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Büchold, Christian. "Synthese und Testung cis-konfigurierter Aziridine als pseudo-irreversible Inhibitoren der sekretorischen Aspartatproteasen von Candida albicans." kostenfrei, 2009. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3935/.
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Smar, Michael William. "Part 1: Reversible and irreversible inhibitors of aldose reductase as probes of the inhibitor binding site. Part 2: Synthesis of permanently charged and permanently uncharged dopamine agonists /." The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487597424138323.
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Borrello, Maria Teresa. "Reversible and irreversible LSD1 inhibitors." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/59682/.
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Environmental factors and lifestyle can alter the way our genes are expressed influencing a network of chemical switches within our cells collectively known as the Epigenome. Among the epigenetic mechanisms orchestrating the gene expression, methylation is of foremost importance and probably fair to say, still incompletely decoded. Dysregulations of histone methylation patterns lead to the repression or activation of signalling pathways that often promote the genesis and progression of disease states. Lysine specific demethylase 1 (LSD1) oxidatively removes methyl groups from histone H3 and its aberrant activity has been correlated with the development of a broad range of pathologies. Therefore, specific inhibitors of LSD1 have potential in pharmacological applications. Research into LSD1 and its functions in normal and abnormal cells has been hindered by the lack of a specific and potent suppressor. The development of a selective inhibitor could not only foster the understanding of the biological roles of LSD1 but also represent a breakthrough for the design of novel drugs for a range of burdensome diseases. Here we investigate on reversible and irreversible inhibitors of LSD1, with the hope of broadening the current knowledge on this epigenetic target. By analysing the LSD1 interaction with the transcription factor Snail-1, we generated a series of small peptides as potential reversible inhibitors. The synthetic peptides were then evaluated in cellular assays. In search of novel non-covalent LSD1 blockers, we next explored Phage Display technology. Thereafter, we targeted LSD1 covalently by synthesising multiple structural analogues of the clinically used antidepressant TCP (Parnate®), which is a known irreversible suppressor of LSD1 activity. We evaluated their ability of inhibiting LSD1 in a cell-free assay and the compounds showing enzymatic inhibition were tested as potential anti-proliferative and differentiating agents in leukaemia cell lines. Finally, we generated activity-based probes to fluorescently label LSD1 for biological applications.
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Burger, Alain. "Inhibiteurs irreversibles de la biosynthese de l'ecdysone." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13081.
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Coxon, Christopher Robert. "Design and synthesis of irreversible inhibitors of Nek2 kinase." Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627743.
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Snider, Catherine E. "Synthesis and biochemical evaluation of irreversible inhibitors of aromatase /." The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487266362338344.
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Berabez, Rayan. "Conception et validation préclinique de nouveaux inhibiteurs de LIMK pour le traitement de la Neurofibromatose de type 1." Electronic Thesis or Diss., Orléans, 2023. http://www.theses.fr/2023ORLE1070.
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La neurofibromatose de type 1 (NF1) est une maladie génétique qui se manifeste entre autre par l'apparition de tumeurs bénignes localisées au niveaux des terminaux nerveux appelés neurofibromes cutanés (NFc). Au cours de ces dernières années, de nouvelles cibles thérapeutiques sont apparues telles que les LIM kinases (LIMKs), enzymes responsables du dynamisme du cytosquelette et dont la suractivation est liée à différentes pathologies comme la NF1, le glioblastome ou l'ostéosarcome. Un travail de chimie médicinale a été donc initié dans le but de concevoir de nouveaux inhibiteurs sélectifs des LIMKs. Dans un premier temps, des études de relations structure-activité (RSA) ont été réalisées sur les 3 principaux sites de pharmacomodulations du composé de type pyrrolopyrimidine préalablement développé par notre équipe. Le développement de différentes stratégies de synthèse a été entrepris permettant un accès efficace à un grand nombre de produits finaux (84). L'optimisation de la partie aniline des composés a mené à la synthèse de 49 inhibiteurs des LIMKs, avec des constantes d'inhibition inférieures à 5 nM pour certains d'entre eux. Par la suite, l'élaboration d'une voie de synthèse optimisée en 15 étapes a permis de remplacer le cycle central 3,6-dihydropyridine jusqu'alors inchangé, par un dérivé de l'acide 1-aminocyclohex-3-ène-1-carboxylique. Enfin, une nouvelle série d'inhibiteurs a été préparée en remplaçant la base hétérocyclique pyrrolo[2,3-d]pyrimidine par des dérivés 7-azaindoliques. Nous avons observé une meilleure sélectivité pour les LIMKs vis-à-vis des ROCKs pour les 23 produits obtenus. Des évaluations in vitro approfondies de nos meilleurs inhibiteurs sur plusieurs lignées cellulaires ont mené à la sélection de deux composés pour être utilisés lors d'essais in vivo sur un modèle de souris original de NF1. En parallèle, de nouveaux modes d'inhibition des LIMKs ont été développés avec la synthèse d'un inhibiteur irréversible ciblant LIMK1, ainsi que 4 PROTACs qui ont provoqué la dégradation des LIMKs par la voie protéasome-ubiquitine sur plusieurs lignées cellulairesNeurofibromatosis type 1 (NF1) is a genetic disease characterized by the development of cutaneous neurofibromas (cNF) (benign tumors) located at nerve endings. LIM kinases (LIMKs), enzymes responsible for cytoskeleton dynamics, have emerged in recent years as valid therapeutic targets for this disease. These enzymes are overactivated in several pathologies including NF1, glioblastoma or osteosarcoma. A medicinal chemistry project was therefore initiated with the aim of designing new selective inhibitors of LIMKs. Initially, structure-activity relationship (SAR) studies were conducted on the 3 main pharmacomodulation sites of the pyrrolopyrimidine-type compounds previously developed by our team. The development of various synthetic strategies was undertaken, allowing efficient access to a large number of final products (84). Optimization of the aniline portion of the compounds led to the synthesis of 49 LIMKs inhibitors, with inhibition constants lower than 5 nM for several derivatives. Subsequently, an optimized 15 steps synthetic route was developed to replace the previously unchanged central ring 3,6-dihydropyridine with a derivative of 1-aminocyclohex-3-ene-1-carboxylic acid. Finally, a new series of inhibitors was developed by replacing the heterocyclic pyrrolo[2,3-d]pyrimidine base by 7-azaindole derivatives. Improved LIMK vs. ROCK selectivity was observed among the 23 obtained products. Following extensive in vitro evaluation of our best inhibitors on several cell lines, two compounds were selected for in vivo trials on an original mouse model of NF1. In parallel, new modes of LIMKs inhibition were developed with the synthesis of an irreversible inhibitor targeting LIMK1, as well as 4 PROTACs that induced LIMKs degradation through the ubiquitin-proteasome system in several cell lines
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Äbelö, Angela. "Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors." Doctoral thesis, Uppsala University, Division of Pharmacokinetics and Drug Therapy, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3778.
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Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.
The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed.
In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme.
Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.
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Ekici, Ozlem Dogan. "Design, synthesis, and evaluation of novel irreversible inhibitors for caspases." Diss., Georgia Institute of Technology, 2003. http://hdl.handle.net/1853/5333.
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Äbelö, Angela. "Pharmacodynamic modelling of irreversible and reversible gastric proton pump inhibitors /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3778.
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Hoang, Jane Vu. "Inactivation of Choline Oxidase by Irreversible Inhibitors or Storage Conditions." Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_theses/4.
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Choline oxidase from Arthrobacter globiformis is a flavin-dependent enzyme that catalyzes the oxidation of choline to betaine aldehyde through two sequential hydride-transfer steps. The study of this enzyme is of importance to the understanding of glycine betaine biosynthesis found in pathogenic bacterial or economic relevant crop plants as a response to temperature and salt stress in adverse environment. In this study, chemical modification of choline oxidase using two irreversible inhibitors, tetranitromethane and phenylhydrazine, was performed in order to gain insights into the active site structure of the enzyme. Choline oxidase can also be inactivated irreversibly by freezing in 20 mM sodium phosphate and 20 mM sodium pyrophosphate at pH 6 and -20 oC. The results showed that enzyme inactivation was due to a localized conformational change associated with the ionization of a group in close proximity to the flavin cofactor and led to a complete lost of catalytic activity.
