Relevant bibliographies by topics / Toxicology and medicinal chemistry

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  1. Journal articles
  2. Dissertations / Theses
  3. Books
  4. Book chapters
  5. Conference papers
  6. Reports

Academic literature on the topic 'Toxicology and medicinal chemistry'

Author: Grafiati
Published: 4 June 2021
Last updated: 14 February 2022

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Journal articles on the topic "Toxicology and medicinal chemistry"

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Timmerman, H., A. Bast, H. Van der Goot, N. P. E. Vermeulen, and F. J. Zeelen. "Comprehensive medicinal chemistry." Trends in Pharmacological Sciences 12 (January 1991): 167–68. http://dx.doi.org/10.1016/0165-6147(91)90535-z.

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Shaw, Subrata. "Welcome to the Journal of Medicinal Chemistry and Toxicology." Journal of Medicinal Chemistry and Toxicology 1, no. 1 (September 7, 2016): 17. http://dx.doi.org/10.15436/2575-808x.16.1079.

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Foye, William O. "Medicinal chemistry, a biochemical approach." Trends in Pharmacological Sciences 6 (January 1985): 488. http://dx.doi.org/10.1016/0165-6147(85)90230-5.

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Leeson, P. D. "Progress in medicinal chemistry. volume 29." Trends in Pharmacological Sciences 13 (January 1992): 451–52. http://dx.doi.org/10.1016/0165-6147(92)90144-u.

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Jyoti, Divya Dheer, Davinder Singh, Gulshan Kumar, Manvika Karnatak, Suresh Chandra, Ved Prakash Verma, and Ravi Shankar. "Thymol Chemistry: A Medicinal Toolbox." Current Bioactive Compounds 15, no. 5 (January 3, 2019): 454–74. http://dx.doi.org/10.2174/1573407214666180503120222.

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Background: Thymol is a natural phenolic monoterpenoid widely used in pharmaceutical and food preservative applications. Thymol isomeric with carvacrol, extracted primarily from Thymus species (Trachyspermum ammi) and other plants sources such as Baccharisgrise bachii and Centipeda minima, has ethnopharmacological characteristics. <p></p> Methods: This review was prepared by analyzing articles published on thymol moiety in last decade and selected from Science Direct, Scopus, Pub Med, Web of Science and SciFinder. The selected articles are classified and gives brief introduction about thymol and its isolation, illustrates its natural as well as synthetic sources, and also therapeutic benefits of thymol worldwide <p></p> Results: Thymol has been covering different endeavors such as antimicrobial, antioxidant, antiinflammatory, antibacterial, antifungal, antidiarrhoeal, anthelmintic, analgesic, digestive, abortifacient, antihypertensive, spermicidal, depigmenting, antileishmanial, anticholinesterase, insecticidal and many others. This phenolic compound is among the essential scaffolds for medicinal chemists to synthesize more bio-active molecules by further derivatization of the thymol moiety. <p></p> Conclusion: Thymol is an interesting scaffold due to its different activities and derivatization of thymol is proved to enhance its biological activities. However, more robust, randomised, controlled clinical trials would be desirable with well-characterised thymol preparations to corroborate its beneficial effects in diseased patients. Moreover, in view of the potential use of thymol and thymol-rich essential oils in the treatment of human infections, comprehensive studies on chronic and acute toxicity and also teratogenicity are to be recommended.
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Metternich, Rainer, and Giorgio Tarzia. "Medicinal Chemistry: Defining Itself." ChemMedChem 3, no. 8 (August 18, 2008): 1147–49. http://dx.doi.org/10.1002/cmdc.200800116.

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Blomme, Eric, and Shana J. Sturla. "Chemical Toxicology and Medicinal Chemistry: A Special Issue Promoting Scientific Advances for Safer Medicines, Part 1." Chemical Research in Toxicology 33, no. 1 (January 21, 2020): 1. http://dx.doi.org/10.1021/acs.chemrestox.9b00496.

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Metternich, Rainer, and Giorgio Tarzia. "“Hot Spots” in Medicinal Chemistry." ChemMedChem 5, no. 8 (May 11, 2010): 1159–62. http://dx.doi.org/10.1002/cmdc.201000266.

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Differding, Edmond. "50 Years European Federation for Medicinal Chemistry (EFMC) – The Ascent of Medicinal Chemistry in Europe." ChemMedChem 15, no. 24 (October 29, 2020): 2338–51. http://dx.doi.org/10.1002/cmdc.202000691.

