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Meschini, Elisa. "Purine-based dual inhibitors of CDK2 and CDK7." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1363.
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Cyclin-Dependent Kinases (CDKs) play a fundamental role in eukaryotic cell cycle progression, particularly at cell cycle checkpoints, and are therefore important targets for anticancer drug discovery. Activation of CDK2 in complex with Cyclin A regulates entry into S phase of the eukaryotic cell cycle. CDK7, a dual-function enzyme, acts both as a CDK-Activating Kinase (CAK) and as a component of the general transcription factor TFIIH. However, experiments with MAT1-knockdown mice have shown that cell cycle arrest by CAK inhibition would not be detrimental for transcriptional activity in non-dividing cells, as CDK9 in complex with Cyclin T can perform transcriptional duties in the absence of TFIIH. Previous studies have resulted in the identification of NU6102 (1, IC50 mM = 0.005 (CDK2), 4.4 (CDK7)) as a potent and selective CDK2 inhibitor, and NU6247 (2, IC50 mM = 0.12 (CDK2), 0.23 (CDK7)) as an equipotent CDK2/7 inhibitor. It was shown that the sulfonamide group of 1 confers potency and selectivity for CDK2, whereas the pendant piperazinyl substituent of 2 diminishes CDK2 actvity whilst improving activity versus CDK7. S NH N N NH N O O O 2 N N AccordinglyAs part of the work described in the present thesis, sulfonamide 3 (IC50 mM = 0.012 (CDK2), 0.67 (CDK7)) was synthesised and found to be is a potent CDK2 inhibitor, but with some CDK7-inhibitory activity (IC50 mM = 0.012 (CDK2), 0.67 (CDK7)). Further elaboration of the side-chain function has enabled the development of structure-activity relationships (SARs), and the identification of purines (e.g. 4, IC50 mM = 2.6 (CDK2), 0.56 (CDK7)) exhibiting some selectivity for CDK7, albeit with a loss of potency. 4 Subsequent SAR studies conducted on 2 have enabled the following observations to be made: firstly, the purine 6-cyclohexylmethoxy substituent is necessary for activity, with the corresponding 6-unsubstituted purine (5, IC50 mM = 46.9 (CDK2), 20.8 (CDK7)) exhibiting a 100-fold loss of potency against both CDK2 and CDK7. A terminal basic group (e.g. piperazinyl in 2) is required for activity, as replacement by a cyclohexyl substituent results in loss of activity against both kinases (6, 11% inhibition at 10 mM (CDK2), 13% inhibition at 100 mM (CDK7)). The sulfone linker is not a prerequisite for CDK7 activity, with the simple alkylpiperazine derivative (7, IC50 mM = 0.48 (CDK2), 0.51 (CDK7)) exhibiting comparable potency and selectivity. Finally, there appears to be some opportunity for expansion into the gatekeeper pocket of CDK7 by introducing small substituents at the purine C-8 position, with the potential for selectivity over CDK2 (8, 47% inhibition at 100 mM (CDK2), IC50 = 5 mM (CDK7)). Isolation and biological evaluation of the vinyl sulfone 9, an intermediate in the synthesis of 2, indicated a time-dependent inhibition of CDK2, suggesting that 9 is an irreversible inhibitor of CDK2. This would be the first reported irreversible inhibitor of a cyclin-dependent kinase, and therefore the activity of the compound against CDK2 was investigated using protein crystallography and site-directed mutagenesis 5 techniques. From these studies, encouraging evidence has emerged that 9 acts as an irreversible inhibitor of CDK2, covalently binding to a lysine residue within the ATP-binding pocket.
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Green, Ian. "The biology of novel dual histone methyltransferase inhibitors." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/25763.
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Background: EZH2 is a histone methyltransferase (HKMT) responsible for the maintenance of epigenetic silencing of genes through maintenance of the repressive H3K27me3 mark and it is aberrantly regulated in numerous cancers, including breast cancer where it is linked to aggressive phenotypes and poor clinical outcomes. EHMT2 is a related HKMT responsible for gene silencing by mediating H3K9me3 levels. EHMT2 is also responsible for H3K27me1 and has been shown to physically interact with EZH2. Specific inhibitors of EZH2 are available and have been shown to be effective in cancers with EZH2 mutation driven phenotypes (e.g. follicular lymphoma) but have shown limited efficacy in epithelial cancers. Here we present the characterisation of novel dual HKMT inhibitors targeting both EZH2 and EHMT2, which we believe will have a greater impact than individual inhibitors in reversing EZH2 mediated silencing. Results: Utilising publicly available data, we show expression of EZH2 and related subunits of the PRC2 complex and related EHMT2/EHMT1 complex range greatly in normal tissue, but EZH2 and EHMT2 expression are consistently up-regulated in numerous cancers. We show that CNV and mutation of EZH2 and EHMT2 infrequently occur in breast cancer- however, in breast cancer high expression of EZH2 is linked to reduced RFS and OS of patients. In breast cancer cell lines, dual HKMT inhibitors up-regulate EZH2 target genes, in gene specific and genome wide manner, to a greater degree than EZH2 or EHMT2 inhibition alone and induce expression of genes associated with apoptotic pathways. This up-regulation of silenced genes occurs concurrently with a decrease in H3K27me3 and H3K9me3 levels on target genes. In breast cancer cells and ovarian cancer cells, dual HKMT inhibitors reduce cell clonogenicity, cancer stem cell activity, cancer stem cell self-renewal capacity, and sensitise cancer stem cells to Paclitaxel and Cisplatin treatment. Conclusions: Novel dual inhibitors of EZH2 and EHMT2 alter gene expression and inhibit cell growth and cancer stem cell activity in wild-type EZH2 tumour cells. These data support the further preclinical and clinical evaluation of such inhibitors in triple negative breast cancer and epithelial ovarian cancer.
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Apsel, Beth. "Dual-specificity inhibitors of lipid and protein kinases." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3311357.
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Ren, Baiping. "Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697.
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Wong, Jacky Sui Ki. "The Evaluation of Dual PI3K/mTOR Inhibitors as a Superior Alternative to mTOR Inhibitors in Pre-B Acute Lymphoblastic Leukaemia." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13644.
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Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. Poor long term survival in adults as well as the bleak outlook for relapsed patients highlights the need for new therapeutic strategies for the treatment of ALL. The major regulators of ALL cell proliferation and survival mediate their effects through the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin. It has been previously shown that the mTOR inhibitor RAD001 extended survival in a non-obese diabetic/severe combined immune deficient (NOD/SCID) mouse xenograft model of ALL. The work presented in this thesis examines the effect of the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in ALL. In summary, dual PI3K/mTOR inhibitors demonstrate primarily superior cytostatic effects in vitro but a mixed level of cytotoxicity when compared to RAD001. In addition, the dual PI3K/mTOR inhibitors extended survival in NOD/SCID mice engrafted with ALL xenografts but failed to demonstrate overall superiority over mTOR inhibition alone. This work contributed to the publication of a paper, presented in two separate chapters. Subsequent unpublished work presented in this thesis examined the effects of the dual PI3K/mTOR inhibitors in combination with conventional chemotherapeutic agents. However, the results presented in this thesis indicate that the dual PI3K/mTOR inhibitors do not cooperate well with the tested agents. Furthermore, the cooperation observed with the dual PI3K/mTOR inhibitors in combination with a MEK inhibitor highlights the need to explore strategies to target multiple signalling pathways.
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Fraser, Sasha. "Development of Dual-Pathway Inhibitors of Raf/MEK/ERK and PI3K/Akt Signaling Pathways." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2619.
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In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity.
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Steinemann, Gustav [Verfasser]. "Charakterisierung der Wirkmechanismen des neuartigen, dual wirksamen HDAC-Inhibitors „Animacroxam“ am Beispiel testikulärer Keimzelltumore / Gustav Steinemann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1234984474/34.
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Tamhaev, Rasoul. "Conception, synthèse et caractérisation de dérivés diaryl éthers comme nouveaux inhibiteurs directs de la protéine InhA de Mycobacterium tuberculosis." Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://thesesups.ups-tlse.fr/6088/.