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Ebrahimian, Soheila. "Synthesis and biochemical evaluation of enzyme-activated irreversible aromatase inhibitors /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487777901661214.
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Ekici, Özlem Doğan. "Design, synthesis, and evaluation of novel irreversible inhibitors for caspases." Available online, Georgia Institute of Technology, 2004:, 2003. http://etd.gatech.edu/theses/available/etd-04062004-164633/unrestricted/ekici%5Fozlem%5Fd%5F200312%5Fphd.pdf.
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Yu, Zhonghua Walter. "Characterization of irreversible inhibition of proteases by mass spectroscopy." Scholarly Commons, 1995. https://scholarlycommons.pacific.edu/uop_etds/2805.
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Proteases are present in all living organisms and are involved in various biological processes. Inhibition of protease activities in disease-causing agents is one strategy for rational drug design. Characterization of the protease inhibition processes is essential for understanding the inhibition mechanisms and for developing efficient therapeutics. This work represents a major challenge in analytical biochemistry. In this study, a strategy based on mass spectrometry has been developed to characterize irreversible inhibition of proteases. Five proteases representing three of the four protease classes were irreversibly inhibited by various irreversible inhibitors, some of which are potential drug candidates. In all the cases, the stoichiometry of each of the protease/inhibitor complexes was determined by electrospray ionization mass spectrometry through measurement of the complex's molecular weight. The inhibited proteases were then enzymatically cleaved and the resulting peptides isolated for further characterization by high performance tandem mass spectrometry. Attention was focused on the determination of the site(s) of the modification and the reaction mechanisms involved. High energy collision induced dissociation mass spectra of each modified peptide provided information on the exact modification site(s) and the detailed chemical nature of the covalent complex. The serine protease trypsin, the cysteine protease cruzain, and the aspartic proteases, HIV-2 protease and SIV protease, were covalently modified only at one amino acid residue, while the aspartic protease, HIV-1 protease, was found to be modified at three sites by the haloperidol derivative compounds. In addition, mass spectrometry has been applied to characterize the plasma glycoprotein, biotinidase, and to obtain partial peptide sequences of a membrane-bound protein, UDP-GalNac:polypeptide N-acetylgalactosaminyl transferase, using a low picomole quantity of sample.
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Fenner, S. "Potential active site directed irreversible inhibitors for phosphatases and leucine aminopeptidases." Thesis, University of Bristol, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379617.
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Xie, Ting. "Targeting `Undruggable' Cancer Proteins with Irreversible Small Molecule Inhibitors: Her3 and KRas." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11384.
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With the lighting speed revolution of technologies in chemistry and biology, increasing number of proteins which eluded scientists' efforts to block them before and were labeled as `undruggable', were successfully targeted with small molecule inhibitors. During the past five years, I have been working on figuring out the path to inhibit two elusive cancer targets: Her3 and KRas.Chemistry and Chemical Biology
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Costa, Elena. "Design, synthesis and biochemical evaluation of novel CK2 and CDK2 inhibitors." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3423919.
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Kinases are a class of enzymes, which catalyse the transfer of the terminal phosphate of a molecule of ATP, or more rarely of GTP, to a protein that acts as a substrate. This process is reversible and is maintained by the presence of other enzymes, namely the phosphatases, which catalyse the reverse reaction. An imbalance between these enzymes plays a crucial role in the occurrence of diseases, which is attributable to abnormal levels of phosphorylation.
The aim of this research was the design and synthesis of novel potent and selective benzimidazole-based inhibitors of Casein Kinase 2 (CK2) and the design and synthesis of pyrimidine-based inhibitors of Cyclin-dependent Kinase 2 (CDK2). This research was carried out at the University of Padua in collaboration with Newcastle University.
CK2 is a ubiquitous, highly pleiotropic Ser/Thr protein kinase, which has been implicated in every stage of cell cycle progression. DRB was the first CK2 ATP-mimetic inhibitor identified (IC50 = 23 μM) and was also the starting point for a new fruitful class of polyhalogenated benzimidazole-based compounds.
The synthesis of CK2 bifunctional inhibitors, which could simultaneously interact with the ATP pocket and the substrate-binding domain, was proposed. A polyhalogenated benzimidazole scaffold was used as starting point and was then coupled to different peptidic chains.
CDK2, belongs to a family of Ser/Thr kinases. In complex with regulatory subunits, cyclin E or A, CDK2 is involved in driving the cell cycle. The overexpression of CDK2 and the deregulation of cyclins associated with CDK2 are often observed in cancer. NU6300 (2), a purine-based CDK2 inhibitor (IC50 = 63 nM), can be considered the first CDK2 irreversible inhibitor due to a covalent interaction between the vinyl sulfone moiety and Lys89 within the ATP-binding domain of CDK2.
Structure-activity relationship (SAR) studies on the O6-alkylguanine series revealed that the purine pharmacophore is not a prerequisite for CDK2-inhibitory activity. Hence, a series of pyrimidine-based CDK2 inhibitors was synthesised. Structural modifications at the pyrimidine scaffold were then considered in order to investigate the binding affinity, potency and selectivity of the novel CDK2 inhibitors.
All new compounds were evaluated for CK2- and CDK2-inhibitory activity, with promising inhibitors being subjected to more comprehensive biological studies.
Concerning CDK2 inhibitors, docking and co-crystallisation studies were also performed in order to rationalise the results and propose new compounds to be synthesisedLe chinasi sono una classe di enzimi in grado di catalizzare il trasferimento di un gruppo fosfato terminale di una molecola di ATP, o più raramente di GTP, ad una proteina che agisce da substrato. Questo processo è reversibile, ed è mantenuto tale dalla presenza di altri enzimi, le fosfatasi, che catalizzano la reazione inversa. Uno squilibrio tra questi enzimi gioca un ruolo rilevante nell’incidenza di diverse patologie, le quali sono attribuibili ad elevati livelli di fosforilazione. Questo lavoro di ricerca ha avuto lo scopo di progettare e sviluppare nuovi potenti e selettivi inibitori di casein chinasi 2 (CK2) a struttura benzimidazolica, e progettare e sviluppare nuovi inibitori a struttura pirimidinica di chinasi ciclina dipendente 2 (CDK2). La ricerca è stata svolta presso l’Università degli Studi di Padova (IT) in collaborazione con l’Università di Newcastle (UK). CK2 è una Ser/Thr chinasi ubiquitaria, altamente pleiotropica e coinvolta in ogni fase della progressione del ciclo cellulare. DRB è stato il primo inibitore di CK2 ATP-mimetico ad essere identificato (IC50 = 23 μM), e anche punto di partenza per la sintesi di una nuova classe di inibitori poli-alogenati a struttura benzimidazolica. E’ stata proposta la sintesi di inibitori bifunzionali di CK2, i quali si pensa vadano ad interagire simultaneamente con la tasca catalitica dell’ATP e con il sito di legame del substrato. Come punto di partenza è stato scelto uno scaffold benzimidazolico poli-alogenato, il quale è stato poi legato ad una serie di sequenze peptidiche. CDK2 appartiene anch’essa ad una famiglia di chinasi Ser/Thr-dipendenti. CDK2, complessandosi con subunità regolatorie (ciclina A o E), è coinvolta nella progressione del ciclo cellulare. Una caratteristica ricorrente nei tumori sono la sovraespressione di CDK2 e la deregolazione delle cicline ad essa associate. NU6300, un inibitore a scaffold purinico di CDK2 (IC50 = 63 nM), è considerato il primo inibitore di CDK2 irreversibile, questo grazie all’interazione covalente tra il gruppo vinilsulfonico e un residuo di lisina (Lys89), presente all’interno della tasca catalitica dell’enzima CDK2. Studi di relazione struttura-attività (SAR) riguardanti una serie di O6-alchilguanine hanno rivelato che il farmacoforo di tipo purinico non è un requisito essenziale per l’attività inibitoria su CDK2. Per questo è stata sviluppata una serie di inibitori CDK2 di tipo pirimidinico. Sono state quindi considerate alcune modifiche strutturali allo scaffold pirimidinico, in modo da esaminare l’affinità di binding, la potenza e la selettività dei nuovi inibitori di CDK2. I nuovi inibitori sono stati valutati per la loro attività inibitoria su CK2 e CDK2 rispettivamente. Gli inibitori più promettenti sono stati poi sottoposti ad ulteriori studi biologici. Per quanto riguarda gli inibitori di CDK2 sono stati effettuati studi di docking molecolare e di co-cristallizzazione per razionalizzare i risultati ottenuti e pianificare nuove vie di sintesi
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Gotz, Marion Gabriele. "Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases." Diss., Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/8072.