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Faruk Khan, M. O., Michael J. Deimling, and Ashok Philip. "Medicinal Chemistry and the Pharmacy Curriculum." American Journal of Pharmaceutical Education 75, no. 8 (October 10, 2011): 161. http://dx.doi.org/10.5688/ajpe758161.

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Dissertations / Theses on the topic "Toxicology and medicinal chemistry"

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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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Books on the topic "Toxicology and medicinal chemistry"

1

Neuwinger, Hans Dieter. African ethnobotany: Poisons and drugs : chemistry, pharmacology, toxicology. London: Chapman & Hall, 1996.

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Paolo, Milani, Da Ros Tatiana, and SpringerLink (Online service), eds. Medicinal Chemistry and Pharmacological Potential of Fullerenes and Carbon Nanotubes. Dordrecht: Springer Science + Business Media B.V, 2008.

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1957-, Kumar M., and Gupta V. 1966-, eds. Heterocyclic chemistry. Berlin: Springer, 1998.

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library, Wiley online, ed. Principles and Practice of Mixtures Toxicology. Weinheim: Wiley-VCH, 2010.

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Schulte, Jurgen. Fundamental Research in Ultra High Dilution and Homoeopathy. Dordrecht: Springer Netherlands, 1998.

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Albee, Sarah. Poison: Deadly deeds, perilous professions, and murderous medicines. New York: Crown Children's Books, 2017.

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Borchardt, Ronald T. Models for Assessing Drug Absorption and Metabolism. Boston, MA: Springer US, 1996.

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Staines, Henry M. Treatment and Prevention of Malaria: Antimalarial Drug Chemistry, Action and Use. Basel: Springer Basel, 2012.

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American Chemical Society. Committee on Professional Training. Directory of graduate research 1999: Faculties, publications, and doctoral and master's theses in departments or divisions of chemistry, chemical engineering, biochemistry, medicinal/pharmaceutical chemistry, clinical chemistry, polymer science, food science, forensic science, marine science, toxicology, materials science, and environmental science at universities in the United States and Canada. [Washington, DC]: American Chemical Society, 1999.

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Chambless, William. Fifty years of research and service: Haskell Laboratory for Toxicology and Industrial Medicine. Wilmington, Del: E.I. du Pont de Nemours & Co., 1985.

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Book chapters on the topic "Toxicology and medicinal chemistry"

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Anastas, Nicholas D. "Green Toxicology." In Green Techniques for Organic Synthesis and Medicinal Chemistry, 1–23. Chichester, UK: John Wiley & Sons, Ltd, 2012. http://dx.doi.org/10.1002/9780470711828.ch1.

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Heckel, Tobias, and Laura Suter-Dick. "Predictive Toxicology: Genetics, Genomics, Epigenetics, and Next-Generation Sequencing in Toxicology." In Methods and Principles in Medicinal Chemistry, 151–70. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. http://dx.doi.org/10.1002/9783527674183.ch08.

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Powley, Mark W. "CHAPTER 16. Toxicology and Drug Development." In The Handbook of Medicinal Chemistry, 413–23. Cambridge: Royal Society of Chemistry, 2015. http://dx.doi.org/10.1039/9781782621836-00413.

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Mesens, Natalie. "The Zebrafish Model in Toxicology." In Methods and Principles in Medicinal Chemistry, 217–40. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. http://dx.doi.org/10.1002/9783527674183.ch11.

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Braggio, Simone, Mauro Corsi, Aldo Feriani, Stefano Fontana, Luciana Marocchio, and Caterina Virginio. "CHAPTER 15. Discovery Toxicology In Lead Optimisation." In The Handbook of Medicinal Chemistry, 364–412. Cambridge: Royal Society of Chemistry, 2015. http://dx.doi.org/10.1039/9781782621836-00364.

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Suter-Dick, Laura, and Friedlieb Pfannkuch. "Introduction to Predictive Toxicology Tools and Methods." In Methods and Principles in Medicinal Chemistry, 1–10. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. http://dx.doi.org/10.1002/9783527674183.ch01.

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Mangiatordi, Giuseppe Felice, Angelo Carotti, Ettore Novellino, and Orazio Nicolotti. "A Round Trip from Medicinal Chemistry to Predictive Toxicology." In Methods in Molecular Biology, 461–73. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3609-0_19.

