. the human DAT. This was achieved by expressing the human DAT protein in transgenic plant cells and selecting gain-of-function mutants for survival on medium containing a neurotoxin that is accumulated by the human DAT. This created a sub-population of mutants with increased DAT inhibitory activity. Some of the active metabolites in these mutants are novel (i.e. not detectable in wild-type cells). Others are cytoprotective, and also protect DAergic neurons against the neurotoxin. This provides proof-of-concept for a novel plant drug discovery platform, which is applicable to many different therapeutic target proteins and plant species.
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Park, Sung H. "High Affinity Block of ICl,swell by Thiol-Reactive Small Molecules." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4433.
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Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of ICl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking ICl,swell. Our experiments showed that 45 nM Ebs can fully block ICl,swell thus suggesting an apparent IC50 result, we predicted Ebs to possess a high kon with a low koff close to zero. As predicted, Ebs failed to washout in the timescale covered by our patch-clamp experiments. The block was also distal to H2O2, previously considered as the most proximate regulator of ICl,swell. And based on further evidence demonstrating irreversible block of ICl,swell distal to H2O2 with Ebs congeners, complete suppression of native ICl,swell with MTS reagents, and failure of Ebs to block ICl,swell from the cytosol, we concluded that Ebs and its congeners can covalently modify important –SH groups required for current activation while functioning as sulfhydryl reagents. Complete irreversible block of ICl,swell with 110 mM cell impermeant MTSES in native DI TNC1 astrocytes contrasts sharply to SWELL1 (Qiu et al., 2014) or LRRC8A (Voss et al., 2014), the latest molecular entity presumably responsible for ICl,swell, where 3.33 mM MTSES failed to demonstrate block of ICl,swell in the wild-type stably expressing SWELL1 (Qiu et al., 2014). Our data with Ebs, its congeners, and MTS reagents indicate the existence of a common extracellular binding site which involves a selenenylsulfide (Se-S) bond that critically modulates ICl,swell. We, therefore, synthesized a derivative of Ebs called ebselen-para-yne (Ebs-p-yne), which provided an even higher affinity for blocking ICl,swell with a presumed IC50 ~picomolar range. Ebs-p-yne is a promising novel molecule that may serve as a tag in identifying the molecular fingerprint ultimately responsible for ICl,swell. Furthermore, we can take advantage of click chemistry to ultimately pull out the channel or channel component which has remained elusive for greater than two decades.
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Akay, Senol. "Diagnosis and Inhibition Tools in Medicinal Chemistry." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/chemistry_diss/41.
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Cell surface saccharides are involved in a variety of essential biological events. Fluorescent sensors for saccharides can be used for detection, diagnosis, analysis and monitoring of pathological processes. The boronic acid functional group is known to bind strongly and reversibly to compounds with diol groups, which are commonly found on saccharides. Sensors that have been developed for the purpose of saccharide recognition have shown great potential. However, they are very hydrophobic and this lack of essential water-solubility makes them useful in biological applications. The first section of this dissertation details the process of developing water-soluble saccharide sensors that change fluorescent properties upon binding to saccharides. The second section of the dissertation focuses on the development of DNA-minor groove binders as antiparasitical agents. Parasitical diseases comprise some of the world’s largest health problems and yet current medication and treatments for these parasitical diseases are often difficult to administer, costly to the patients, and have disruptive side effects. Worse yet, these parasites are developing drug resistance, thus creating an urgent need for new treatments. Dicationic molecules constitute a class of antimicrobial drug candidates that possess high activity against various parasites. The second section details the development of a series of di-cationic agents that were then screened in in vitro activities against parasitical species.
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Brown, Stacy D. "Using Guided Inquiry to Teach Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/5249.
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Kristovich, Robert Lee. "Chemistry and toxicology of respirable airborne particulates." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1100898370.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xvii, 260 p.; also includes graphics (some col.). Includes bibliographical references (p. 242-260).
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Gal, Aharon. "The toxicology of nitric oxide In vitro." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/39614.
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Lunga, Mayibongwe J. "A medicinal chemistry study in nitrogen containing heterocycles." Thesis, Rhodes University, 2018. http://hdl.handle.net/10962/63521.