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La tuberculose, bien que maladie très ancienne, est toujours une des causes majeures de mortalité due à un agent infectieux unique. En 2021, 10 millions de personnes ont contracté la maladie et 1.5 millions de décès étaient directement imputables à cette dernière. Malgré la disponibilité de toute une panoplie d'antibiotiques, peu d'entre eux s'avèrent efficaces contre l'agent pathogène responsable de la tuberculose, Mycobacterium tuberculosis. Cette inefficacité est principalement due au caractère imperméable de l'enveloppe cellulaire mycobactérienne, composée majoritairement d'acides mycoliques. L'isoniazide, l'antituberculeux de première ligne le plus utilisé, cible la biosynthèse de ces acides mycoliques via la protéine InhA. L'isoniazide agit comme une pro-drogue nécessitant une activation par la protéine KatG. Cependant, l'émergence de résistances lors de l'étape d'activation de l'isoniazide implique la nécessité de développer des inhibiteurs directs d'InhA. Les travaux réalisés durant cette thèse avaient pour objectif de développer de nouveaux inhibiteurs directs d'InhA. Ces derniers ont été développés autour de la structure d'un motif diaryl éther, connu pour sa capacité à inhiber l'enzyme. La chimie combinatoire dynamique combinée à la cristallographie aux rayons X a été utilisée comme méthode de criblage de fragments pour découvrir de nouveaux inhibiteurs. Trois adduits, visualisés directement à l'intérieur du site actif de la protéine, ont ainsi été caractérisés et montrent des interactions avec le portail majeur de la protéine. Dans un autre projet, une nouvelle famille de diaryl éthers comportant trois pharmacophores a été conçue afin d'occuper entièrement le site de liaison du substrat. Une des molécules synthétisées possède une activité inhibitrice inférieure au micromolaire contre InhA. La structure du complexe correspondant a été résolue par cristallographie aux rayons X, mettant en évidence une ouverture inédite d'une des régions de la protéine, appelée portail mineur. Enfin, des approches multi-cibles, ciblant à la fois InhA et le complexe déshydratase HadABC du système FAS II, ont également été développées durant cette thèse. Plusieurs molécules duales ont été produites et montrent une inhibition de l'activité d'InhA de l'ordre du nanomolaire. Ces molécules montrent également une inhibition de la croissance de différentes souches mycobactériennesTuberculosis, despite being a very ancient disease, remains one of the major causes of mortality due to a single infectious agent. In 2021, 10 million people contracted the disease and 1.5 million deaths were directly attributable to it. Despite the availability of a variety of antibiotics, few of them prove effective against the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. This ineffectiveness is primarily due to the impermeable nature of the mycobacterial cell envelope, composed mainly of mycolic acids. Isoniazid, the most widely used first-line antitubercular drug, targets the biosynthesis of these mycolic acids through the protein InhA. Isoniazid acts as a pro-drug requiring activation by the protein KatG. However, the emergence of resistance during the activation stage of isoniazid necessitates the development of direct inhibitors of InhA. The work carried out during this thesis aimed to develop new direct inhibitors of InhA. These inhibitors were designed basedon the structure of a diaryl ether motif, known for its ability to inhibit the enzyme. Dynamic combinatorial chemistry combined with X-ray crystallography was used as a fragment screening method to discover new inhibitors. Three adducts, visualized directly within the active site of the protein, were characterized and showed interactions with the major portal of the protein. In another project, a new family of diaryl ethers with three pharmacophores was designed to fully occupy the substrate binding site. One of the synthesized molecules exhibited sub-micromolar inhibitory activity against InhA. The structure of the corresponding complex was resolved by X-ray crystallography, highlighting a wider opening of one of the protein's regions, called the minor portal. Finally, multi-target approaches, targeting both InhA and the dehydratase complex HadABC of the FAS II system, were also developed during this thesis. Several dual molecules were produced, showing inhibition of InhA activity in the nanomolar range. These molecules also demonstrated inhibition of the growth of different mycobacterial strains
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Yule, Ian Andrew. "Design, synthesis and biological evaluation of novel, dual targeting inhibitors of bacterial DNA gyrase and topoisomerase IV." Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713881.
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The inevitability of bacterial drug resistance to all marketed antibiotic drug classes warrants continual research into the development of novel chemotype antibacterial agents. Drug resistant `superbugs' such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE) account for >70% of US hospital bound bacteremias. Such infections are associated with vastly increased rates of morbidity and mortality resulting in a heavy economic burden on health care authorities. The bacterial topoisomerase enzymes DNA gyrase and topoisomerase IV are highly conserved amongst almost all bacterial species on account of their unique and essential function in the conservation of chromosomal integrity during DNA replication and transcription. Furthermore, structural similarity between gyrase and topo IV, and distinction from human homologues, makes the selective dual-inhibition of these enzymes a realistic goal. In this thesis, three distinct approaches were utilized in the discovery of novel inhibitors of gyrase (GyrB) and topoisomerase IV (ParE) acting at the ATP binding domains of these enzymes. In the initial strategy, structural variants based on known inhibitors were modelled within the GyrB ATPase site in a bid to displace a highly conserved water molecule at the ligand-enzyme interface. Synthesis and biological screening of these variants proved that such changes were to the detriment of activity, although the work did yield a novel, convenient preparation of Nsubstituted thieno[2,3-d]pyrimidinones. In an alternative strategy, the de novo molecular design software SPROUT was used in concert with crystallographic data on the GyrB ATP binding site. Putative inhibitors were thus generated 'from scratch', the most attractive of which were further modelled using docking software (AUTODOCK), synthesised and screened for enzyme inhibitory and antimicrobial activity. A number of early series were derived which demonstrated modest (GyrB IC50 <100 μM) enzyme activity. The most promising of these, a series of pyridine-3-carboxamides, was optimized to offer potent (GyrB IC50 <100 nM) enzyme inhibitory activity, dual target specific antibacterial activity (MICs <0.5 μg / mL) and a low potential for resistance development. Finally, using the GLIDE docking software, virtual compound libraries were screened in silico against the ATP binding domain of GyrB. Though largely unsuccessful, the process did identify a moderate inhibitor (GyrB IC50 118 μM, MIC 32 μg / mL), in a cost and time effective manner relative to high-throughput screening.
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Foka, Germaine Boulenoue. "Synthesis and evaluation of novel coumarin-donepezil derivatives as dual acting monoamine oxidase B and cholinesterase in Alzheimer's disease." University of the Western Cape, 2016. http://hdl.handle.net/11394/5549.
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Magister Pharmaceuticae - MPharmAlzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity.
National Research Foundation (NRF)
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Potter, Nicola Jane. "Design, synthesis, and biological evaluation of novel dual-target inhibitors of aminoacyl-tRNA synthetases as potential antibacterial agents." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536093.
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Heider, Fabian Andreas [Verfasser]. "Design and synthesis of novel dual GSK3β/p38α MAPK inhibitors and their optimization towards GSK3β selectivity / Fabian Andreas Heider." Tübingen : Universitätsbibliothek Tübingen, 2021. http://d-nb.info/1238594778/34.
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Louizos, Connie Celest. "Sexual Inhibition and Sexual Excitation in Erectile Dysfunction." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15843.
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Erectile dysfunction (ED) is a common problem with many aetiologies. The development of phosphodiesterase type 5 inhibitors (PDE5Is) has offered a highly efficacious therapeutic approach to the treatment of ED. However, a significant number of men fail to respond to medication, and others discontinue its use despite good therapeutic responses. Little is known about the determinants of low PDE5I efficacy or compliance. It is recognised that adequate sexual arousal is necessary in order for PDE5Is to have an effect, but arousability is rarely assessed during the routine therapeutic workup. It is therefore possible that unidentified low arousability contributes to therapeutic failure. The Dual Control Model of Sexual Response offers a theoretical framework for the investigation of sexual excitation and inhibition (which may impact on arousability) that can be undertaken using its associated questionnaire, the sexual excitation/sexual inhibition questionnaire (SIS/SES). The purpose of the studies reported in this thesis was to evaluate how the propensities of sexual excitation and inhibition relate to ED sufferers response to PDE5I therapy. The studies focused on men being treated by general practitioners for apparent psychogenic ED. Four studies were conducted. In the first study, the aim was to investigate whether individual differences in the propensity for sexual inhibition and excitation measured using the SIS/SES questionnaire predicted responses to PDE5Is. The study was based on the hypothesis that men with lower arousability, operationalized as low excitation, would be less responsive to PDE5I then men with higher excitation. Men aged 18 and older (N = 100) who were prescribed PDE5Is for the first time were recruited into the study and assessed at baseline and 3 months as part of their normal course of care. The severity of ED was assessed using the erection function (EF) scale of the International Index of Erectile Function (IIEF), and sexual inhibition and excitation were measured using the SIS/SES questionnaire. The results of this study showed that higher SES and IIEF-EF scores at the beginning of therapy were predictive of a larger improvement in IIEF-EF score in response to therapy. Sexual inhibition scores were not predictive of changes in IIEF-EF scores. The findings suggest that an individual’s propensity for sexual excitation influences their response to PDE5I therapy. In the clinical setting, evaluation of the propensity for sexual excitation may help practitioners determine which of the treatment options available is most likely to have the best result. It is possible that men with lower SES scores should receive PDE5Is at the highest possible dose. The second study evaluated whether the ongoing failure of PDE5I therapy to improve erectile function had an adverse impact on sexual excitation and/or inhibition, and therefore decreased the likelihood of a successful response in the future. Established PDE5I users completed the SIS/SES questionnaire at recruitment and three months later. On the basis of IIEF scores at recruitment, subjects were divided into two groups according to the severity of their ED - mildly affected (M) and mild – moderately affected (MM). SES scores were significantly lower, and SIS1 scores significantly higher in Group MM at recruitment and at three months (P < 0.001). In Group M, SES scores increased (P < 0.005) and SIS1 (P < 0.001) and SIS2 (P = 0.01) scores decreased over the three months of the study. In Group MM, SES scores decreased while SIS1 scores increased over the study period (P < 0.001). The results for Group M showed that men whose EF scores increased were more likely to experience increased SIS2 and decreased SES scores. Analysis of the results using multiple linear regression showed that SIS/SES variables were of little value in predicting erectile function (EF) at recruitment, or change in EF during the study period. This was an unexpected finding, because previous studies have consistently shown a link between SIS1 and IIEF-EF scores. It is possible that sexual excitation and inhibition, although fundamentally traits, may also be influenced by the current state of the patient. The findings of this study suggest that the severity of ED in non-responders influences how the state component of measured excitation and inhibition changes over time, with more severely affected patients experiencing changes that decrease the likelihood of a successful response to PDE5Is in the future. The third study built on the finding reported by Lykins et al (2012) that couples’ similarities in sexual excitation and inhibition predict sexual function in men who were not experiencing clinical ED. The aim was to investigate whether the degree of between-partner similarity or dissimilarity in the propensity for sexual inhibition and excitation in heterosexual couples (N = 189) predicted the severity of ED in patients who had sought treatment for ED. The severity of ED was assessed using the erection function domain of the International Index of Erectile Function (IIEF-EF), and sexual inhibition and excitation were measured, in both men and women, using the SIS/SES questionnaire. Regression analyses showed that men (ß = -0.21, t = -2.9, P = 0.004) and women’s SIS1 scores (ß = -0.42, t = -6.2, P = 0.001), and couple similarity in SES scores (ß = 0.19, t = 3.0, P = 0.002), were significant predictors of IIEF-EF score, and that couple similarity in SIS1 scores negatively predicts IIEF-EF, meaning better erectile function. In other words, lower SIS1 scores at baseline predicted a higher erectile function score on the IIEF-EF. In the fourth study, the aim was to determine whether sexual excitation and inhibition influenced patients’ expectations of the therapeutic response to PDE5Is, and whether those expectations were predictive of the actual therapeutic response. A questionnaire was developed and used to collect data on expectations in eighty men commencing PDE5I therapy, and after three and six months of treatment. At the same time, subjects completed the IIEF, SIS/SES and Beck’s Depression Inventory (BDI). SIS/SES scores were not predictive of scores of any items on the expectations questionnaire, nor was there any evidence of an effect on expectations on changes in IIEF or BDI scores. Although changes in IIEF and BDI scores from recruitment to 3 months were indicative of improved sexual function and less depression, scores on items on the expectations scale decreased, suggesting that expectations were not being met. The items for which scores decreased were the expectation to be prescribed a drug, that the drug would restore the sexual function to normal, would work within 30 minutes of administration, improve patients confidence to engage in sexual activity, and that the medication was the best treatment for ED across the three data collection points. The findings of the study suggested that the education of patients about how PDE5Is should be used was sub- optimal. The findings of these studies suggest that the measurement of sexual inhibition and excitation can provide some information that may be of use in planning PDE5I therapy. Specifically, the capacity to predict the response to medication may enable clinicians to create more realistic expectations in their patients, and therefore decrease the risk of dissatisfaction and discontinuation. If men with low arousability can be identified, it may be possible to implement counselling strategies to address the problem and improve the likelihood of therapeutic success. This concept can be extended to partners, given that these studies have shown that partner similarities predict some of the therapeutic response to PDE5Is.