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Cysteine proteases are a class of proteolytic enzymes, which are involved in a series of metabolic and catabolic processes, such as protein turnover, digestion, blood coagulation, apoptosis, fertilization and cell differentiation, and the immune response system. The development of novel potent and selective inhibitors for cysteine proteases has therefore gained increasing attention among medicinal chemists. In this thesis we have reported the design, synthesis, and evaluation of several peptidyl inhibitors for clan CA and clan CD cysteine proteases.
We have continued the investigation of dipeptidyl vinyl sulfones as potent and selective inhibitors for dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease, which is involved in the processing of intracellular proteases, such as granzymes. We have found that DPPI tolerates negatively charged amino acid residues in the P2 position with inhibition rates of 7,600 M-1s-1. Dipeptidyl vinyl sulfones with positively charged amino acid residues at the P1 position, however, do not inhibit DPPI at all.
A second project focused on the epoxidation of the double bond of the vinyl sulfone moiety of the dipeptidyl vinyl sulfones. Instead of epoxidizing the double bond, we found that an isomerization had occurred. The newly formed compounds were determined to be allyl sulfones. We tested this new class of inhibitors with clan CA proteases and obtained inhibition rates of 560 M-1s-1 for Cbz-Leu-Phe-AS-Ph with calpain I.
Two new classes of compounds for the clan CD protease S. mansoni legumain were designed, synthesized, and evaluated. Aza-peptidyl epoxides were found to be potent and selective inhibitors of S. mansoni legumain with IC50’s as low as 45 nM. Aza-peptide Michael acceptors were derived from the aza-peptide epoxide design and synthesized in an analogous fashion. The aza-peptide Michael acceptors inhibited S. mansoni legumain with even lower IC50’s, as low as 10 nM. However, the aza-peptide Michael acceptors react with thioalkylating agents contained in the buffer, such as DTT. The rates of degradation were determined spectroscopically, and half-lives of 3 to 20 minutes were measured. This observation gave us insights into the enzymatic mechanism and allowed us to determine the point of attack for the legumain active site cysteine thiol.
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Götz, Marion Gabriele. "Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases." Available online, Georgia Institute of Technology, 2004, 2004. http://etd.gatech.edu/theses/available/etd-01282004-095929/unrestricted/Gotz%5FMarionG%5F200405%5Fphd2.pdf.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2004.Dr. Suzanne Shuker, Committee Member ; Dr. Niren Murthy, Committee Member ; Dr. Donald Doyle, Committee Member ; Dr. Nicholas Hud, Committee Member ; Dr. James C. Powers, Committee Chair. Includes bibliographical references.
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SCHMITT-HOFFMANN, ANNE. "Pharmacocinetique et metabolisme des enantiomeres de l'eflornithine (alpha-difluoromethyl-ornithine), un inhibiteur irreversible de l'ornithine decarboxylase et de la vigabatrine (acide gamma-vinyl-gamma-aminobutyrique), un inhibiteur irreversible de l'oxoglutarate aminotransferase." Université Louis Pasteur (Strasbourg) (1971-2008), 1990. http://www.theses.fr/1990STR13154.
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L'alpha-difluororomethylornithine (dfmo) ainsi que l'acide gamma-vinyl-gamma-aminobutyrique (gvg) sont deux inhibiteurs irreversibles d'enzymes. Le premier par inhibition irreversible de l'ornithine decarboxylase, permet une application therapeutique dans la trypanosomiase africaine. Le gvg inhibe la gaba-t et est commercialise sous le nom de sabril#r dans le traitement de l'epilepsie. Tous deux sont un melange racemique de deux enantiomeres, le distomere n'exercant que peu ou pas d'activite propre. La methode d'analyse des enantiomeres dans les fluides biologiques est une technique de chromatographie en phase gazeuse sur colonne capillaire a phase stationnaire chirale couplee a un detecteur a capture d'electrons pour le dfmo et a un spectrometre de masse pour le gvg. La resolution des enantiomeres du gvg est obtenue sous forme d'un derive lineaire (ester n-acyl) contrairement aux enantiomeres du dfmo qui ne sont resolus que sous forme cyclique (n-acyl-delta-lactame). L'etude de la pharmacocinetique des enantiomeres du dfmo et du gvg chez le chien apres administration orale (po) et intraveineuse unique (iv) de 20 mg/kg a permis de montrer pour le dfmo des differences dans les concentrations plasmatiques po (le ()-dfmo ne represente qu'un tiers du dfmo total) et iv (l'eutomere: ()-dfmo ne represente que 45% du dfmo total) corroborant les resultats obtenus chez les patients cancereux et les patients atteints de la maladie du sommeil. Les concentrations plasmatiques de (r)- et du (s)-gvg sont quasiment identiques apres administration po et iv chez le chien. Aucune difference significative (clairance totale, demi-vie d'elimination et biodisponibilite) n'a pu etre mise en evidence dans les parametres pharmacocinetiques obtenus apres administration po ou iv, ni entre les enantiomeres respectifs du dfmo et du gvg. Le (+)-, ()- dfmo et le (r)-, (s)-gvg ne se lient pas aux proteines plasmatiques. Leur eliminat
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Mehrtens, (nee Nikkel) Janna Marie. "The Design, Synthesis and Biological Assay of Cysteine Protease Specific Inhibitors." Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/3271.