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Elboray, Elghareeb Elshahat Elghareeb. "Catalytic cascades creating novel architecture for medicinal chemistry." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/8036/.
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The thesis comprises five chapters. Chapter one, the introduction, starts with a brief discussion of the more famous Pd catalysed reactions and their relevance to Pd as a catalyst in allene chemistry. The main part of the introduction reviews the recent work in Pd catalysed allene chemistry (formation of C-C, C-O and C-N bonds) and its importance in both synthetic and natural product syntheses. The second chapter “results and discussion” discusses the author own work including the selection of a broad series of novel substrates chosen to enable a wide range of multicomponent cascades to be designed. These cascades enable the combination of 3, 4, 5, 7 and 9 substrates in a regio and stereoselective manner delivering novel products that enabled exploration of “biochemical space”. In all cases 1-4 Z-double bonds are created stereoselectively. These strategies are applied to the novel synthesis of potentially bioactive heterocycles including those derived from reactions of the rigid adamantyl tecton involving formation of eight new bonds. The third chapter “results and discussion” summarises preliminary work on 1,3-dipolar cycloaddition generating pyrimidinylpyrrolidine. The fourth chapter contains the experimental details of all new compounds.
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Li, Ju-Yun. "Quantitative structure-activity relationship studies in medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062596938.
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Waghela, M. B. "Pyrrolizine derivatives of potential medicinal interest." Thesis, De Montfort University, 1986. http://hdl.handle.net/2086/13287.
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Njaria, Paul Magutu. "Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26954.
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Tuberculosis (TB) is a life-threatening infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, TB is a major public health burden with an estimated 10.4 million new cases and 1.8 million deaths reported in 2015. Although TB is curable, the treatment options currently available are beset by numerous shortcomings such as lengthy and complex treatment regimens, drug-drug interactions, drug toxicities, as well as emergence of widespread multi-drug resistance. Therefore, there is an urgent and compelling need to develop new, more effective, safer drugs with novel mechanisms of action, and which are capable of shortening treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had previously been identified through phenotypic whole-cell in vitro screening.
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Chen, Dianne Tzu-Hsiu. "Phytochemical studies on traditional medicinal plants with antimalarial activities." Master's thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/21853.
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The active antimalarial principles of three traditional medicinal plants, Passerina obtusifolia (Thymelaeaceae), Tetradenia riparia (Labiatea) and Xerophyta retinervis (V elloziaceae) were investigated by employing bioassay guided fractionation. Two novel compounds and five known constituents were isolated from the active fractions of these three plants. The types of compounds isolated included: three triterpenoids (20(29)-Lupene-3α,28- diol (30), 20(29)-Lupene-3α, 16β,28-triol (32) and 3β-Hydroxy-20(29)-Lupen-28-oic acid (42)); two diterpenoids (8-Abietene-7 β,13 β -diol (45) and cariocal (51)); one flavonoid ( 5-Hydroxy:.4' ,6, 7-trimethoxyflavone ( 44)) and one flavonolignan ( 11-0- acetyl hydnocarpin (62)). In addition, one analogue of 7α-hydroxyroyleanone (41) (which was previously isolated from T riparia and was found to be the active antimalarial principle of the plant) was prepared.
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Ni, Nanting. "Application of Boronic Acids in Medicinal Chemistry (Inhibitors, Sensors)." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/chemistry_diss/34.
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It is well known boronic acids have its unique chemistry and related applications in organic synthesis. The boronic acid functionally group also plays very important roles in medicinal chemistry and chemical biology. For example, boronic acids have been developed as potential therapeutic agents, chemical biology tools. All these applications are directly related to the unique electronic and chemical properties of the boronic acid group. Herein, several application of boronic acids have been studied: 1) several groups of compounds were found as bacterial quorum sensing inhibitors; 2) a boronate compound was developed as a probe for detecting reactive oxygen species (ROS); and 3) boronic acid-modified aptamers can be used for glycoprotein recognition.
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Baxter-Jones, C. S. "Some aspects of the medicinal chemistry of immunomodulatory compounds." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235379.
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Foster, R. W. "Sustainable approaches to novel heterocyclic scaffolds for medicinal chemistry." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1470876/.