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Hamed, Mostafa Mohamed Mostafa [Verfasser], and Rolf W. [Akademischer Betreuer] Hartmann. "Design and synthesis of novel quinazoline-based EGFR kinase inhibitors and dual EGFR/NF-κB inhibitors as potential anti-cancer drugs with enhanced efficacy / Mostafa Mohamed Mostafa Hamed. Betreuer: Rolf W. Hartmann." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2013. http://d-nb.info/1078017077/34.
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Wang, Danni. "Synthesis and evaluation of antibacterial activity of the dual-action agents : beta-lactamase inhibitors with cytotoxic agents or beta-lactam antibiotics." Thesis, Aston University, 2001. http://publications.aston.ac.uk/12362/.
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Schmitt, Christian [Verfasser], and Rolf W. [Akademischer Betreuer] Hartmann. "Development of new lead-like dual inhibitors of the cdc2-like kinase 1 (Clk1) and dual specificity Y-phosphorylation regulated kinases 1A and 1B (Dyrk1A and Dyrk1B) / Christian Schmitt. Betreuer: Rolf W. Hartmann." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1056906855/34.
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Harmse, Rozanne. "Syntheses of 8-(phenoxymethyl)caffeine analogues and their evaluation as inhibitors of monoamine oxidase and as antagonists of the adenosine A2A receptor / Rozanne Harmse." Thesis, North-West University, 2013. http://hdl.handle.net/10394/9663.
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Background and rationale: Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system and is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The loss of functional dopamine in the striatum is thought to be responsible for the typical symptoms of PD. Cardinal features of PD include bradykinesia, muscular rigidity, resting tremor and impairment of postural balance. This study focuses on the inhibition of monoamine oxidase B (MAO-B) and antagonism of A2A receptors as therapeutic strategies for PD.
Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing mitochondrial bound isoenzyme which consists of two isoforms namely MAO-A and MAO-B. The primary function of MAO is to catalyze the oxidative deamination of dietary amines, monoamine neurotransmitters and hormones. MAO-A is responsible for the oxidative deamination of serotonin (5-HT) and norepinephrine (NE), while MAO-B is responsible for the oxidative deamination of dopamine (DA). The formation of DA takes place in the presynaptic neuron where it is stored in vesicles and released into the presynaptic cleft. The released DA then either binds to D1 and D2 receptors which results in an effector response. The excess DA in the presynaptic cleft is metabolized by MAO-B which may result in the formation of free radicals and a decrease in DA concentrations. Under normal physiological conditions free radicals are removed from the body via normal physiological processes, but in PD these normal physiological processes are thought to be unable to remove the radicals and this may lead to oxidative stress. Oxidative stress is believed to be one of the leading causes of neurodegeneration in PD. The rationale for the use of MAO-B inhibitors in PD would be to increase the natural DA levels in the brain and also diminish the likelihood of free radicals to be formed.
Adenosine is an endogenous purine nucleoside and yields a variety of physiological effects. Four adenosine receptor subtypes have been characterized: A1, A2A, A2B and A3. They are all part of the G-protein-coupled receptor family and have seven transmembrane domains. The A2A receptor is highly concentrated in the striatum. There are two important pathways in the basal ganglia (BG) through which striatal information reaches the globus pallidus, namely the direct pathway containing A1 and D1 receptors and the indirect pathway containing A2A and D2 receptors. The direct pathway facilitates willed movement and the indirect pathway inhibits willed movement. A balance of the two pathways is necessary for normal movement. In PD, there is a decrease in DA in the striatum, thus leading to unopposed A2A receptor signaling and ultimately resulting in overactivity of the indirect pathway. Overactivity of the indirect pathway results in the locomotor symptoms associated with PD. Treatment with an A2A antagonist will block the A2A receptor, resulting in the restoration of balance between the indirect and direct pathways, thus leading to a decrease in locomotor symptoms.
Aim: In this study, caffeine served as a lead compound for the design of dual-targeted drugs that are selective, reversible MAO-B inhibitors as well as A2A antagonists. Caffeine is a very weak MAO-B inhibitor and a moderately potent A2A antagonist. Substitution on the C8 position of caffeine yields compounds with good MAO-B inhibition activities and A2A receptor affinities. An example of this behaviour is found with (E)-8-(3-chlorostyryl)caffeine (CSC), which is not only a potent A2A antagonist but also a potent MAO-B inhibitor. The goal of this study was to identify and synthesize dual-targeted xanthine compounds. Recently Swanepoel and co-workers (2012) found that 8-phenoxymethyl substituted caffeines are potent reversible inhibitors of MAO-B. Therefore, this study focused on expanding the 8-(phenoxymethyl)caffeine series and evaluating the resulting compounds as both MAO-A and -B inhibitors as well as A2A antagonists.
Synthesis: Two series were synthesized namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines. The analogues were synthesized according to the literature procedure. 1,3-Dimethyl-5,6-diaminouracil or 1,3-diethyl-5,6-diaminouracil were used as starting materials and were acylated with a suitable substituted phenoxyacetic acid in the presence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) as an activating reagent. The intermediary amide was treated with sodium hydroxide, which resulted in ring closure to yield the corresponding 1,3-dimethyl-8-phenoxymethyl-7Hxanthinyl or 1,3-diethyl-8-phenoxymethyl-7H-xanthinyl analogues. These xanthines were 7-N-methylated in the presence of an excess of potassium carbonate and iodomethane to yield the target compounds.
In vitro evaluation: A radioligand binding assay was performed to determine the affinities of the synthesized compounds for the A2A receptor. The MAO-B inhibition studies were carried out via a fluorometric assay where the MAO-catalyzed formation of H2O2 was measured.
Results: Both series showed good to moderate MAO-B inhibition activities, while none of the compounds had activity towards MAO-A. Results were comparable to that of a known MAOB inhibitor lazabemide. For example, lazabemide (IC50 = 0.091 μM) was twice as potent as the most potent compound identified in this study, 8-(3-chlorophenoxymethyl)caffeine (compound 3; IC50 = 0.189 μM). Two additional compounds, 8-(4-iodophenoxymethyl)caffeine and 8-(3,4-dimethylphenoxymethyl) caffeine, also exhibited submicromolar IC50 values for the inhibition of MAO-B. The structure-activity relationships (SARs) indicated that 1,3-diethyl substitution resulted in decreased inhibition potency towards MAO-B and that 1,3-dimethyl substitution was a more suitable substitution pattern, leading to better inhibition potencies towards MAO-B.
The compounds were also evaluated for A2A binding affinity, and relatively weak affinities were recorded with the most potent compound, 1,3-diethyl-7-methyl-8-[4-chlorophenoxymethyl]xanthine (compound 16), exhibiting a Ki value of 0.923 μM. Compared to KW-6002 (Ki = 7.94 nM), a potent reference A2A antagonist, compound 16 was 35-fold less potent. Comparing compound 16 to CSC [Ki(A2A) = 22.6 nM; IC50(MAO-B) = 0.146 nM], it was found that compound 16 is 31-fold less potent as an A2A antagonist and 21-fold less potent as a MAO-B inhibitor. Loss of MAO-B inhibition potency may be attributed to 1,3-diethyl substitution which correlates with similar conclusions reached in earlier studies. In addition, the replacement of the styryl functional group (as found with CSC and KW-6002) with the phenoxymethyl functional group (as found with the present series) may explain the general reduction in affinity for the A2A receptor. This suggests that the styryl side chain is more appropriate for A2A antagonism than the phenoxymethyl functional group.
Conclusion: In this study two series of xanthine derivatives were successfully synthesized, namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines (11 compounds in total). Three of the newly synthesized compounds were found to act as potent inhibitors of MAO-B, with IC50 values in the submicromolar range. None of the compounds were however noteworthy MAO-A inhibitors. The most potent A2A antagonist among the examined compounds, compound 16, proved to be moderately potent compared to the reference antagonists, CSC and KW-6002. It may be concluded that the styryl functional group (as found with CSC and KW-6002) is more optimal than the phenoxymethyl functional group (as found with the present series) for A2A antagonism. 1,3-Diethyl substitution of the xanthine ring was found to be less optimal for MAO-B inhibition compared to 1,3-dimethyl substitution. These results together with known SARs provide valuable insight into the design of 8-(phenoxymethyl)caffeines as selective and potent MAO-B inhibitors. Such drugs may find application in the therapy of PD.Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.
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Seegers, Julia [Verfasser], and Oliver [Akademischer Betreuer] Werz. "Identification and Characterization of natural products as dual inhibitors of microsomal Prostaglandin E2 Synthase-1 and 5- Lipoxygenase / Julia Seegers ; Betreuer: Oliver Werz." Tübingen : Universitätsbibliothek Tübingen, 2014. http://d-nb.info/1196877912/34.