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This thesis investigates the design, synthesis and biological assay of cysteine protease inhibitors within the papain superfamily of cysteine proteases. This is achieved by examining the effect of inhibitor design, especially warheads, on IC₅₀ values and structureactivity relationships between cysteine protease inhibitors of the papain superfamily. The representative proteases used are m-calpain, μ-calpain, cathepsin B and papain. Chapter One is an introductory chapter; Chapters Two-Four describe the design and synthesis of cysteine protease inhibitors; Chapter Five discusses assay protocol; and Chapter Six contains the assay results and structure-activity relationships of the synthesised inhibitors. Chapter One introduces cysteine proteases of the papain family and examines the structure, physiology and role in disease of papain, cathepsin B, m-calpain and μ-calpain. The close structural homology that exists between these members of the papain superfamily is identified, as well characteristics unique to each protease. Covalent reversible, covalent irreversible and non-covalent warheads are defined. The generic inhibitor scaffold of address region, recognition and warhead, upon which the inhibitors synthesised in this thesis are based, is also introduced. Chapter Two introduces reversible cysteine protease inhibitors found in the literature and that little is known about the effect of inhibitor warhead on selectivity within the papain superfamily. Oxidation of the dipeptidyl alcohols 2.6, 2.26, 2.29, 2.30, 2.35 and 2.36 utilising the sulfur trioxide-pyridine complex gave the aldehydes 2.3, 2.27, 2.19, 2.2, 2.21 and 2.22. Semicarbazones 2.37-2.40 were synthesised by a condensation reaction between the alcohol 2.3 and four available semicarbazides. The amidoximes 2.48 and 2.49 separately underwent thermal intramolecular cyclodehydration to give the 3-methyl-1,2,4- oxadiazoles 2.41 and 2.50. The aldehydes 2.3 and 2.27 were reacted with potassium cyanide to give the cyanohydrins 2.51 and 2.52. The cyanohydrins 2.51 and 2.52 were separately reacted to give 1) the α-ketotetrazoles 2.43 and 2.55; 2) the α-ketooxazolines 2.42 and 2.58; 3) the esterified cyanohydrins 2.60 and 2.61. A two step SN2 displacement reaction of the alcohol 2.6 to give the azide 2.62, an example of a non-covalent cysteine protease inhibitor. Chapter Three introduces inhibitors with irreversible warheads. The well-known examples of epoxysuccinic acids 3.1 and 3.5 are discussed in detail, highlighting the lack of irreversible cysteine protease specific inhibitors. The aldehydes 2.3 and 2.27 were reacted under Wittig conditions to give the α,β-unsaturated carbonyls 3.14-3.18. Horner- Emmons-Wadsworth methodology was utilised for the synthesis of the vinyl sulfones 3.20- 3.23. The dipeptidyl acids 2.24 and 2.28 were separately reacted with diazomethane to give the diazoketones 3.25 and 3.26. The diazoketones 3.25 and 3.26 were separately reacted with hydrogen bromide in acetic acid (33%) to give the α-bromomethyl ketones 3.27 and 3.28, which were subsequently reduced to give the α-bromomethyl alcohols 3.29-3.32. Under basic conditions the α-bromomethyl alcohols 3.29-3.32 ring-closed to form the peptidyl epoxides 3.33-3.36. Chapter Four introduces the disadvantages of peptide-based inhibitors. A discussion is given on the benefits of constraining inhibitors into the extended bioactive conformation known as a β-strand. Ring closing metathesis is utilised in the synthesis of the macrocyclic aldehyde 4.4, macrocyclic semicarbazone 4.15, the macrocyclic cyanohydrin 4.16, the macrocyclic α-ketotetrazole 4.18 and the macrocyclic azide 4.19. Chapter Five introduces enzyme inhibition studies. The BODIPY-casein fluorogenic assay used for establishing inhibitor potency against m-calpain and μ-calpain is validated. Assay protocols are also established and validated for cathepsin B, papain, pepsin and α- chymotrypsin. A discussion of the effect of solvent on enzyme activity is also included as part of this study. Chapter Six presents the assay results for all the inhibitors synthesised throughout this thesis and an extensive structure-activity relationship study between inhibitors is included. The alcohols 2.26 and 2.30 are unprecedented examples of non-covalent, potent, cathepsin B inhibitors (IC₅₀ = 0.075 μM selectivity 80-fold and 1.1 μM, selectivity 18-fold). The macrocyclic semicarbazone 4.15 is an unprecedented example of a potent macrocyclic cysteine protease inhibitor (m-calpain: IC₅₀ = 0.16 μM, selectivity 8-fold). The cyanohydrin 2.51 contains an unprecedented cysteine protease warhead and is a potent and selective inhibitor of papain (IC₅₀ = 0.030 μM, selectivity 3-fold). The O-protected cyanohydrin 2.61 is a potent and selective inhibitor of pepsin (IC₅₀ = 1.6 μM, selectivity 1.5-fold). The top ten warheads for potent, selective cathepsin B inhibition are: carboxylic acid, methyl ester, diazoketone, esterified cyanohydrin, α-bromomethyl ketone, α,β- unsaturated aldehyde, vinyl sulfones, α-bromomethyl-C₃-S,R-alcohol, alcohol and α,β- unsaturated ethyl ester. The selectivity of these warheads was between 5- and 130-fold for cathepsin B. The best inhibitors for cathepsin B were the α-bromomethyl ketone 3.26 (IC₅₀ = 0.075 μM, selectivity 16-fold), the α,β-unsaturated aldehyde 3.18 (IC₅₀ = 0.13 μM, selectivity 13-fold) and the esterified cyanohydrin 3.59 (IC₅₀ = 0.35 μM, selectivity 22- fold). Chapter Seven outlines the experimental details and synthesis of the compounds prepared in this thesis.
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Campos, Sébastien André. "The synthesis & optimisation of irreversible ITK inhibitors as a potential new treatment for severe asthma." Thesis, University of Strathclyde, 2015. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=26052.
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Interleukin-2-inducible tyrosine kinase (ITK) is a member of the Tec family of non-receptor tyrosine kinases and plays an important role in T cell receptor signalling. Phosphorylation of ITK ultimately results in the release of several cytokines from T cells which are involved in the inflammatory response in asthmatic patients. ITK inhibitors could represent useful anti-inflammatory agents for severe asthma. This thesis describes the design and development of irreversible ITK inhibitors. It was envisaged that these compounds could provide a better duration of action in vivo compared to typical reversible inhibitors. After explaining first how irreversible ITK inhibition may be achieved, the medicinal chemistry undertaken to synthesise the designed molecules, and assess their activity profiles in various biological assays, is presented. Evidence of the covalent binding between some specific analogues and ITK is illustrated, the most explicit proof being a crystal structure of a kinase/inhibitor complex, clearly displaying a bond between the inhibitor and the cysteine residue present in the ITK active site. However, the early irreversible ITK inhibitors developed did not possess the required profile (cellular activity, duration of action) expected from an irreversible ITK inhibitor drug candidate. Three approaches are then described to improve the cellular activity of these irreversible ITK inhibitors. Firstly, the nature of the electrophilic moieties was investigated. Compounds presenting improved irreversible ITK inhibitor profiles (activities and rate of the covalent reaction) have been developed but these species could not be progressed further due to their high probability of toxicity issues in the body. Secondly, the positioning of the electrophilic group with respect to the ITK active site cysteine is then discussed; this strategy did not lead to any improved compounds. Finally, moving to a chemically more challenging pyridine template provided inhibitors with enhanced non-covalent ITK recognition. Optimisation of the compounds from this series provided irreversible inhibitors with the required in vitro and in vivo activity profiles for a drug candidate within our laboratories. The progression of the lead covalent ITK inhibitor from this research programme was ultimately halted due to toxicology findings from a 14 day rat study. The final part of the thesis studies the Buchwald-Hartwig amination reaction used in the synthetic route leading to the best covalent ITK inhibitors. This coupling required 30 mol % of palladium catalyst, which, on large scale, represents a significant amount of metal waste. The investigation of this coupling strongly suggested that the substrates involved in the reaction were poisoning the catalyst. The final results from this study indicate that an alternative palladium catalyst, allowing full conversion to the required product at room temperature, has been identified.
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Akbar, Abdullah. "Design, Synthesis and Evaluation of Covalent Inhibitors for Tissue Transglutaminase and Factor XIIIa." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39645.
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Transglutaminases are a family of enzymes expressed in various tissues of our body. Some are expressed ubiquitously while others are specific to a tissue. Their primary catalytic activity is to crosslink substrates via an isopeptidic bond. The work described in this thesis focuses on two of these transglutaminases; human tissue transglutaminase (hTG2) and human factor XIIIa (FXIIIa). Divided into two projects for each enzyme, the main objective of this thesis was directed towards the discovery of potent and selective covalent inhibitors for each isozyme, namely hTG2 and hFXIIIa. The first project was concentrated on the inhibition of hTG2 activity. Ubiquitously expressed in tissues, hTG2 is a multifunctional enzyme. Its primary activity is the formation of isopeptide bonds between glutamine and lysine residues found on the surface of proteins or substrates. In addition to its catalytic activity, hTG2 is also a G-protein, distinguishing it from other members of the transglutaminase family. Much evidence illustrates that hTG2’s multifunctional abilities are conformationally regulated between its “open” and “closed” forms. Overexpression and unregulated hTG2 activity has been associated with numerous human diseases; however, most evidence has been collected for its association with fibrosis and celiac sprue. More recently, elevated hTG2 expression has been linked to cancer stem cell survival and metastatic phenotype in certain cancer cells. These findings call for the development of suitable and potent inhibitors that selectivity inactivate human hTG2 as a potential therapeutic target. Starting with previously designed acrylamide based peptidomimetic irreversible inhibitors, a structure-activity relationship (SAR) study was conducted. In this work, >20 novel irreversible inhibitors were prepared and kinetically evaluated. Our lead inhibitors allosterically inhibited GTP binding by locking the enzyme in its open conformation, as demonstrated both in vitro and in cells. Furthermore, our most potent and efficient irreversible inhibitors revealed selectivity for hTG2 over other relevant members of the transglutaminase family (hTG1, hTG3, hTG6 and hFXIIIa), providing higher confidence towards our goal of developing an ideal drug candidate. The second project was concentrated on the inhibition of hFXIIIa activity. In the blood, coagulation factor XIII (FXIII) is a tetrameric protein consisting of two catalytic A subunits (FXIII-A2) and two carrier/inhibitory B (FXIII-B2) subunits. It is a zymogen, which is converted into active transglutaminase (FXIIIa) in the final phase of coagulation cascade by thrombin proteolytic activity and Ca2+ binding. hFXIII is essential for hemostasis and thus its deficiency results in severe bleeding conditions. Further, hFXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Due to the enzyme’s involvement in the stability of blood clots, inhibition of hFXIIIa activity has been linked to thrombotic diseases. Furthermore, inhibitors of the enzyme have the therapeutic potential to be used as anticoagulant agents. The current number of selective and potent inhibitors of hFXIIIa are few, mainly due to the similarity between its catalytic pockets and hTG2. Inspired by a poorly reactive hTG2 inhibitor discovered in this work’s hTG2 SAR study, we synthesized a small library of covalent inhibitors for hFXIIIa. Our kinetic results from this pioneering SAR study will pave the way for future hFXIIIa inhibitor SAR studies.