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This thesis investigates new methods for the environmentally sustainable synthesis of heterocyclic scaffolds for application in medicinal chemistry. Chapter I introduces general principles of sustainability in synthetic organic chemistry. This includes the characterization and application of sustainable solvents and the use of biomass feedstocks in synthesis. Chapter II explores the synthesis of substituted isoindolinones via a ruthenium-catalyzed alkyne cyclotrimerization. The introduction details the synthesis and medicinal application of isoindolinones and describes previous research involving alkyne cyclotrimerizations. Following this, the development of a regioselective alkyne cyclotrimerization reaction in a sustainable solvent is reported. The optimized alkyne cyclotrimerization conditions are then used to synthesize a selection of isoindolinone products. Chapter III describes the application of a kinetically-controlled furan-Diels–Alder reaction to the synthesis of heterocyclic scaffolds, including the endo-cantharimide. The study and application of furan-Diels–Alder reactions are introduced. Following this, the Diels–Alder reaction of a 3-alkoxyfuran under sustainable reaction conditions is explored experimentally and applied to the diastereoselective synthesis of endo-cantharimides. The potential application of endo-cantharimides in medicinal chemistry is discussed with the aid of biological testing and the Diels–Alder reactions of 3-alkoxyfurans is probed with the aid of computational calculations. Chapter IV concerns the cyclization of reducing sugars to prepare chiral tetrahydrofurans. The role of tetrahydrofurans in medicinal chemistry, the synthesis of tetrahydrofurans from sugar derivatives and the application of hydrazones in synthetic chemistry are introduced. Following this the development of a hydrazone-mediated cyclization of L-arabinose under sustainable reaction conditions is reported. The optimized conditions are applied to prepare tetrahydrofurans from other sugars. The manipulation of the tetrahydrofuran products is also explored. Chapter V draws some general conclusions from the thesis and describes potential future directions for the research. Chapter VI contains the details of experimental procedures and compound characterization for the results discussed in Chapters II–IV.
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Sherer, Christopher. "A multidisciplinary investigation into the design, synthesis and evaluation of a novel class of anti-glioblastoma drug fragments." Thesis, University of Central Lancashire, 2017. http://clok.uclan.ac.uk/20462/.
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Cancer is the second biggest global killer,[1,2] with cancers of the brain and central nervous system accounting for a disproportionately high number of deaths.[3] The most prolific cancer of the central nervous system is glioblastoma, for which prognosis is still very poor. In this project, analogues of two lead compounds with known activity against glioblastoma cell lines (compounds 4 and 5, Figure 1) were produced in order to develop structure-activity relationships and discover compounds with superior activities against glioblastoma. Figure 1 - The structures of the lead compounds 4 and 5 Analogues of compound 4 were the result of a rigorous similarity search of the ZINC database,[4,5] as well as using chemical intuition to identify potential analogues. A scaffold-hopping approach was undertaken, through which two new compound classes were identified as potentially superior lead compounds for future work (Figure 2). Figure 2 - The structures of two analogues of compound 4 with different scaffolds and superior activity, compounds 168 and 214 Compound 4 is known to induce cell death through the induction of elevated levels of cellular reactive oxygen species (ROS),[6] which may be formed via the radical form of compound 4 and its analogues. The connection between the anticancer activity of 4 and its analogues with the propensity of these compounds to form radicals was also investigated. Enthalpic values relevant to radical formation (BDE, AIP, PDE, PA and ETE) were calculated using a density functional theory (DFT) approach. Although no strong correlation was found for the whole series of compounds, the data indicates that correlations may exist within certain structural classes. The anticancer activity of compound 5, a prodrug, was compared against 11 analogues of both the prodrug and active form of the compound (Scheme 1). It was found that compound 9 has superior activity to that of the prodrug 5. Substitutions at the N-position of 5 were also found to have a significant effect on activity, with an N-tosyl analogue having significantly improved activity against glioblastoma cell lines and short term cultures. The results obtained suggest that future work on this series should therefore be based around compound 9, a subclass of indoles that have wide ranging anticancer activity, but have not yet been reported against glioblastoma. Scheme 1 - The degradation of 5 into its suspected active form (9) In conclusion, analogues were discovered within this project which improved upon the anticancer activity of both compounds 4 and 5. For compound 4, two alternative scaffolds were identified as superior and novel lead compounds against glioblastoma, and there is some indication that there may be a correlation between radical formation and anticancer activity within specific structural classes of this functional class of compounds. For prodrug 5, substituents at the N positon were found to have a significant effect on activity, and the activity of the active form (9) was found to be superior to the activity of the prodrug.