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Formosa, Márquez Xavier. "Síntesi i avaluació farmacològica d'inhibidors de l'acetilcolinesterasa de lloc d'unió dual com a potencials fàrmacs anti-Alzheimer i estudis relacionats." Doctoral thesis, Universitat de Barcelona, 2006. http://hdl.handle.net/10803/671014.
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Se ha llevado a cabo la síntesis y evaluación farmacológica de dos nuevas familias de inhibidores de acetilcolinesterasa de sitio de unión dual, los heterodímeros huprina-tacrina y los heterodímeros donepezilo-tacrina. Los ensayos farmacológicos han puesto de manifiesto que estos compuestos poseen una afinidad y potencia inhibidora extraordinariamente aumentadas respecto a los compuestos modelo, hecho que los presenta como interesantes candidatos a fármacos anti-Alzheimer.
Paralelamente, como consecuencia de unos resultados inesperados obtenidos en el contexto de la síntesis de los heterodímeros donepezilo-tacrina, se han llevado a cabo unos estudios adicionales basados en la síntesis, purificación y caracterización de diversos compuestos espiropolicíclicos complejos de esteroquímica relativa perfectamente definida, obtenidos por reacción multicomponente indanona y aldehídos como productos de partida, orientados a profundizar en el efecto de la substitución en el curso de la reacción, y de paso, con la ayuda a métodos químico-teóricos, dirigidos a proponer un mecanismo definitivo para esta interesante reacción.
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Nörz, Dominik Sebastian [Verfasser], and Manfred [Akademischer Betreuer] Jücker. "Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-Inhibitors / Dominik Sebastian Nörz. Betreuer: Manfred Jücker." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1093411325/34.
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Mohamad, Taib Mohamad Nurul Azmi. "Isolation and identification of cyclic polyketides from endiandra kingiana gamble (lauraceae), as bcl-xl/bak and mcl-1/bid dual inhibitors, and approaches toward the synthesis of kingianins." Palaiseau, Ecole polytechnique, 2015. https://tel.archives-ouvertes.fr/tel-01260359/document.
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Un criblage biologique préliminaire a montré que l'extrait des écorces d'Endiandrakingianapossédait une forte affinité pour la protéine anti-apoptotique Bcl-xL, motivant ainsi la réalisationd’une étude chimique complète. Deux groupes de composés ont été isolés et caractérisés: d’une part, huit nouveaux dérivés de l'acide endiandrique (les acides kingianiques A à H [120−127]) et d’autre part, trois nouvelleskingianines (les kingianines O à Q [128−130]). Le potentiel inhibiteur des nouvelles molécules vis-à-vis des interactionsBcl-xL/Bak et Mcl-1/Bida ensuite été évalué, ainsi que leurs propriétés cytotoxiques sur diverses lignées cellulaires tumorales humaines. La seconde partie du manuscrit présente une approche vers la synthèse totale des kingianines et de composés analogues. Le squelette pentacyclique des produits naturels résulte formellement d’une réaction de Diels-Alder entre deux unités bicyclo[4. 2. 0]octadiène, elles-mêmes issues d’une cascade d’électrocyclisation de tétraènes entièrement conjugués. Une stratégie de construction directe de motifs bicyclo[4. 2. 0]octadiènespar une cycloaddition [2+2] entre des cycloalcènes et des cétènes convenablement choisisdoit assurer l’obtention des molécules cibles avec de bons rendements globaux. Au total, cinq approches ont été implémentées. Elles débutent par la cycloaddition [2+2] entre des cyclohexadiènes et des cétènes fonctionnalisés et se poursuivent par la fonctionnalisation des positions C7 et C8 en contrôlant la configuration relative de ces centres. Les résultats obtenus ont conduit à identifier les composés 280 et 311 comme des intermédiaires clefs à même d’être convertis en diènes ou en diénophiles, pouvant alors être engagés dans des cycloadditions de Diels-Alder pour accéder à la structure pentacyclique des kingianinesThe preliminary screening showed that the bark of Endiandra kingiana Gamble exhibited potency as a modulating agent between Bcl-xL and Bak, which prompted its chemical investigation. Two groups of compounds were isolated and characterized; the endiandric acid series and the kingianin series. Eight new endiandric acid analogues (kingianic acids A-H [120-127]) and three new kingianin analogues (kingianin O-Q [128-130]) were isolated and structurally elucidated. The isolated compounds were evaluated for two bioassays; Bcl-xL/Bak and Mcl-1/Bid of binding affinities and cytotoxic effects against various human tumour cells. The second part describes the progression towards the total synthesis of kingianin analogues. The pentacyclic kingianin skeleton was formed by Diels-Alder reaction between two monomers having a bicyclo[4. 2. 0]octadiene backbone formed by a stereospecific electrocyclization of polyenes. The research was focusing on construction of bicyclo[4. 2. 0]octadiene monomer using [2+2] ketene cycloaddition approach at the early stage of the synthesis. One of the main advantages of such a strategy is the rapid assembly of the carbon skeleton of kingianins, thus maximizing the chances for good overall yields of the final products. So far, an efficient synthesis of the bicyclo[4. 2. 0]octene backbone was successfully achieved. Five approaches to synthesize this backbone starting from [2+2] cycloaddition of the cyclohexadienes to functionalized ketenes followed by functionalization of substituent at C-7 and C-8 positions with the correct relative configuration were described. From these approaches, compounds 280 and 311 were identified as the key intermediates. This key step of the synthesis provided an access to the kingianins skeleton
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Abdelrahim, Mohamed Salah Rezk [Verfasser]. "Development of the first dual inhibitors for steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) : a novel treatment approach for endometriosis / Mohamed Salah Rezk Abdelrahim." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1236897048/34.
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VALLONE, ALESSANDRA. "INVESTIGATION OF NOVEL THERAPEUTIC TOOLS AGAINST INFECTIOUS DISEASES Part 1. Medicinal Chemistry Investigation of MMV019918 Derivatives as Dual Schizonticide And Gametocytocidal Agents Against Plasmodium falciparum Part 2. Investigation of 5-Aryl-Heterocycles As Potential Inhibitors of Metallo beta-Lactamase Enzymes." Doctoral thesis, Università di Siena, 2017. http://hdl.handle.net/11365/1004943.
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Among infectious diseases, two large groups have great clinical relevance: parasitic and bacterial
infections. Belonging to the first category is malaria, caused by the parasite Plasmodium
falciparum. Transmission of Plasmodium parasites between humans and Anopheles mosquitoes is
one of the most important contributors to the global impact of malaria and to the difficulties
encountered in eliminating this parasite1
. Gametocytogenesis, the process by which merozoites
switch from asexual replication to produce male and female gametocytes, represents a critical step
in malaria transmission and Plasmodium genetic diversity. Still too little is known about the
biochemical events that regulate gametocytogenesis and there are few existing drugs able of
inhibiting the gametocytes development and block malaria transmission2
. To encourage drug
discovery and research, the non-profit foundation Medicines for Malaria Venture (MMV) has
provided a library of 400 compounds that present antimalarial activity in the micromolar range, but
their molecular targets and mode of action are not necessarily known3
. Here we describe the
medchem investigation of one of the most promising hit compound included in this library,
MMV019918. MMV019918 has been highlighted in several in vitro studies for its promising antigametocyte
activity coupled to activity against schizonts. On the basis of its structure, the synthesis
of a new series of compounds with transmission-blocking activity has been designed. It has been
found very interesting the activity of one derivative NF2350 which resulted active also in the
standard membrane feeding assay (SMFA), to measure subsequent mosquito infection, and which
has an improved toxicological profile compared to MMV019918. A further investigation of NF2350
will allow us to optimize the transmission-blocking activity and to indentify its putative target.
Regarding bacterial infections, a critical issue to be addressed is bacterial resistance to antibiotics
and in particular to β-lactams. Metallo-β-lactamases (MBL) are a family of enzymes involved in the
widespread mechanisms of resistance to beta-lactam antibiotics, The diffusion of MBL-producing
isolates of Pseudomonas aeruginosa, a bacterial pathogen of primary relevance for both
nosocomial and chronic infections of the respiratory tracts in cystic fibrosis patients, is notably
increasing in some specific settings. No clinically useful MBLs inhibitors are currently available in
therapy3
Here we will present the design, synthesis, and biological investigation of a series of
functionalized 2-arylfuran compounds with sub-micromolar antiplasmodial activity, against both
asexual and sexual stages. Furthermore, appropriate decoration of this molecular scaffold allowed
to obtain activity against some isoforms of MBL (including IMP-1and NDM-1).
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Christofakis, Steven. "SCRIBBLE: A POTENTIAL DUAL KINASE INHIBITOR." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/72.
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Extracellular signal-regulated kinases (ERKs) modulate cellular activities in response to extracellular stimuli and play important biological roles. Thus, perturbed kinase pathways induce pathological conditions, such as tumor development. Rit, a novel member of the Ras family GTPases, activase ERK6, and its over-expression confers tumorigenicity. We hypothesized the presence of scaffolding molecules specific to ERK6, similar to other known MAP kinases. We performed yeast two-hybrid assays using ERK6 as bait, and Scribble was identified as a binding partner. Scribble contains 16 LRR domains and four PDZ domains. We performed immunoprecipitation (IP) assays and discovered ERK2 as another binding partner. Surprisingly, no interaction was observed with the highly homologous MAP kinase, ERK1. No other representative kinases showed binding capabilities with Scribble. IP data confirmed that both ERK2 and ERK6 bind to Scribble through its LRR and PDZ domains. Deletion of ten aminoi acids from the C-terminus of ERK2 and ERK6 abolished these interactions. In vitro kinase assays indicated the kinase suppressing ability of Scribble. Focus formation assays were performed with RitQ79L and H-RasV12 as constitutive activators of ERK6 and ERK2, respectively, in the presence of Scribble. Results confirmed the role of Scribble as a tumor suppressor.
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Venkateswaran, Rashmi. "The dual nature of carbon: Catalyst and inhibitor." Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/9910.