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Campbell, Amy. "Design, synthesis, and evaluation of cysteine protease inhibitors." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-11222005-132114/.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.Murthy, Niren, Committee Member ; Doyle, Donald, Committee Member ; Fahrni, Christoph, Committee Member ; May, Sheldon, Committee Member ; Powers, James, Committee Chair.
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Ni, Liming. "Synthesis and evaluation of new peptidyl phosphonate analogs of benzamidine, lysine and homolysine as irreversible inhibitors for thrombin and other trypsin-like enzymes." Diss., Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/27080.
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Reuter, Cécile [Verfasser]. "Mutationsabhängige Aktivität von niedermolekularen reversiblen und irreversiblen Inhibitoren der EGFR Signalkaskade in NSCLC / Cécile Reuter." Köln : Deutsche Zentralbibliothek für Medizin, 2012. http://d-nb.info/1026215080/34.
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Cole, Kyle S. "Synthesis and Characterization of Triazine-Based Chemical Probes." Thesis, Boston College, 2018. http://hdl.handle.net/2345/bc-ir:107697.
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Thesis advisor: Eranthie WeerapanaThe 1,3,5-triazine is a privileged scaffold in that it is planar and has three-fold symmetry which allows for controlled modification around the ring structure with various substituents. In this thesis, we report on two modular inhibitor libraries that center around a 1,3,5-triazine core scaffolding system, which have been shown to target protein disulfide isomerase A1 (PDIA1), glutaredoxin-3 (GLRX3), and 6-phosphofructo-1-kinase (PFKP). Protein disulfide isomerase A1 (PDIA1) is a thiol-disulfide oxidoreductase localized in the lumen of the endoplasmic reticulum (ER), and is an important folding catalyst and chaperone for proteins in the secretory pathway. PDIA1 contains two active-site domains (a and a’), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. Here, we synthesize a targeted library o second-generation triazine-based inhibitors to optimize the potency and selectivity of our lead compound, RB-11-ca. Characterization of this targeted library afforded an optimized PDIA1 inhibitor, KSC-34, which covalently modifies C53 in the a site of PDIA1 and demonstrates time-dependent inhibition of the reductase activity of PDIA1 in vitro with a kinact/KI = 9.66 x 103 M-1s-1. Interestingly, KSC-34 treatment demonstrated that a-site inhibition led to decreased secretion of amyloidogenic antibody light chain, thus illustrating that site-selective inhibitors like KSC-34 provide useful tools for delineating the pathological role and therapeutic potential of PDIA1. In 2014, our lab first reported on RB7, a dichlorotriazine-based electrophilic small molecule which displayed extremely high reactivity and selectivity toward lysine residues in the proteome. Herein, we further on this study by investigating the unique reactivity of RB7 through the synthesis of a second-generation small molecule electrophile library and investigating proteome-wide reactivity in vitro and in situ. This library afforded KSC-46, an RB-7 analogue with p-chlorothiophenol tuning element, which provided optimal proteome reactivity to use as a scaffold for the generation of a targeted library. To take advantage of the tuned reactivity of KSC-46, a second-generation targeted library was generated to target react residues in the proteome. This library yielded two molecules, KSC-56 and KSC-65, which were identified to target glutaredoxin-3 (GLRX3) and 6-phosphofructo-1-kinase (PFKP), respectively. GLRX3 is a cytosolic, monothiol iron-sulfur cluster chaperon protein which relies on two nucleophilic cysteine residues to bind and transfer iron clusters. PFKP is known to catalyze the first irreversible step in glycolysis and regulates the flux of glucose metabolism in the cell, which makes PFKP an attract therapeutic target. KSC-56 was further characterized to bind to Cys261 in the C-terminal glutaredoxin domain of GLRX3
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Kontos, Christopher D. "The Irreversible Inhibition of D-amino Acid Oxidase with Trans-3-bromoacrylic Acid and Four Others Halo-vinylic Acids." W&M ScholarWorks, 1985. https://scholarworks.wm.edu/etd/1539625302.
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Tantishaiyakul, Vimon. "Part I. Synthesis of idocatecholamine derivatives as adrenergic stimulants and thromboxane A₂ antagonists ; Part II. Synthesis of irreversible inhibitors of aldose reductase /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487677267730112.
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Ares, Jeffrey Joseph. "Part 1: Synthesis of irreversible inhibitors of Aldose reductase with subsequent development of carbon-13 NMR protein probe. Part 2: Synthesis of selenium analogs of dopamine as potential dopamine receptor agonists /." The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487268021748119.
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Ansorg, Kay [Verfasser], and Bernd [Gutachter] Engels. "Development of Accurate Physically Grounded Force Fields for Intermolecular Cation-$\pi$ Interactions based on SAPT Energy Decomposition Analysis and Computational Investigation of Covalent Irreversible Vinyl Sulfone-based Protease Inhibitors / Kay Ansorg. Gutachter: Bernd Engels." Würzburg : Universität Würzburg, 2016. http://d-nb.info/111204101X/34.
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Ahmed, Vanessa. "Reversible and Mechanism-Based Irreversible Inhibitor Studies on Human Steroid Sulfatase and Protein Tyrosine Phosphatase 1B." Thesis, 2009. http://hdl.handle.net/10012/4803.
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The development of reversible and irreversible inhibitors of steroid sulfatase (STS) and protein tyrosine phosphatase 1B (PTP1B) is reported herein. STS belongs to to the aryl sulfatase family of enzymes that have roles in diverse processes such as hormone regulation, cellular degradation, bone and cartilage development, intracellular communication, and signalling pathways. STS catalyzes the desulfation of sulfated steroids which are the storage forms of many steroids such as the female hormone estrone. Its crucial role in the regulation of estrogen levels has made it a therapeutic target for the treatment of estrogen-dependent cancers. Estrone sulfate derivatives bearing 2- and 4-mono- and difluoromethyl substitutions were examined as quinone methide-generating suicide inhibitors of STS with the goal of developing these small molecules as activity-based probes for proteomic profiling of sulfatases. Kinetic studies suggest that inhibition by the monofluoro derivatives is a result of a quinone methide intermediate that reacts with active-site nucleophiles. However, the main inhibition pathway of the 4-difluoromethyl derivative involved an unexpected process in which initially formed quinone methide diffuses from the active site and decomposes to an aldehyde in solution which then acts as a potent, almost irreversible STS inhibitor. This is the first example where this class of inactivator functions by in situ generation of an aldehyde. 6- and 8-mono- and difluoromethyl coumarin derivatives were also examined as quinone methide-generating suicide inhibitors of STS. The 6-monofluoromethyl derivative acted as a classic suicide inhibitor. The partition ratio of this compound was found to be very large indicating that this class of compounds is not likely suitable as an activity-based probe for proteomic profiling of sulfatases. Boronic acids derived from steroid and coumarin platforms were also examined as STS inhibitors with the goal of improving our understanding of substrate binding specificity of STS. Inhibition constants in the high nanomolar to low micromolar range were observed for the steroidal derivatives. The coumarin derivatives were poor inhibitors. These results suggest that the boronic acid moiety must be attached to a platform very closely resembling a natural substrate in order for it to impart a beneficial effect on binding affinity compared to its phenolic analog. The mode of inhibition observed was reversible and kinetic properties corresponding to the mechanism for slow-binding inhibitors were not observed.