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Orrling, Kristina M. "On the Versatility of Microwave-Assisted Chemistry : Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101356.
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Yu, Wenyuan. "Reaction Mechanisms and Synthesis of Oxidized Lipids." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1377387469.
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Duffin, Roger. "Molecular toxicology studies on the quartz hazard." Thesis, Edinburgh Napier University, 2003. http://researchrepository.napier.ac.uk/Output/2777.
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Silicon makes up almost 28% of the Earth's crust and within that crust, quartz (crystalline silica) is one of the most abundant minerals. Exposure to quartz can occur in a number of occupations, including the mining and construction industries in which respirable quartz particles are generated and become airborne. Inhalation of quartz can lead to the fibrosing lung disease silicosis and cancer. Silicosis has been recognised for many decades as one of the most prevalent occupational lung diseases. In 1997, an IARC working Group classified quartz as a class 1 lung carcinogen, but only in some industries, suggesting that the quartz hazard is a variable entity. The reactivity of the quartz surface may underlie its ability to cause inflammation and treatments that ameliorate this reactivity would then reduce the quartz hazard. In the present study the effect of treating quartz with aluminium lactate, a procedure reported to decrease the quartz hazard, on the highly reactive quartz surface and on proinflammatory events in the rat lung were explored. Aluminium lactate-treated quartz showed a reduced surface reactivity as measured by electron spin resonance. Eighteen hours post-instillation of quartz into the rat lung, there was massive inflammation as indicated by the number of neutrophils in the bronchoalveolar lavage (BAL) and an increase in BAL macrophage inflammatory protein-2 (MIP-2). However, aluminium lactate-treated quartz had no significant effect when compared to control. Epithelial damage as indicated by BAL protein and gamma glutamyl transpeptidasea lso increased with quartz instillation but not with aluminium lactate-treated quartz and furthermore, quartz induced an increase in MIP-2 mRNA content of BAL cells while aluminium lactate-treated quartz had no effect compared to controls. There was an increase in nuclear binding of the transcription factor nuclear factor-kappa B (NF-xB) in the quartz exposed BAL cells and again, no effect on nuclear NF-xB binding in BAL cells from aluminium lactate-treated quartz instilled rats. In addition, the effect of aluminium lactate and PVNO quartz treatment on DNA damage, cell cytotoxicity and particle uptake by A549 cells was assessed. DNA strand breakage, as produced by quartz at non-toxic concentrations, could be completely prevented by both coating materials. Particle uptake by A549 cells appeared to be significantly inhibited by the PVNO coating, and to a lesser extent by the aluminium lactate coating, demonstrating that respirable quartz particles induce oxidative DNA damage in human lung epithelial cells and indicating that the surface properties of the quartz as well as particle uptake by these target cells are important in the cytotoxic and genotoxic effects of quartz in vitro. Finally, the role played by surface area and specific reactivity in the acute inflammatory response to particles was investigated. Acute inflammatory response following instillation of particles has been used to evaluate hazard but has been criticised because of the non-physiological delivery and the problems of local overload. Here, a number of low toxicity dusts of various particle sizes were instilled and the neutrophil influx into the lung 18-24 hours post-instillation assessed. The extent of inflammation was shown to be a function of the surface area instilled and ultrafine particles, which present a case of high surface area per unit mass, were inflammogenic pro rata with their surface area. There is no evidence that ultrafine particles of carbon black, titanium dioxide or polystyrene have any special reactivity in addition to their large surface area. We further tested whether this approach could be used to model the reactivity of highly toxic dusts. Rats were instilled with either quartz or aluminium lactate-treated quartz and, as anticipated, the high specific surface reactivity of quartz meant that it was much more inflammogenic than was predicted using the relationship described for `low toxicity' dusts. This approach represents the possibility of modelling potential toxicity for nuisance dusts based on the inflammatory response of a given instilled surface area dose.