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The goal of this project was to study the reactivity of thin pyrolitic carbon films on quartz, formed from propylene, methane and butadiene, using the methane conversion reaction as a test. The reactivity was compared to that of quartz. The rate of dissociation of methane on the carbon surface was as much as forty times greater than on quartz. The actual rate increase depended on the precursor of the carbon film. When the reproducibility of the carbon films was tested, the rate was observed to decrease with consecutive experiments. Subsequent analysis showed that small amounts of carbon were deposited during the course of each reaction. Since small amounts of carbon caused inhibition, but carbon films caused catalysis, the rate of formation of ethane, a measure of the rate of dissociation of methane, was determined as a function of the amount of carbon. The rate was also determined as a function of methane reactant pressure and temperature. All the results indicated that the methane was dissociated on the carbon surface to form methyl and hydrogen radicals. The increase in formation of these radicals led to the increased rate. The subsequent mechanism was similar to the homogeneous mechanism of methane decomposition. In order to confirm this result, the rate was determined in a reaction vessel with a different surface to volume ratio. The surface mechanism was confirmed. The carbon film was characterized using different techniques. The hydrogen content of the films was determined and related to the reactivity of the carbon formed from different precursors. The film was studied by electron microscopy, XRD, FTIR and mass spectrometry. An overall mechanism was developed for the methane decomposition reaction in the presence of carbon which was extended over the different temperature and pressure conditions studied. Finally, a new technique of synthesizing a catalyst containing carbon and iron, and results obtained in the study of water vapour gasification and methane conversion in the presence of this catalyst are discussed.
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Copin, Chloé. "Exploration moléculaire en série imidazo[2, 1-b][1, 3, 4]thiadiazole : applications à la synthèse d'inhibiteurs de kinases impliqués dans les maladies neurodégénératives." Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2074.
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Depuis plus d’un siècle, la chimie hétérocyclique représente l’un des plus vastes domaines de recherche en chimie organique. En particulier, les hétérocycles bicycliques fusionnés à 5 chaînons, contenant à la fois des atomes de soufre et d’azote, présentent, de par leur rareté et leur potentiel biologique, un champ d’intérêt croissant pour les équipes de recherche et développement académiques ou des entreprises pharmaceutiques. Parmi les nombreux composés bicycliques [5-5], notre étude s’est focalisée sur le noyau imidazo[2,1-b][1,3,4]thiadiazole décrit sporadiquement dans la littérature et pour lequel les voies d’accès actuelles ne se limitent qu’à une seule méthode faisant intervenir une étape de cyclisation et des conditions drastiques. Ce verrou entraine inéluctablement une faible diversité fonctionnelle autour de cet hétérocycle, restreignant ainsi les domaines d’applications notamment biologiques. Afin de pallier à cette problématique, nous avons initié une étude de la réactivité de chacune des trois positions fonctionnalisables du bicycle imidazo[2,1-b][1,3,4]thiadiazole, développant ainsi diverses réactions pallado-catalysées (Suzuki-Miyaura, CH-arylation, Buchwald-Hartwig), de substitution nucléophile aromatique et de Pictet-Spengler. L’étude des propriétés biologiques des différents composés synthétisés et hautement valorisables durant ces travaux a abouti à la découverte de deux séries de molécules inhibant sélectivement les kinases DYRK-1A et CLK-1, deux protéines d’intérêt dans le traitement des affections du système nerveux central (neuropathies, Alzheimer…)For more than a century, heterocyclic chemistry is one of the largest area in organic chemistry research. In particular, because of their rarity and their biological potential, [5-5] fused ring heterocycles containing both sulfur and nitrogen atoms are a large area of interest for both academic and industrial research and development teams. Among these numerous [5-5] bicycles, our study is focused on imidazo[2,1-b][1,3,4]thiadiazole scaffold, which is quite few described in the literature and whose pathways are limited to almost one method involving a cyclisation step and drastic conditions. This lock leads inevitably to low functional diversity around this heterocycle, thus restricting its applications, including biological. In order to overcome this problematic, we then initiated the reactivity study of each three positions of the bicycle imidazo[2,1-b][1,3,4]thiadiazole, developing thereby several palladium couplings (Suzuki-Miyaura, direct arylation, Buchwald-Hartwig), as well as aromatic nucleophilic substitution and Pictet-Spengler reaction. The study of the biological properties of the different compounds synthesized in this work and highly valuable led to the discovery of two series of molecules, inhibiting selectively DYRK-1A and CLK-1, two kinases of interest in the treatment of dysfunction of central nervous system (neuropathies, Alzheimer…)
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Hall, Drew Anthony. "Investigating the structure and binding mechanism of QseM, a novel dual-target protein-inhibitor." Thesis, Curtin University, 2021. http://hdl.handle.net/20.500.11937/87895.
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This thesis details the structural characterisation of a novel protein, QseM, through the use of X-ray crystallography and nuclear magnetic resonance. QseM contains the uncharacterised DUF2285 domain, which, through this work, has been revealed to be a novel helix-turn-helix motif.
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Ströbele, Stephanie [Verfasser]. "Glioblastoma : the effects of the dual kinase inhibitor PI-103 on glioblastoma cells / Stephanie Ströbele." Ulm : Universität Ulm, 2020. http://d-nb.info/121518851X/34.
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CAMPANER, ELENA. "A new covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action." Doctoral thesis, Università degli Studi di Trieste, 2017. http://hdl.handle.net/11368/2908180.
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In the last decades targeted drugs have improved cancer treatment, but revealed to be ineffective mainly in the treatment of solid tumors, largely because of tumor heterogeneity, activation of redundant pathways, and drug resistance. A common and central signal transduction mechanism in many oncogenic pathways is the phosphorylation of proteins at serine or threonine residues followed by proline (S/T-P). Importantly, the phospho-S/T-P motifs of these proteins are recognized by the peptidyl-prolyl cis/trans isomerase (PPIase) PIN1, which catalyzes the cis-trans or trans-cis conformational change around the S-P or T-P bond. Among PPIases, PIN1 is the only enzyme able to efficiently bind proteins containing phosphorylated S/T-P motifs. As a consequence, the phosphorylation dependent prolyl-isomerase PIN1 acts as a critical modifier of multiple signaling pathways. It is overexpressed in the majority of cancers and its activity strongly contributes to tumor initiation and progression. Conversely, inactivation of PIN1 function curbs tumor growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 among other prolyl-isomerases, and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinine-mimicking drug that generates reactive oxygen species and DNA damage inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.
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Leary, Alexandra. "Laboratory and clinical studies of the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib in breast cancer." Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538329.
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Morooka, Satoshi. "Identification of a Dual Inhibitor of SRPK1 and CK2 that Attenuates Pathological Angiogenesis of Macular Degeneration in Mice." Kyoto University, 2015. http://hdl.handle.net/2433/202798.
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Miguel, Mariana Cardoso. "Produção recombinante e caracterização de duas cistatinas de cana-de-açúcar." Universidade Federal de São Carlos, 2014. https://repositorio.ufscar.br/handle/ufscar/5553.
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Cystatins are reversible inhibitors of cysteine peptidases. The cystatins found in plants are called phytocystatins, and represent an independent subfamily of the cystatins superfamily. Some studies have reported significant pleiotropic effects for recombinant cystatins expressed in transgenic plants, notably including tolerance phenotypes against attack of herbivorous arthropods and pathogens, and against abiotic and biotic stresses. Besides, the recombinant sugarcane cystatin, CaneCPI-4, showed potential to inhibit development of melanoma cells. Thus, the study and knowledge about phytocystatins, become interesting from agricultural and medicinal point of view. The sugarcane genome project (SUCEST) allowed the identification of about 25 putative cystatins in this plant, which were gathered in 4 groups, by phylogenetic analysis. In this study, we propose a new classification for the putative cystatins found in the SUCEST database. Furthermore, we describe the heterologous expression, purification and characterization of two novel sugarcane cystatins, CaneCPI-5 and CaneCPI-6, which showed different inhibitory activities against human cathepsin B. While protein CaneCPI-6 was not able to inhibit this enzyme efficiently (Ki = 1,83 μM), the protein CaneCPI-5 showed a good inhibitory capacity against the same enzyme (Ki = 6,87 nM). The CaneCPI-5 cystatin was also analyzed against recombinant cathepsin L from the beetle Sphenophorus levis (rSl-CathL), and showed a good inhibitory capacity against this enzyme (Ki = 0,059 nM). Finally, both of proteins, CaneCPI-5 and CaneCPI-6, proved to be thermostable when kept at 100°C for 30 minutes.
Cistatinas são inibidores reversíveis de cisteíno-peptidases. As cistatinas encontradas em plantas são denominadas fitocistatinas, e constituem uma subfamília independente da superfamília das cistatinas. Alguns estudos têm relatado importantes efeitos pleiotrópicos para cistatinas recombinantes expressas em plantas transgênicas, incluindo principalmente, fenótipos com tolerância ao ataque de artrópodes herbívoros e patógenos, e contra estresses bióticos e abióticos. Ademais, a cistatina recombinante de cana-de-açúcar, CaneCPI-4, apresentou potencial para inibir o desenvolvimento de células de melanoma. Dessa maneira, o estudo e conhecimento sobre as fitocistatinas, tornam-se interessantes do ponto de vista agrícola e na saúde. O projeto genoma da cana-de-açúcar (SUCEST) possibilitou a identificação de 25 possíveis cistatinas nesta planta, que foram reunidas em 4 grupos, por meio de análises filogenéticas. Nesse trabalho propomos uma reanálise das prováveis cistatinas encontradas no banco de dados do SUCEST. Além disso, descrevemos a expressão heteróloga, purificação e caracterização de duas novas cistatinas de cana-de-açúcar, CaneCPI-5 e CaneCPI-6, as quais apresentaram diferenças na ação inibitória contra a catepsina B humana. Enquanto a proteína CaneCPI-6 não foi capaz de inibir esta enzima de forma eficiente (Ki = 1,83 μM), a proteína CaneCPI-5 apresentou um bom poder inibitório contra a mesma enzima (Ki = 6,87 nM). A cistatina CaneCPI-5 foi analisada também contra a catepsina L recombinante do inseto Sphenophorus levis (rSl-CathL), e apresentou alto poder inibitório contra essa enzima (Ki = 0,059 nM). Por fim, ambas as proteínas, CaneCPI-5 e CaneCPI-6, mostraram-se termoestáveis quando mantidas à 100°C durante 30 minutos.