PTP1B catalyzes the dephosphorylation of phosphotyrosine residues in the insulin receptor kinase and is a key enzyme in the down regulation of insulin signaling. Inhibitors of PTP1B are considered to have potential as therapeutics for treating type II diabetes mellitus. The difluoromethylenesulfonic (DFMS) acid group, one of the best monoanionic phosphotyrosine mimics reported in the literature, was examined as a phosphotyrosine (pTyr) mimic in a non-peptidyl platform for PTP1B inhibition. The DFMS-bearing inhibitor was found to be an approximately 1000-fold poorer inhibitor than its phosphorus analogue. It was also found that the fluorines in the DFMS inhibitor contributed little to inhibitory potency. In addition, [sulfonamido(difluoromethyl)]-phenylalanine (F2Smp) was examined as a neutral pTyr mimic in commonly used hexapeptide and tripeptide platforms. F2Smp was found to be a poor pTyr mimic. These inhibition studies also revealed that the tripeptide platform is not suitable for assessing pTyr mimics for PTP1B inhibition.
Taken together, the kinetic data on the inhibition of STS and PTP1B provide valuable information relevant for future design of inhibitors of these two therapeutic targets.
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Muscate, Angelika. "Mechanistic investigations of novel, irreversible inhibitors of S-adenosylhomocysteine hydrolase." Thesis, 1992. http://hdl.handle.net/1911/16532.
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Isolation of bovine S-adenosylhomocysteine hydrolase by affinity chromatography unexpectedly yielded two forms of the enzyme. Type A contained 4 moles of NAD$\sp+$/mole of enzyme tetramer, while Type B had only half that number of nucleotide cofactors associated with it. The acetylenic analog of adenosine, 9-(5$\sp\prime$,6$\sp\prime$-dideoxy-$\beta$-D-ribo-hex-5$\sp\prime$-ynofuranosyl)-adenine, was synthesized, and its behavior as an inhibitor of Type A enzyme examined. Irreversible inactivation of the enzyme with excess inhibitor was accompanied by the reduction of 2 equivalents of NAD$\sp+$ to NADH, release of the remaining NAD$\sp+$ from the enzyme, and binding of 4 equivalents of inhibitor per enzyme tetramer. Denaturation studies suggested that two equivalents of the inhibitor may form a covalent bond between the enzyme and the oxidized inhibitor. The inactivation behavior exhibited by Type A and Type B enzyme with 2$\sp\prime$-deoxy-2$\sp\prime$,2$\sp\prime$-difluoroadenosine was compared. The Type B enzyme was irreversibly inactivated by excess inhibitor with concurrent reduction of 1 mole of NAD$\sp+$ to NADH and release of 1 mole of NAD$\sp+$. Inactivation of the Type A enzyme was accompanied by the reduction of 1 mole of NAD$\sp+$ to NADH and release of ca. 2 moles of NAD$\sp+$. Upon dialysis, 50% of the original activity of the enzyme was regained. Binding stoichiometries of 1 and 3 moles inhibitor/mole of enzyme tetramer were determined for the Type B and Type A enzyme, respectively. Denaturation studies indicated that 1 equivalent of the oxidized inhibitor may have formed a covalent bond with the Type A enzyme, but not with Type B. The binding behavior of adenosine with both types of the enzyme was also studied. Type B enzyme exhibited a large binding affinity of 4-25 moles of adenosine/mole of enzyme tetramer, while Type A bound only 3 moles of adenosine/mole enzyme tetramer. The binding of adenosine to the Type B enzyme was accompanied by the reduction of 1 equivalent of NAD$\sp+$ to NADH. Denaturation experiments suggested the formation of a covalent bond between the enzyme and one equivalent of adenosine. However, peptide mapping of the reduced enzyme-adenosine complex failed.
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TANG, JHIH-YAN, and 湯之彥. "Discovery of novel irreversible HER2 inhibitors for breast cancer treatment." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/shugvc.
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碩士國立臺北科技大學
化學工程與生物科技系化學工程碩士班
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Previous studies have indicated that overexpression of human epidermal growth factor receptor 2 (HER2) is associated with the carcinogenesis of breast cancer. Therefore, HER2 has been considered as a drug target for breast cancer treatment. So far, many reversible HER2 inhibitors have been developed for treating HER2-positive breast cancer. Among them, lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA). However, three types of HER2 point mutations, including L755S, T798I and T798M, have been shown to confer drug resistance toward lapatinib. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them are still under clinical trials. Therefore, several computational approaches, including structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics simulation and ADMET analysis, were adopted in this study to discover novel irreversible HER2 inhibitors with better efficacy and less side effects. Three different pharmacophore models were constructed based on the built homology models of HER2 L755S, T798I and T798M. These models were subsequently validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Then, the best models were utilized as 3D queries to screen compounds from the National Cancer Institute (NCI) database. Only compounds which fit well with all the features of the pharmacophore models and show the covalent interaction termed as Michael acceptor, an essential substructure of irreversible inhibitors, were retrieved as hit compounds. Then, they were submitted to molecular docking experiments to investigate their binding interactions in their respective binding pockets. Based on the docking scores and docking poses, three compounds, NSC278329, NSC642003 and NSC718305, were selected as the potential irreversible HER2 inhibitors. Finally, these three binding complexes were subjected to molecular dynamics (MD) simulations and the results showed that these binding complexes were stable during the entire MD simulation courses. To reduce the risk of clinical failure, ADMET analyses were performed towards these three compounds and the results showed that NCS642003 exhibited high carcinogenicity and CYP450 inhibitory promiscuity, making it unsuitable for clinical use. Finally, only NSC278329 and NSC718305 were considered as safe and novel irreversible HER2 inhibitors, which can be further subjected to in vitro/vivo analyses to estimate their efficacy or the possibility to act as the lead compounds for designing more potent irreversible HER2 inhibitors.
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Valente, Cláudia Sofia dos Santos 1975. "Potential irreversible inhibitors of cysteine proteases based on sultam and naphthoquinone scaffolds." Doctoral thesis, 2007. http://hdl.handle.net/10451/277.
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Li, Jing Ph D. "Dialkynylimidazoles as irreversible MAPK inhibitors, kinase docking site probes, and anti-cancer agents." Thesis, 2011. http://hdl.handle.net/2152/ETD-UT-2011-08-4070.
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This dissertation research was aimed at investigating an interesting class of 1,2-dialkynylimidazoles as: 1. irreversible p38 MAP kinase α-isoform (p38α) inhibitors; 2. p38α docking site probes; 3. anti-cancer agents.
Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles was designed as potential irreversible p38α inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity were reported. Interestingly, one of the 1-ethynyl-substituted dialkynylimidazoles is a potent (IC50 = 200 nM) and selective inhibitor of p38α. Additionally, this compound covalently modifies p38α as determined by ESI-MS after 12 h incubation at 37 °C. The unique kinase inhibition, covalent kinase adduct formation, and minimal CYP450 2D6 inhibition by this compound demonstrate that dialkynylimidazoles are a new, promising class of p38α inhibitors.
Blocking docking interactions between kinase network partners is a promising alternative approach for selectively inhibiting kinases. The second project involves the identification of a new class of small molecules, covalent p38α MAP kinase docking site probes. We proposed that the mechanism may involve the addition of a thiol to the N-ethynyl group. Moreover, we demonstrated that such probes can be used fluorescently to label p38α both in vitro and in cells via azide-alkyne “Click” chemistry. This serves as the basis of an assay that can be used to identify inhibitors that specifically target the substrate docking site of p38α.