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Di, Martino Giovanni Paolo <1985>. "Computational Methods in Biophysics and Medicinal Chemistry: Applications and Challenges." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6329/.
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In this thesis I described the theory and application of several computational methods in solving medicinal chemistry and biophysical tasks. I pointed out to the valuable information which could be achieved by means of computer simulations and to the possibility to predict the outcome of traditional experiments. Nowadays, computer represents an invaluable tool for chemists.
In particular, the main topics of my research consisted in the development of an automated docking protocol for the voltage-gated hERG potassium channel blockers, and the investigation of the catalytic mechanism of the human peptidyl-prolyl cis-trans isomerase Pin1.
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Holloway, C. M. "Aspects of the medicinal chemistry associated with the ergopeptide alkaloids." Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373332.
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Brown, Stacy D. "A Process-Oriented Guided Inquiry Approach to Teaching Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2010. https://doi.org/10.5688/aj7407121.
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Objective: To integrate process-oriented guided-inquiry learning (POGIL) team-based activities into a 1-semester medicinal chemistry course for doctor of pharmacy (PharmD) students and determine the outcomes.
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Chau, Yasmin-Pei(Yasmin-Pei Kamal). "Biosynthesis and medicinal chemistry of therapeutically promising plant natural products." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122839.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
Modern molecular biology, biochemical, and chemical techniques have made it possible to identify individual natural products that possess pharmacological activity from medicinal plants. While approximately 50% of all new FDA-approved small molecule therapeutics in the past 40 years were natural products or natural product analogs, challenges including limited natural resources and the difficulty of solving the total synthesis or semi-synthesis of natural products has limited our ability to harness the full diversity of chemical structures provided by nature to treat human diseases. One solution to these challenges is the elucidation of plant specialized metabolite biosynthetic pathways. Identifying and characterizing the enzymes involved in specialized metabolite biosynthesis will provide insight into the evolution of enzymes performing interesting chemistries and provide new tools for the enzymatic production of therapeutically promising natural products. The goal of this dissertation is to explore the aspects of both medicinal chemistry and the elucidation of biosynthetic pathways that can contribute to the development of novel therapeutics. First, we analyzed the structure-activity relationship of analogs of the the flavonoid icariin and identified analogs with improved potency in inhibiting human phosphodiesterase-5. We subsequently identified and characterized a novel flavonoid prenyltransferase and O-methyltransferase from the medicinal herb Epimedium sagittatum that is known to produce many bioactive prenylated and methylated flavonoids.
by Yasmin-Pei Chau.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
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Srivastava, Sanjay. "Structure-activity relationship studies in medicinal chemistry and drug design." Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1056054628.
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Baig, Ghouse U. "The medicinal chemistry of bicyclic systems containing a NNN bond." Thesis, Aston University, 1986. http://publications.aston.ac.uk/12464/.
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Rafael, Christopher Carlos Ferreira. "Synthesis of chromium carbene scaffolds for use in medicinal chemistry." Thesis, Rhodes University, 2014. http://hdl.handle.net/10962/d1010863.
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This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.
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Schwehm, Carolin Maria. "Synthesis of 3-dimensional scaffolds for application in medicinal chemistry." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/32362/.
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In this thesis the successful synthesis of a novel tricyclic scaffold containing a ring fused triazole and piperidine will be discussed and furthermore its utility as a new potential privileged structure will be evaluated. As starting material for the synthesis of the considered scaffolds the commercially available ethyl 4-oxopiperidine-1-carboxylate 108 was used. Piperidone 108 was converted into scaffolds 96, 97 and 98 alternating the ring size (n=1, 2, 3) of the fused bicyclic ring. This tricyclic triazole scaffold was incorporated into known biologically active molecules (Sitaglitpin, a DPP-4 inhibitor; Maraviroc, a CCR-5 receptor antagonist and GDC-0941, a pi3K inhibitor) to test its potential to serve as a new possible Privileged Scaffold. Through scaffold hopping, analogues with excellent biological activity against the chosen biological targets were achieved. Additionally, the stereoselective synthesis of one of the four possible isomers of the tricyclic triazole 178 was obtained in 4 steps to give the synthetically access towards the synthesis of all feasible enantiomeric and diastereomeric analogues.