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ZUCCOLO, MARCO. "NEW APPROACHES IN THE DISCOVERY OF NATURAL PRODUCT-BASED AGROCHEMICALS." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/606602.
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Currently, the increase of food demand of a steadily growing human population is not balanced by a global agricultural supply. As a consequence, crop protection plays a crucial role in maximising crop productivity and preventing losses caused by biological and not biological agents. Biological agents, collectively named as pests, are responsible for quantitative losses ranging from 20 % to 40 %, and qualitative losses, thus reducing the value of crops. For these reasons, new methods to control pests must be developed.The discovery of new agrochemicals is necessary to face the problem of the emergence of resistances and the increasing of stringent regulatory standards, which are leading to the ban of many products no longer considered acceptable. All these factors are changing the research of new pesticides that is becoming a more expensive and time-consuming process. Thus, new methods to improve and speed up the discovery of new agrochemicals must be developed. In this context, the aim of this Ph.D. thesis was to explore new approaches to the synthesis of agrochemicals. Our attention was focused on the naturally derived compound-based molecules, due to the proved value of these compounds in development of agrochemicals and more in general of biologically active compounds.
The first part of this Ph.D. thesis is focused on the development of dual-target fungicides obtained by combination of the naturally derived strobilurin fungicides with succinate dehydrogenase inhibitors. The development of dual-target molecules is a well-known approach in pharmaceutic research, while it is still underexplored in the field of agrochemicals. The research work was organized following a cycle of design, synthesis, in vitro tests, and evaluation of the mechanism of action. The dual-target compounds were designed on the basis of the reported structure-activity relationship for both the classes of fungicides. The designed compounds were synthetized, and the antifungal activity was screened in vitro by measurement of the mycelium growth inhibition. Finally, the mechanism of action was evaluated in silico by docking studies and in vitro in a cell free system.
The second part of this dissertation was focused on the development of versatile synthetic approaches in the synthesis of biologically active natural compounds. SmI2 chemistry was employed in light of the remarkable synthetic power of this reagent. First, a SmI2-mediated Reformatsky reaction was developed as a complementary approach to Evans aldol reaction for the synthesis of precursors of cembranoids. Then, a SmI2-mediated pinacol coupling was investigated as a key step for the synthesis of the natural herbicide auscalitoxin aglycone.
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Starok, Marcelina Anna. "EGFR inhibition by curcumin in cancer cells : a dual mode of action." Thesis, Compiègne, 2014. http://www.theses.fr/2014COMP2093.
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Le récepteur de facteur de croissance épidermique (EGFR) est une cible commune de thérapie anticancéreuse. Aujourd'hui, la recherche de nouvelles molécules inhibitrices de ce récepteur se tourne vers des substances naturelles. Un des composés naturels les plus prometteurs qui ont montré une activité anti-EGFR est la curcumine, un polyphénol présent dans les rhizomes de Curcuma longa. Il y a de nombreux rapports décrivant son effet sur l'activité kinase du récepteur, le rendement d'autophosphorylation, le niveau d'expression et les processus liés à la fonction EGFR comme la prolifération cellulaire. Néanmoins, l'ensemble des mécanismes d’intercation de la curcumine avec l'de l'EGFR n’est pas entièrement élucidée. Nous avons démontré que le mode d'action de la curcumine est double. La curcumine est capable d'inhiber partiellement, mais directement l'activité enzymatique du domaine intracellulaire de l'EGFR. Mais le travail présenté attire l'attention sur le rôle de l'environnement de la membrane de l'EGFR au niveau d'action de la curcumine. Nous avons montré que l'insertion de curcumine dans la membrane plasmique aboutit à sa rigidification et par conséquent la limitation de la diffusion du récepteur. Le suivi de particules à l'unité analyses a confirmé que le coefficient de diffusion de l'EGFR dans la membrane des cellules cancéreuses diminué de manière significative en présence de la curcumine, susceptibles d'influencer la dimérisation du récepteur et l'activation tour à tourEpidermal Growth Factor Receptor (EGFR) is a common target of anticancer therapy. Nowadays the search for new molecules inhibiting this receptor is turning towards natural substances. One of the most promising natural compounds that have shown an anti-EGFR activity is curcumin, the polyphenol found in the rhizomes of Curcuma longa. There are numerous reports describing its effect on the receptor kinase activity, the autophosphorylation yield, the expression level and the processes related to EGFR function like cell proliferation. Nevertheless, the entire mechanism of how curcumin interact with the EGFR is not fully elucidated. We demonstrated that the mode of action of curcumin is dual. Curcumin is able to inhibit directly but partially the enzymatic activity of the EGFR intracellular domain. But the presented work brings attention to the role of the EGFR membrane environment at the curcumin action level. We showed that the curcumin insertion in plasma membrane leads to its rigidification and as a consequence to limitation of the receptor diffusion. Single particle tracking analyses confirmed that the diffusion coefficient of EGFR in the cancer cell membrane significantly decreased in the presence of the curcumin, which might influence the receptor dimerization and in turns its activation
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Guéret, Pierre. "Développement clinique de l'EP217609 et de son antidote l'avidine." Thesis, Brest, 2017. http://www.theses.fr/2017BRES0130.
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Les pentasaccharides sont des inhibiteurs indirects du facteur Xa ayant des profils pharmacocinétiques très prédictibles. En raison de la liaison de forte affinité des pentasaccharides à l'antithrombine, cette pharmacocinétique peut être prédite mais aussi transférée à d'autres molécules qui leur sont liées de manière covalente. L'EP42675 combine dans une seule molécule, une antithrombine directe réversible peptidomimétique (analogue de l'α-NAPAP), et un pentasaccharide inhibiteur indirect du facteur Xa antithrombine dépendant (analogue du fondaparinux). L'EP217609 est le dérivé biotinylé de l'EP42675. Son action anticoagulante peut être neutralisée par l'avidine qui se lie avec une grande affinité et spécificité à la fraction biotine de l'EP217609. La première indication cible de l'EP217609 et de son antidote l'avidine est la chirurgie cardiaque nécessitant une circulation extracorporelle. La deuxième indication cible est le traitement des syndromes coronariens aigus nécessitant ou non une intervention coronarienne percutanée. Les études précliniques et cliniques de phase I et phase IIa résumées ici démontrent l'intérêt d'un tel concept de couplage avec un pentasaccharide : absence de dissociation entre les deux entités, faible variabilité intra et interindividuelle des paramètres pharmacocinétiques et pharmacodynamiques, et une neutralisation de l'activité anticoagulante de l'EP21609 quasi complète et sans effet rebondPentasaccharides are indirect inhibitors of factor Xa with highly predictable pharmacokinetic profiles. Because of the high affinity binding of pentasaccharides to antithrombin, this pharmacokinetics can be predicted but also transferred to other molecules covalently bound to them. EP42675 combines in a single molecule, a reversible direct antithrombin (α-NAPAP peptidomimetic analog), and a pentasaccharide similar to fondaparinux with an indirect anti-factor Xa activity. EP217609 is the biotinylated derivative of EP42675 whose anticoagulant activity can be neutralized by avidin which binds with high affinity and specificity to the biotin moiety of EP217609.The first target indication of EP217609 and its antidote avidin is cardiac surgery requiring extracorporeal circulation. The second target indication is the treatment of acute coronary syndromes requiring or not a percutaneous coronary intervention.The preclinical and clinical Phase I and IIa studies summarized here demonstrate the value of such a coupling concept to the pentasaccharide: absence of dissociation between the two entities, low intra- and interindividual variability of the pharmacokinetic and pharmacodynamic parameters, and an almost complete neutralization of the EP217609 anticoagulant activity with no rebound effect
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Bendjeddou, Lyamin. "Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P615.
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La phosphorylation des protéines par les kinases est l’une plus importantes modification post-traductionnelle dans les processus cellulaires tels que la division, la différenciation, la prolifération et l’apoptose. Due à leur rôle clef, un dérèglement des protéines kinases peut entrainer de nombreuses pathologies proliférative telles que le cancer et non prolifératives telles que les maladies neurodégénératives. Le travail de thèse s’est construit autour de 2 séries d’inhibiteurs de protéine kinases comportant les noyaux imidazo[1,2-b]pyridazine et imidazo[4,5-b]pyridine. L’objectif est d’inhiber sélectivement les protéines kinases choisies, pour leurs implications dans les pathologies visées au laboratoire. Les imidazo[1,2-b]pyridazines ont été préparées pour identifier des inhibiteurs de CLK1 et DYRK1A, cibles potentielles dans la maladie d’Alzheimer. Parmi les imidazo[1,2-b]pyridazines synthétisées, plusieurs molécules se sont révélées particulièrement sélectives de DYRKs et CLKs, avec des IC50 < 100 nM. Une relation structure-activité basée sur la synthèse de 70 molécules, a permis de dégager des éléments structuraux de la sélectivité des molécules. L’évaluation des produits a également été portée sur les kinases de parasites. Il a ainsi été possible d’identifier quelques inhibiteurs actifs sur PfCLK1. La seconde partie de cette thèse avait pour objectif l’optimisation du protocole de synthèse imidazo[4,5-b]pyridines, analogue de la roscovitine. Des dérivés s’étaient révélés capables d’inhiber la formation de kystes, dans un modèle cellulaire de polykystose rénale. Une synthèse en sept étapes a conduit à plusieurs grammes d’imidazo[4,5-b]pyridine 3,5,7 trisubstitués, qui sont ainsi disponibles pour l’évaluation in vivoPhosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo
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Schweppenhäuser, Johannes. "Selektive und duale COX-1-COX-2-Inhibitoren aus der Reihe der Methanone Synthese, Testung, Struktur-Wirkungs-Beziehungen /." [S.l.] : [s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=960235728.