The last project was focused on evaluating a new class of 1,2-dialkynylimidazoles as anti-cancer agents. One 1,2-dialkynylimidazole analog was found to be cytotoxic against a range of human cancer lines and to induce apoptosis in the human non-small cell lung cancer cell line A549. In order to elucidate the relationship between the structural basis and role of the thermal generation of diradical or carbene intermediates, a series of dialkynylimidazoles and related N-alkynylimidazoles was prepared and their cytotoxicity was determined against A549 cell line. Although the experimentally determined activation energy is in excellent agreement with that predicated from the DFT calculation, there is no correlation between the rate of Bergman cyclization and cytotoxicity to A549 cells. An alternative mechanism was proposed involving the unexpected selective thiol addition to the N-ethynyl group of certain 1,2-dialkynylimidazoles.text
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Mulchande, Jalmira 1980. "Irreversible inhibitors of serine proteases based on the \03B2-lactam scaffold as potential drug candidates." Doctoral thesis, 2009. http://hdl.handle.net/10451/263.
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Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), 2009, Universidade de Lisboa, Faculdade de FarmáciaDisponível no documento
Centro de Estudos de Ciências Farmacêuticas (CECF)/iMed.UL (Institute for Medicines and Pharmaceutical Sciences), Faculdade de Farmácia da Universidade de Lisboa. Fundação para a Ciência e a Tecnologia (SFRH/BD/17534/2004 e projecto PTDC/QUI/64056/2006)
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Büchold, Christian. "Synthese und Testung cis-konfigurierter Aziridine als pseudo-irreversible Inhibitoren der sekretorischen Aspartatproteasen von Candida albicans." Doctoral thesis, 2009. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-39358.
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Candida albicans gehört zu den für den Menschen fakultativ pathogenen Hefepilzen. Der normalerweise harmlose Begleiter der humanen Mikroflora findet sich hauptsächlich auf Schleimhäuten der Mundhöhle und des Magen-Darm-Trakt sowie in der vaginalen Flora. Menschen, deren Immunsystem geschwächt ist, sind jedoch besonders anfällig für Infektionen, die durch den Pilz hervorgerufen werden können. Neben oberflächlichen kann es dabei auch zu lebensbedrohlichen systemischen Infektionen kommen, die nicht selten zum Tod des Patienten führen. Durch ein zunehmendes Auftreten von Resistenzen gegen gebräuchliche Pharmaka besteht aktuell ein dringender Bedarf an neuen Wirkstoffen gegen Candida. Die zehn vom Hefepilz exprimierten sekretorischen Aspartatproteasen (SAP1-10), die als wichtige Virulenzfaktoren gelten, stellten sich dabei zunehmend als vielversprechende Targets heraus. Das Ziel dieser Arbeit war die Weiterentwicklung der literaturbekannten cis-konfigurierten 3-Phenylaziridin-2-carboxylate A-07 und A-08 als irreversible Inhibitoren der SAP-Isoenzyme. Die Variation der Substituenten am Aziridinstickstoff für die Adressierung der S3-Tasche im Enzym erfolgte durch Alkyl-, Aryl- und Acylreste. Die Aminosäureester wurden in Konfiguration und Art der Seitenkette modifiziert, um eine Verbesserung der Anpassung an die S1‘-Tasche zu ermöglichen. Die cis-3-Phenylaziridin-2-carboxylate wurden durch Cromwell-Synthese als Racemate erhalten. Aminosäure- und Peptidkupplungen erfolgten mit gängigen Kupplungsreagenzien (PPA, DPPA). Die stereoselektive Synthese des methylenverbrückten Aziridin-2-carboxylats A-10 erfolgte durch Redoxkondensation nach Mukaiyama. Die synthetisierten Verbindungen wurden in einem fluorimetrischen FRET-Assay auf ihre inhibitorische Wirkung gegen SAP2 getestet. Dabei war das im FRET-Assay bislang an SAP2 verwendete Substrat Dabcyl-Arg-Lys-Pro-Ala-Leu-Phe-Phe-Arg-Leu-Glu(EDANS)-ArgOH auch für Testungen an SAP1, 3 & 8 sowie Cathepsin D geeignet. Neben den jeweiligen Km-Werten konnten für diese Enzyme auch die zugehörigen kcat-Werte bestimmt werden. Zur Bestimmung der Hemmkonstanten wurde für die aktiven Verbindungen ein Verdünnungsassay nach Kitz und Wilson durchgeführt. 20 der 46 Aziridin-2-carboxylate erreichten SAP2 k2nd-Werte von mindestens 7880 M-1min-1. Die mit k2nd-Werten von 60608 bis 118582 M-1min-1 potentesten Verbindungen wurden durch (R)-Aminosäuresubstitution (A-28, A-31) bzw. durch Cyclohexylmethyl-Verknüpfung am Aziridinstickstoff (A-43, A-45) erhalten. Für die einzelnen Diastereomere von A-31, A-31a und A-31b, wurde eine signifikant unterschiedliche Hemmwirkung festgestellt. Die Inhibitoren zeigten eine zeitabhängige Hemmung, die nach ca. 30 min Inkubationszeit jedoch wieder schwächer wurde. LC-MS- und NMR-Studien lassen einen pseudo-irreversiblen Hemmmechanismus vermuten: Der Inhibitor bindet zunächst irreversibel unter Ringöffnung des Aziridins an das Enzym. Der entstehende Ester wird danach unter den sauren Assaybedingungen wieder hydrolysiert. Der resultierende Aminoalkohol bindet anschließend als Übergangszustandsanalogon reversibel an das Enzym. Selektivitätsstudien an Cathepsin D zeigten für 36 der 46 Aziridin-2-carboxylate k2nd-Werte von 10350 bis 936544 M-1min-1. Damit sind die Verbindungen an CathD aktiver als an SAP2. Die 1-Cyclohexylmethyl-verknüpften Aziridine wiesen auch an CathD die höchsten k2nd-Werte auf, wenngleich sich dabei die (R)-Konfiguration der Aminosäurereste (A-57, A-59) als die aktivere Variante herausstellte. Mit dem (R)-Phe-substituierten 1-tert-Butylaziridin A-58 erreichte der potenteste Vertreter der Reihe bereits einen Ki-Wert im dreistelligen nano-molaren Bereich. Ebenso wurden für die (R)-Aminosäure-Analoga von A-07 und A-08 (A-28, A-31) erhöhte Hemmkonstanten erhalten. Wie SAP2 wird auch CathD durch die (an)getrennten Diastereomere A-31a und A-31b signifikant unterschiedlich stark inhibiert. Mit den (R)-Valin-verknüpften Aziridinen A-81, A-82 und A-85 fanden sich aktive verzweigt-Alkyl-substituierte CathD-InhibitorenCandida albicans is one of the most common fungal pathogens of human beings. Usually, Candida species reside as commensal organisms as part of the normal microflora, predomi-nantly colonizing the mucosal surfaces of the oral cavity, the gastrointestinal tract or the va-ginal flora. However, notably in immunosuppressed individuals, C. albicans can evolve into an opportunistic pathogen, causing superficial as well as life-threatening systemic infections with high mortality. Increasing resistances to current drug therapies demand research for new antifungal phar-maceuticals. The secreted aspartic proteases (SAP1-10), encoded by ten different sap genes, were discovered as key virulence factors and hence are considered to be potential targets for new antimycotic drugs. The goal of the present work was the improvement of the known cis-configured 3 phenyl-aziridine-2-carboxylates A-07 und A-08 as irreversible inhibitors of the SAP isoenzymes. In order to address their S3 pocket, the substituent at the aziridine-nitrogen was modified (alkyl, aryl and acyl residues). Furthermore, various amino acid esters (D, L) were included in order to improve their fit into the S1’ pocket. The cis-3-phenylaziridine-2-carboxylates were obtained as racemates via Cromwell synthesis. Amino acid and peptide coupling reactions were performed with common coupling reagents (PPA, DPPA). The stereoselective synthesis of the methylene-bridged aziridine-2-carboxylate A-10 was achieved via redox condensation according to Mukaiyama. The synthesized compounds were tested for inhibition of SAP2 by using a fluorometric FRET assay using Dabcyl-Arg-Lys-Pro-Ala-Leu-Phe-Phe-Arg-Leu-Glu(EDANS)-ArgOH as sub-strate. This substrate, designed for SAP2, was found to be also suitable for assays with SAP1, 3 & 8 and Cathepsin D. Additionally, the corresponding Km- and kcat values were determined. For the determination of the inhibition constants of the active compounds a dilution assay according to Kitz and Wilson was performed. 20 of the 46 aziridine-2-carboxylates yielded k2nd values of at least 7880 M-1min-1 against SAP2. With k2nd values between 60608 and 118582 M-1min-1, the most potent compounds were achieved with (R)-amino acids (A-28, A-31) and by cyclohexylmethyl substitution of the aziridine-nitrogen (A-43, A-45). Significantly different inhibition potencies were found for the single diastereomers of A-31, A-31a and A-31b. The inhibitors showed a time-dependent inhibition that decreased after 30 min incubation time. LC-MS and NMR studies suppose a pseudo-irreversible mechanism of inhibition: First, the inhibitor irreversibly binds to the enzyme under ring opening of the aziridine. Then the generated ester is hydrolyzed under the acidic assay conditions. The resulting amino alcohol subsequently could bind as a transition-state mimetic inhibitor to the enzyme. In selectivity studies on CathD 36 of the 46 aziridine-2-carboxylates showed k2nd values be-tween 10350 and 936544 M-1min-1. Thus, the compounds show higher activity against CathD than against SAP2. Again, the 1-cyclohexylmethyl-substituted aziridines show the highest k2nd values. However, in these cases the compounds with (R)-configured amino acid residues are the more active ones (A-57, A-59). With the (R)-Phe-substituted 1-tert-butylaziridine A-58, the most active compound reached a Ki value in the nanomolar region. Similarly to the results obtained for SAP2, the (R)-amino acid analogues to A-07 und A-08 (A-28, A-31) show higher inhibition constants. Again, the separated diastereomers A-31a and A-31b display significantly different inhibition potencies. With the (R) valin linked aziridines A-81, A-82 and A-85 a highly active group of alkyl-substituted inhibitors with branched side-chains was found
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Burstein, Gayle Diane. "An investigation of the irreversible inhibition of human N[superscript ω], N[superscript ω]- dimethylarginine dimethylaminohydrolase (DDAH1)." Thesis, 2014. http://hdl.handle.net/2152/31281.