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Lima, Barbosa Ana Soraya. "Organometallic compounds of tin and ruthenium : applications in medicinal chemistry." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAF029.
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Nous avons synthétisé des composés d'étain avec des acides undécylénique, ricinoléique et caprylique. Ils ont une activité importante contre certaines souches de microrganismes, puisque ils agissent pour certains d’entre eux à des concentrations nanomolaires. Staphylococcus aureus semble être 4000 fois plus sensible à leur toxicité que les cellules de mammifères. Nous avons obtenu des composés du ruthénium qui présentent cytotoxicité contre des cellules cancéreuses suivant un mécanisme d'action différent de ceux observés pour le Cisplatine ou d'autres composés de Ru, grâce à leur grande stabilité dans les réactions de substitution. Enfin, pendant la vectorisation des composés dérivés du Ru avec une Affitine nous avons pu acquérir des connaissances importantes sur un éventuel mécanisme d'action de ce type de molécules dont le potentiel redox très abaissé par rapport aux composés correspondants pourrait être responsable de la polymérisation de protéines cibles par transfert d’électronRelated to antimicrobial research, we synthesized tin compounds derived from undecylenic, ricinoleic and caprylic acids and we found that they show very high activity against some strains of bacteria and yeast, even in nM range, being up to four thousand times more potent against Staphylococcus aureus than against mammalian cells. For ruthenium compounds, in turn, we have confirmed that the mode of action of some compounds that were synthesized recently is undoubtedly different from Cisplatin or other ruthenium compounds, because of their high stability toward substitution reactions. Finally, during the vectorization of compounds derived from Ru with Affitin we have gained important knowledge about a possible mechanism of action of this type of molecule: it could indeed be possible that these compounds which have a very reduced redox potential compared to corresponding compounds can cause polymerization of proteins by electron transfer
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Thompson, Meghan L. "Physicochemical and Structural Analysis of Polymers as Putative Drugs." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4061.
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Sulfated low molecular weight lignins (LMWLs) have shown good activity as anticoagulants by allosterically inhibiting thrombin, as well as promising agents for treating emphysema through inhibition of elastolysis, oxidation, and inflammation. Sulfated LMWLs are chemo-enzymatically synthesized from starting monomers caffeic, ferulic, and sinapic acid into sulfated dehydropolymers known as CDS, FDS, and SDS. To further the LMWLs’ development as drugs, their structural composition and physicochemical characteristics were defined in this work. The molecular weight distribution profile of the sulfated LMWLs from size exclusion chromatography performed on a high pressure liquid chromatography system (SEC-HPLC) changed from bimodal when no surfactant is used in the mobile phase of the HPLC to unimodal when surfactant is used in the mobile phase. This indicates that some large molecular weight species, likely an aggregate of smaller molecular weight chains, are disrupted when surfactant is present. The resulting estimates of molecular weight calculated when surfactant is used in the mobile phase resulted in peak average molecular weights of 5700 Da for CDS, 7400 Da for FDS, and 4300 Da for SDS. These molecular weights are 17-45% higher and can be considered more accurate than the previously reported molecular weights (CDS: 3320 Da, FDS: 4120 Da, SDS: 3550 Da) because they were measured directly whereas previous estimates were calculated from GPC-HPLC data of the unsulfated LMWL precursors. Elemental analysis and distribution coefficient measurements were also performed on the LMWL library, revealing information about the level of sulfation and hydrophobic character of the sulfated LMWLs.
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MacGregor, James Orrock. "Some chemistry of muconaldehyde pertinent to the toxicology of benzene." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261267.
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Segretti, Natanael Dante. "Planejamento e síntese de tuberculostáticos potenciais com base na estrutura de maltosiltransferase (GlgE) de Mycobacterium tuberculosis." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-24042017-101741/.