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Eyermann, Barbara [Verfasser], Stephan A. [Akademischer Betreuer] Sieber, Wolfgang [Gutachter] Eisenreich, and Stephan A. [Gutachter] Sieber. "A Dual Inhibitor Attenuates Biofilm Formation and Virulence in Staphylococcus aureus and Manipulation of ClpP Activity / Barbara Eyermann ; Gutachter: Wolfgang Eisenreich, Stephan A. Sieber ; Betreuer: Stephan A. Sieber." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1201482755/34.
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Rennó, André Lisboa 1984. "Efeitos de duas estatinas sobre células-tronco neoplásicas em modelo murino de carcinogênese mamária por indução química." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312485.
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Orientador: André Almeida SchenkaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O câncer mamário é a neoplasia maligna mais incidente e a principal causa de óbito por malignidade no sexo feminino no Brasil e no mundo. Estipula-se que há mais de 1.2 milhões de novos casos anuais de câncer de mama, e que a heterogeneidade e a complexidade molecular do câncer de mama dificultam estratégias terapêuticas de prevenção e tratamento desta doença. Atualmente, acredita-se que, em diversas neoplasias, incluindo o câncer de mama, a célula alvo de mutações cumulativas responsáveis pelo desenvolvimento do fenótipo canceroso é uma célula-tronco adulta. Independentemente da origem da neoplasia (se em célula madura/diferenciada ou em CT), é possível constatar in vitro e in vivo, na grande maioria dos tumores malignos, uma subpopulação de células indiferenciadas, com características fenotípicas de célula-tronco. Tais células são designadas como "células tronco cancerosas ou neoplásicas (CTNs)". Com frequência, especula-se se as CTNs seriam responsáveis pela heterogeneidade morfológica e molecular de algumas neoplasias mamárias. Em conjunto, essas peculiaridades das CTNs as tornam importantes alvos no desenvolvimento de novas abordagens farmacoterapêuticas antineoplásicas. Recentemente, Gauthaman et al (2009) demonstraram de forma inédita em estudos in vitro que estatinas apresentam efeito inibitório específico sobre células tronco embrionárias com alterações cariotípicas e células de linhagens neoplásicas mamárias com fenótipo CTN, não afetando o crescimento de células tronco normais. As estatinas são inibidores competitivos da 3-hidroxi-3-metilglutaril coenzima A (HMG-CoA) e são amplamente utilizada para o tratamento de doenças cardiovascular primário e secundário. Além de amplamente utilizadas na prevenção e tratamento de doenças cardiovasculares secundárias a dislipidemias, evidências cumulativas apontam para um possível papel destas drogas na prevenção ou regressão de processos neoplásicos. Entre os efeitos antineoplásicos comprovados das estatinas, destacam-se: a inibição da proliferação celular, a promoção de apoptose, a inibição da angiogênese e a prevenção de metástases. Assim, buscou-se neste trabalho elucidar o efeito da sinvastatina e pravastatina sobre células progenitoras e CTNs e em algumas vias de sinalização intracelular em modelo de carcinogênese mamária (baseado na indução com 7,12 dimetilbenz(a)antraceno[DMBA]) em ratas Sprague-Dawley. Após um tratamento de 14 dias com as estatinas, as mamas das ratas foram analisadas para verificar a imunoexpressão de células progenitoras e CTNs (CD133, CD24, CD44 e EpCAM), variáveis biológicas (volume tumoral, mitose, índice proliferativo) além da análise proteica de Akt e Src. A maior dose da sinvastatina testada (40 mg/Kg) diminui o número de tumores desenvolvidos, volume e incremento tumoral e os índices de proliferação celular. Não houve alteração da percentagem de necrose com o tratamento com as estatinas. Ainda, sinvastatina diminuiu os níveis da fosforilação da Akt e aumento da PTEN, não havendo diferenças significantes nos níveis da Src. Sinvastatina também foi capaz de reduzir o número de células positivas CD133, CD24 e CD44. Pelas doses testadas, não houve diferença dos parâmetros biológicos analisados com o tratamento com a pravastatina. Em conclusão, neste modelo, o tratamento crônico com a sinvastatina apresentou efeitos citostáticos, ações reguladoras na via da Akt além do controle de células progenitoras e CTNs em modelo in vivo de carcinoma mamário
Abstract: Breast cancer is the malignant neoplasm with the highest incidence and the main cause of death by cancer within females in Brazil and in the world. It is estimated that there are over 1.2 million new annual cases of breast cancer. The heterogeneity and the molecular complexity of this type of cancer complicate the therapeutic strategies for its prevention and treatment. Nowadays, it is believed that in many different neoplasms, including breast cancer, the cell which is the target of cumulative mutations responsible for the development of the cancerous phenotype is an adult stem cell. Regardless the origin of the neoplasm (whether in mature/differentiated cell or in SC), a subpopulation of undifferentiated cells with phenotypic characteristics of stem cells can be seen in vitro and in vivo in most malignant tumours. These cells are designated as "neoplastics or cancer stem cells (CSCs)". It is often especulated whether CSCs would be responsible for the molecular and morphological heterogeneity in some breast neoplasms. The peculiarities of the CSCs make them a relevant/an important/a serious object for the development of new antineoplastic pharmacotherapeutic approaches. Recently, Gauthaman et al (2009) demonstrated in unprecedented in vitro studies that statins exhibit specific inhibitory effect on embryonic stem cells with karyotypic alterations and neoplastic mammary cell lines with phenotype CSC, not affecting the growth of normal stem cells. Statins are competitive inhibitors of coenzyme 3-hydroxy-3-methylglutaryl A (HMG-CoA) reductase and are widely used for the primary and secondary treatment of cardiovascular diseases. Moreover, cumulative evidence points to a possible role of these drugs in the prevention or regression of neoplastic processes. Amongst the proven anticancer effects of statins, some of them stand out such as: inhibition of cell proliferation, promotion of apoptosis, inhibition of angiogenesis and metastasis prevention. Thus, this study sough to elucidate simvastatin and pravastatin effects on progenitor cells and NSCs, and on some signaling pathways in breast carcinogenesis model (based on induction 7,12 dimethylbenz (a) anthracene [DMBA]) in female Sprague-Dawley rats. After a 14 days treatment with the statins, the rats' breasts were examined to verify immunostaining of progenitor cells and CSCs (CD133, CD24, CD44 and EpCAM), biological variables (tumor volume, mitosis, proliferation index) in addition to protein analysis of Akt and Src. The highest dose of the tested simvastatin (40mg/kg) decreased the number of tumors developed, volume and tumor growth as well as the cell proliferation index. There was no change in the percentage of necrosis to treatment with statins. Furthermore, simvastatin decreased the levels of Akt phosphorylation and increased PTEN levels, without significant differences in Src levels. Simvastatin was also able to reduce the number of CD133, CD24 and CD44 positive cells. For the doses tested, there was no difference on the analyzed parameters in the treatment with pravastatin. As a conclusion, in this model, chronic treatment with simvastatin showed cytostatic effects, regulatory actions towards Akt, as well as the control of CSCs and progenitor cells in the in vivo model of mammary carcinoma
Doutorado
Farmacologia
Doutor em Farmacologia
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Yokota, Asumi. "INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph[+] leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity." Kyoto University, 2009. http://hdl.handle.net/2433/126449.
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Kyoto University (京都大学)0048
新制・課程博士
博士(医学)
甲第14902号
医博第3387号
新制||医||977(附属図書館)
27340
UT51-2009-M816
京都大学大学院医学研究科医学専攻
(主査)教授 武藤 誠, 教授 武田 俊一, 教授 松岡 雅雄, 教授 戸井 雅和
学位規則第4条第1項該当
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Moraes, Bibiana Silveira. "Alterações fisiológicas e morfológicas de duas cultivares de arroz irrigado após aplicação do herbicida imazamox na fase reprodutiva." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/3216.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorWeed control is one of the main agricultural practices indispensable to ensure profitability and crop success. In paddy rice field, red rice is the most important weed due to its difficult control. A widespread control method is the use of rice cultivars resistant to herbicides which are inhibitors of ALS, since it is possible to have a selective chemical control. Studies showed that the late control with imazamox promotes efficient control of red rice escapes. Thus, the objective of this research was to check the effects of imazamox application in the reproductive phase of two rice cultivars that differ in the level of resistance to imidazolinones. Two studies were carried out at the Federal University of Santa Maria in the years of 2009/10 and 2010/11. Imazamox was applied in different stadium of development and doses. At the end of the application the final dose was 80 g a.i ha-1 for all treatments. Results showed that independent of the date of the imazamox application in the reproductive phase of rice, the grain yield reduced and spikelet sterility of IRGA 422 CL increased. In general, the parameters 1000-grain weight, flag leaf length, panicule length, fresh and dry weight of panicles, and panicles per m2 showed a reduction in practically all imazamox treatments in the IRGA 422 CL cultivar. Changes in the biochemical parameters (chlorophyll, carotenoids, thiobarbituric acid reactive substances, superoxide dismutase, catalase and ascorbate peroxidase) were observed in leaves and panicles from main culm in some treatments, demonstrating that the oxidative stress promoted by imazamox may have contributed to grain yield reduction and the high percentage of sterile spikelet from IRGA 422 CL cultivar. Morphologic and anatomical changes showed that imazamox application in the panicle differentiation promoted similar changes to homeotic changes observed in rice mutant. Moreover, in the other treatments different morphologic and anatomical changes were observed. Therefore, morphologic and anatomical changes were likely to be responsible for grain yield reduction and high percentage of spikelet sterile from IRGA 422 CL.