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Walz, Antje-Christine, Hans Peter Grimm, Christophe Meille, Antonello Caruso, Neil Parrott, and Thierry Lavé. "Role of Modeling and Simulation in Toxicology Prediction." In Methods and Principles in Medicinal Chemistry, 53–72. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. http://dx.doi.org/10.1002/9783527674183.ch04.

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Park, Tae-Joon, Jeffrey G. Martin, and Robert J. Linhardt. "Pharmacological Applications of Biocompatible Carbon Nanotubes and Their Emerging Toxicology Issues." In Medicinal Chemistry and Pharmacological Potential of Fullerenes and Carbon Nanotubes, 283–316. Dordrecht: Springer Netherlands, 2008. http://dx.doi.org/10.1007/978-1-4020-6845-4_12.

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Jarvis, Bruce B. "Chemistry and Toxicology of Molds Isolated from Water-Damaged Buildings." In Advances in Experimental Medicine and Biology, 43–52. Boston, MA: Springer US, 2002. http://dx.doi.org/10.1007/978-1-4615-0629-4_5.

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Conference papers on the topic "Toxicology and medicinal chemistry"

1

Ahangar, A. G., R. J. Smernik, and R. S. Kookana. "Role of the chemistry of soil organic matter on the sorption of diuron." In ENVIRONMENTAL TOXICOLOGY 2008. Southampton, UK: WIT Press, 2008. http://dx.doi.org/10.2495/etox080341.

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Benito, Elena, Rocío Recio, Belén Begines, Victoria Valdivia, Lorenzo Gabriel Borrego, Lucía Romero-Azogil, Ana Alcudia, et al. "CASE STUDY: MEDICINAL CHEMISTRY." In 10th annual International Conference of Education, Research and Innovation. IATED, 2017. http://dx.doi.org/10.21125/iceri.2017.1425.

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Chou, Kuo-Chen. "Trends in Medicinal Chemistry." In MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd edition. Basel, Switzerland: MDPI, 2017. http://dx.doi.org/10.3390/mol2net-03-04615.

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Gieré, Reto. "Mineralogy, Chemistry, and Toxicology of Particulate Emissions from Combustion Processes." In Goldschmidt2020. Geochemical Society, 2020. http://dx.doi.org/10.46427/gold2020.827.

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DAGO, Déliko. "Development of New 5-Arylidene-3-(arylmethyl)aminobutyl-2-thioxo-1,3-thiazolidine-4-one under Microwave Irradiation and Their Biological Effects on Protein Kinases and Tumoral Cell Lines." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/ecmc-1-a001.

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Donno, Dario, Maria Gabriella Mellano, Alessandro Cerutti, and Gabriele Beccaro. "Biomolecules and Natural Medicine Preparations: Analysis of New Sources of Bioactive Compounds from Ribes and Rubus spp. ." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/ecmc-1-a002.

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KOMARAGIRI, RAJESH. "Recycling of Drugs from Expired Drug Products." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2016. http://dx.doi.org/10.3390/ecmc-1-a003.

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Fruit, Corinne, Julien Godeau, Marine Harari, Sylvain Laclef, Vincent Levacher, and Thierry Besson. "Microwave-assisted C-H arylation of Quinazolin-4-one-type Precursors of Bioactive Heterocycles." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/ecmc-1-a004.

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KOMARAGIRI, RAJESH. "Recycling of Drugs from Expired Drug Products." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/ecmc-1-a005.

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Gadgoli, Chhaya, Lalit Sali, Mahesh Abhyankar, and Prachi Pathak. "Complex of zinc and lectins from seeds of Vigna radiata as potential anti-diabetic agent." In 1st International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/ecmc-1-a006.

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Reports on the topic "Toxicology and medicinal chemistry"

1

Ward, C. H. Environmental Toxicology and Chemistry. An International Journal. Volume 15, Number 11, November 1996,. Fort Belvoir, VA: Defense Technical Information Center, November 1996. http://dx.doi.org/10.21236/ada332986.

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Munavalli, Shekar, Dennis K. Rohrbaugh, and H. D. Durst. Chemistry, Biochemistry, Pharmacology, and Toxicology of CS and Synthesis of Its Novel Analogs. Fort Belvoir, VA: Defense Technical Information Center, October 2007. http://dx.doi.org/10.21236/ada474594.

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