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A tuberculose (TB) é uma doença infectocontagiosa causada principalmente pelo Mycobacterium tuberculosis (Mtb). A TB era uma doença considerada em vias de extinção, porém sua incidência voltou a aumentar devido a diversos fatores, como o fluxo migratório dos chamados \"Países Reservatórios\" e a pandemia da AIDS. Em 2013, a OMS estimou 9 milhões de novos casos de TB e 1,5 milhões de mortes. A multirresistência aos quimioterápicos disponíveis justifica a procura por novos tuberculostáticos. Face ao exposto, o trabalho objetivou a síntese de potenciais inibidores da maltosiltransferase (GlgE), um novo e promissor alvo contra o Mtb, utilizando Planejamento com base na Estrutura do Alvo Molecular -- Structure-Based Drug Design (SBDD). A comparação das simulações de dinâmica molecular do sistema apo da GlgE e em complexo com a maltose-1-fosfato (M1P) mostrou as mudanças estruturais, em nível atômico, decorrentes da ligação com seu substrato. Levando em consideração estes dados, as simulações de docking dos potenciais inibidores revelaram que análogos glicosídicos e maltosídicos triazólicos ligados a grupos aromáticos substituídos possuem melhores perfis de interação com o sítio ativo da GlgE e, por essa razão, foram escolhidos para síntese. Assim, sintetizaram-se análogos glicosídicos e maltosídicos através da click chemistry, obtendo-se rendimentos variados. Posteriormente, realizaram-se ensaios enzimáticos e microbiológicos no Institute for Tuberculosis Research (ITR), University of Illinois at Chicago, USA. Apesar de os ensaios enzimáticos estarem em andamento, os compostos ensaiados apresentaram atividades que variaram de moderada a fraca, frente à cepa H37Rv. Dois compostos glicosídicos exibiram valores de Concentração Inibitória Mínima (CIM) inferiores a 60 µM, sem efeito citotóxico em células VERO em concentrações superiores a 250 µM. Tais resultados indicam que o análogo glicosídico triazólico aromático, como o NDS 112, pode ser utilizado como protótipo interessante para o planejamento de novas séries de compostos capazes de atuar como tuberculostáticosTuberculosis (TB) is an contagious infectious disease mainly caused by Mycobacterium tuberculosis (Mtb). TB was a disease considered in extinction, but its incidence has risen again due to several factors, such as the migration from \"Reservatoir Countries\" and AIDS pandemic. In 2013, WHO estimated 9 million new TB cases and 1.5 million deaths. Multidrug resistance to drugs available in chemotherapy validates the search for new TB drugs. In this context, this work aimed to the design and synthesis of potential inhibitors of maltosyltransferase (GlgE), a new and promissor target against Mtb using Structure-Based Drug Design. Comparison between molecular dynamic simulations of GlgE apo system and in complex with maltose-1-phosphate (M1P) showed important structural changes at molecular level due to substrate binding. Considering these data, docking simulations of potential inhibitors revealed that glucoside and maltoside triazoles analogues bound to substituted aromatic groups have better interaction profiles with the GlgE active site and for this reason they were chosen for synthesis. Thus, glucoside and maltoside triazole analogues were synthetized through click chemistry with different yields. Then, enzymatic and microbiological assays were performed at Institute for Tuberculosis Research (ITR), University of Illinois at Chicago, USA. Although the enzymatic assays are ongoing, componds were tested against H37Rv strains and they have shown activity ranging from moderate to weak. Two compounds presented Minimal Inhibitory Concentration (MIC) values below 60 µM, without cytotoxic effect in VERO cells in concentrations higher than 250 µM. These results indicate that glucosidic aromatic triazoles analogues, such as NDS 112, can be used as a prototype for design new series of compounds capable of acting as antituberculosis agents
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Hartman, Alwin Mathijs [Verfasser], and A. K. H. [Akademischer Betreuer] Hirsch. "New applications of dynamic combinatorial chemistry to medicinal chemistry / Alwin Mathijs Hartman ; Betreuer: A.K.H. Hirsch." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1201647282/34.
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Peterson, Kristina L. "Advances in flow extraction techniques : applications in forensic toxicology /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/11552.
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Fitzgerald, Leona. "The preparation of novel pyrrolo[2,1-c][1,4]benzodiazepine building blocks and their application to the synthesis of A-to C-ring linked PDB oligomers." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288994.
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