O controle de plantas daninhas é uma das práticas agrícolas indispensáveis para garantir rentabilidade e sucesso no cultivo. No cultivo de arroz irrigado, o arroz vermelho é a planta daninha de maior importância, devido sua dificuldade de controle. Um método de controle bastante difundido é o uso de cultivares resistentes aos herbicidas inibidores da ALS, pois permite um controle químico seletivo. Estudos demonstram que o controle tardio com o herbicida imazamox promove controle eficiente de escapes de arroz vermelho. Por isso, o objetivo deste trabalho foi verificar os efeitos da aplicação do imazamox na fase reprodutiva de duas cultivares de arroz irrigado (IRGA 422 CL e PUITÁ INTA CL) que diferem quanto ao nível de resistência as imidazolinonas. Em vista do exposto, foram conduzidos dois estudos na área experimental da Universidade Federal de Santa Maria (2009/10 e 2010/11). O imazamox foi aplicado em diferentes estádios de desenvolvimento e doses, sendo que a dose final foi de 80 g i.a ha-1. Com os resultados obtidos conclui-se que independente da data de aplicação do imazamox na fase reprodutiva da cultura ocorreu redução da produtividade de grãos e aumentou a esterilidade de espiguetas da cultivar IRGA 422 CL. De maneira geral, os parâmetros: peso de mil grãos, comprimento da folha bandeira, comprimento de panícula, peso fresco e seco de panículas, e número de panículas por metro quadrado mostraram redução em praticamente todos os tratamentos na cultivar IRGA 422 CL. Alterações nos parâmetros bioquímicos (clorofila, carotenoides, substâncias reativas ao ácido tiobarbitúrico, superóxido dismutase, catalase e ascorbato peroxidase) foram observadas em folhas e panículas do colmo principal em alguns tratamentos, demonstrando que o estresse oxidativo provocado pela aplicação do imazamox pode ter contribuído para a redução da produtividade de grãos e o elevado percentual de espiguetas estéreis da cultivar IRGA 422 CL. A cultivar PUITÁ INTA CL não sofreu alterações em todos os parâmetros avaliados neste estudo. As alterações morfológicas e anatômicas demonstraram que a aplicação de 80 g i.a ha-1 imazamox na diferenciação da panícula promoveu alterações semelhantes às alterações homeóticas observadas em arroz mutante. Além disso, nas plantas que receberam a dose de 80 g i.a ha-1 após 14 dias da diferenciação do primórdio floral (DPF) e as plantas que receberam a dose de 80 g i.a ha-1 em aplicação fracionada (metade da dose 7 dias após DPF e metade da dose aos 14 dias após DPF) mostraram alterações morfológicas e anatômicas do grão de pólen. Dado o exposto, os resultados obtidos sugerem que as alterações morfológicas e anatômicas foram responsáveis pela redução da produtividade de grãos e alto percentual de espiguetas estéreis da cultivar IRGA 422 CL.
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Wang, Qinzhe. "Developing Approaches to Treat Canavan Disease." University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493301078219765.
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Geny, Charlotte. "Recherche d'inhibiteurs naturels des protéines anti-apoptotiques Bcl-xL et Mcl-1." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114833/document.
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Dans le but de rechercher des inhibiteurs naturels des protéines anti-Apoptotiques Bcl-XL et Mcl-1, deux essais biologiques ont été mis au point sur Bcl-XL/Bak-CF et Mcl-1/Bid-CF. Ces deux tests utilisent la polarisation de fluorescence et sont basés sur la liaison d’un peptide pro-Apoptotique marqué à la fluorescéine (Bak-CF ou Bid-CF) avec une protéine anti-Apoptotique (Bcl-XL ou Mcl-1). Au total, près de 600 extraits de pantes, provenant de diverses régions du monde, ont été criblés sur les deux protéines Bcl-XL et Mcl-1 permettant de sélectionner les extraits acétate d’éthyle des écorces de Knema hookeriana (Myristicaceae) et de Fissistigma latifolium (Annonaceae). L’analyse chimique des constituants des écorces de K. hookeriana a conduit à l’isolement de 12 lipides phénoliques dont 6 n’avaient jamais été isolés d’un organisme vivant. Seuls les acides anacardiques ont révélé de très fortes inhibitions de l’interaction Bcl-XL/Bak-CF et Mcl-1/Bid-CF dans les essais par polarisation de fluorescence. Une étude plus approfondie des interactions entre le plus actif des produits et les protéines (Bcl-XL, Mcl-1, Bak et Bid) par RMN, a montré que la modulation des interactions Bcl-XL/Bak et Mcl-1/Bid n’est pas liée à l’affinité de l’acide anacardique pour les protéines Bcl-XL et Mcl-1 mais a une forte affinité pour les peptides Bid et Bak. Le fractionnement bioguidé de l’extrait AcOEt des écorces de F. latifolium a conduit à l’isolement d’une nouvelle chalcone prénylée, la (±)-Écarlottone possédant une dual activité sur les protéines, Bcl-XL et Mcl-1. Par la suite, le fractionnement "RMN-Guidé" a mené à l’isolement de 6 analoguesIn order to search for natural inhibitors of anti-Apoptotic protein Bcl-XL and Mcl-1, two bioassays were developed on Bcl-XL/Bak-CF and Mcl-1/Bid-CF. Both assays use fluorescent polarisation, and are based on binding of a fluorescein labeled pro-Apoptotic peptide (Bak-CF or-CF Bid) with an anti-Apoptotic protein (Bcl-XL or Mcl-1). Nearly 600 extracts from various parts of the world were screened on both Bcl-XL and Mcl-1 proteins to select the ethyl acetate bark extracts of Knema hookeriana (Myristicaceae) and Fissistigma latifolium (Annonaceae). The chemical analysis of the constituents of K. hookeriana has led to the isolation of 12 phenolic lipids. 6 of them were never isolated from a living organism. Only anacardic acids showed very strong inhibition of the interaction Bcl-XL/Bak-CF and Mcl-1/Bid-CF in fluorescent polarisation assays. Further study of the interactions between the most active anacardic acid and proteins (Bcl-XL, Mcl-1, Bak and Bid) by NMR showed that the modulation of Bcl-XL/Bak and Mcl-1/Bid is not related to the affinity of the compoun to the anti-Apoptotic proteins, Bcl-XL and Mcl-1 but to its affinity for peptides, Bid and Bak. The bioguided fractionation of the AcOEt bark extract of F. latifolium led to the isolation of a novel prenylated chalcone, (±)-Écarlottone having a dual activity on protein, Bcl-XL and Mcl-1. Subsequently, fractionation "NMR-Guided" led to the isolation of 6 new analogs
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Huang, Hung-Jin, and 黃泓縉. "Virtual screening and drug design for H1N1 dual-target inhibitors." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/70524014777917613113.
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碩士中國醫藥大學
生物科技學系碩士班
98
Influenza viruses contain two major surface glycoproteins, hemagglutinin and neuraminidase, which are therapeutic targets for inhibiting influenza viruses from infecting host cell. Pandemic of H1N1/09 virus has been reported, and drug resistance was regarded as an important issue since 2009. Thus, the purpose of this research is to design novel potent dual inhibitors for the two surface glycoproteins on H1N1 virus. In this study, structure-based and ligand-based drug designs were performed to analyze interactions between target proteins and ligands, and molecular dynamics (MD) simulations were carried out to analyze the interaction of receptor-ligand complexes. Potent derivatives from structure-based design were ranked by sum of DockScore of two target proteins (H1 and N1) and were compared with Tamiflu (Oseltamivir) and Relenza (Zanamivir) to select the top 10 candidates. Among the scaffold of top 10 candidates, five key features were recognized for binding to H1 and N1. In quantitative structure-activity relationship models, these features were able to fit with their steric, electrostatic, hydrogen bond acceptor and donor fields. These fields were close to key residues of H1 and N1 binding site. Finally, 2-aminopyridinium group was noticed to play an important role in binding ability during 20ns MD simulations. From structure-based and ligand-based designs, we hope that we provided useful information for designing anti-viral compounds targeting H1 and N1, and we recommend the top 10 candidates from our experiments for further drug development testing.
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Kuo, Chia-Chen, and 郭家珍. "Discovery of dual target inhibitors for Alzheimer's disease by virtual screening." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/7269ab.
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碩士國立東華大學
生命科學系
105
The most common type of dementia is Alzheimer's disease (AD), which makes up 60% to 70% of cases. Globally, dementia affects 47 million people. Patients will have cognitive and memory function of brain degeneration symptoms. Acetylcholine (ACh) is the neurotransmitter used at the Central Nervous System (CNS). Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease. Two types of ACh enzyme are found in the CNS, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). BuChE enzyme activity extended to all parts of the brain receiving cholinergic innervation and that it could hydrolyze the ACh surrogate AChE. Screening compounds that inhibit both hydrolases is the primary objective of this study. The experiment by virtual screening, including genetic function approximation (GFA), multiple regression analysis (MLR), support vector machines (SVM), molecular docking and molecular dynamics simulation (MD). The model was subsequently used as a molecular docking to identify potential hits form Traditional Chinese Medicine (TCM) database. The binding stabilities of these hits were further validated using molecular dynamics simulations. Finally, three candidate drugs were identified as Saussureamine B, Scoulerine and Anisodine. It is desirable to provide more inhibitory activity dual target inhibitor for AD.
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Capitosti, Scott Michael. "Thalidomide analogues : dual inhibitors of both angiogenesis and human cancer cell proliferation /." 2004. http://wwwlib.umi.com/dissertations/fullcit/3144655.
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Elsinghorst, Paul Wilhelm [Verfasser]. "Dual-mode cholinesterase inhibitors targeting muscarinic receptors / vorgelegt von Paul Wilhelm Elsinghorst." 2007. http://d-nb.info/983086427/34.
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Kuo, Po-Hsien, and 郭柏賢. "The Developments of Dual EGFR and c-Met Kinase Inhibitors and DBPR104 Phosphate Prodrugs." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/eg23ma.
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Sola, I., S. Castellà, E. Viayna, C. Galdeano, M. C. Taylor, Stephen Y. Gbedema, B. Pérez, et al. "Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity." 2015. http://hdl.handle.net/10454/7485.
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YesDual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
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Yo-HuaLi and 李祐華. "Targeting Dual-Specificity Phosphatase-2 by Novel Histone Deacetylase Inhibitors as a Cancer Therapeutic Strategy." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/x9a783.
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