Full textAbstract:
Nitric oxide synthases (NOS) are responsible for the production of nitric oxide (NO), an essential cell-signaling molecule, in mammals. There are three isoforms of NOS with widely different tissue distribution. The overproduction of NO is marked in many human disease states and cancers, however due to the similarities of the enzyme isoforms, targeting NOS for inhibition has proven challenging. Endogenously, the methylated arginines, N[superscript ω]-monomethyl-L-arginine (NMMA) and asymmetric N[superscript ω], N[superscript ω]-dimethyl-L-arginine (ADMA), inhibit NOS. N[superscript ω], N[superscript ω]-Dimethylarginine dimethylaminohydrolase (DDAH1) metabolizes these methylated arginines and thus relieves NOS inhibition. The role of DDAH1 in the regulation of diseases such as cancer and septic shock is still being elucidated. It is thought that targeting DDAH1 for inhibition rather than NOS may circumvent many of the current problems with the treatment of NO overproduction such as isoform selectivity. My PhD studies focus on the synthesis of a series of irreversible inhibitors of DDAH1, an extensive study of their in vitro mode of inhibition, a comparison of analytical fitting methods, and the viability and efficacy of the inactivators in a human cell line. I also studied a potential endogenous inactivator of DDAH1, nitroxyl (HNO), a one-electron reduction product of NO.text
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Büchold, Christian [Verfasser]. "Synthese und Testung cis-konfigurierter Aziridine als pseudo-irreversible Inhibitoren der sekretorischen Aspartatproteasen von Candida albicans / vorgelegt von Christian Büchold." 2009. http://d-nb.info/997873698/34.
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Ansorg, Kay. "Development of Accurate Physically Grounded Force Fields for Intermolecular Cation-$\pi$ Interactions based on SAPT Energy Decomposition Analysis and Computational Investigation of Covalent Irreversible Vinyl Sulfone-based Protease Inhibitors." Doctoral thesis, 2015. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-131084.
Full textAbstract:
Part 1 of this work describes the development of accurate physically grounded force fields for intermolecular Cation-π interactions based on SAPT energy decomposition analysis. The presented results demonstrate the benefits of the used DFT-SAPT method to describe non-bonding interactions. First of all, this method is able to reproduce the high level CCSD(T) energy values but using much less computational time. Second it provides the possibility to separate the total intermolecular interaction energy into several physically meaningful contributions. The relative contributions of the dimers investigated can be seen in Fig. 6.16. In Tab. 6.3 the percentage contribution of the attractive energy parts to the stabilization energy is shown. The polarization energy is important for the NH+...C6H6 interaction, whereas it becomes less crucial considering other dimers. The dispersion energy contribution is large in the case of the C6H6...H2O dimers, whereas it is relatively less important for the NH+...C6H6 interaction. The electrostatic energy contributes a large amount of stabilizing energy in all considered dimer interactions.In Teil 1 dieser Arbeit wird die Entwicklung eines akkuraten physikalisch fundierten Kraftfeldes für die exakte Beschreibung zwischenmolekularer Cation-π Wechselwir- kungen basierend auf Analysen der SAPT Energieaufspaltungen beschrieben. Die Ergebnisse zeigen die Vorteile der benutzten DFT-SAPT Methode zur Beschreibung von nicht-kovalent gebundenen Wechselwirkungen. Diese Methode ist zum einen in der Lage höchst akkurate CCSD(T) Ergebnisse zu reproduzieren wobei ein sehr viel geringerer computertechnicher Aufwand benötigt wird. Zum anderen ermöglicht es diese Methode die gesamte Wechselwirkungsenergie in einzelne physikalisch sinn- volle Komponenten zu separieren. In Abb. 6.17 sind die Energiekomponenten der untersuchten Dimere graphisch dargestellt. In Tab. 6.4 sind die Anteile der attrak- tiven Energiebeiträge zur Gesamtstabilisierungsenergie prozentual aufgelistet. Die Polarisationsenergie repräsentiert einen entscheidenden Anteil an der NH+...C6H6 Wechselwirkung, wobei diese für die weiteren hier gezeigten Dimere keine entschei- dende Rolle spielt. Die Dispersionsenergie hingegen liefert einen großen Beitrag zur C6H6...H2O Wechselwirkung, ist aber für die NH+...C6H6 Wechselwirkung rela- tiv unbedeutend. Die Elektrostatische Energie liefert in allen untersuchten Dimeren einen entscheidenden Anteil zur Stabilisierungsenergie.
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Borrego, Inês Sofia Branco. "Optimization of MALDI-TOF MSI in grapevine leaves and development of MALDI-TOF MS screening test to evidence if Resveratrol , Pterostilbenes and Synthetic Polysulfane derivates are reversible or irreversible inhibitors of Tubulin." Master's thesis, 2014. http://hdl.handle.net/10451/26770.
Full textAbstract:
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2015MALDI-TOF MS is a rapid, accurate, specific, and reproducible method that matches all the criteria for the screening ability, it offers great possibilities and potential in terms of reactivity and analysis. The present study was divided in three different subjects: The first one consisted in the optimization of the matrix deposition by a semi- automated matrix spraying by MALDI-TOF MSI for the simultaneous location of Resveratrol, Pterostilbenes and Viniferins on Grapevine leaves. After the optimization of several factors, the optimal parameters are: applied volume= 0.05 µl/ track/ mm of leaf; application speed/ track= 300 nl/s; space between tracks =0,5 mm; energy intensity= 52%. The second one consisted in the development of a MALDI-TOF MS screening test to evidence if Resveratrol and Pterostilbenes are reversible or irreversible inhibitors of Tubulin. And it's possible to conclude that Pterostilbenes are reversible inhibitors and that Resveratrol is or not linked to Tubulin or an irreversible inhibitor. The third and last one concerns to the development of a MALDI-TOF MS screening test to evidence if synthetic polysulfane derivates (DATTS and DBTTS) are reversible or irreversible inhibitors of Tubulin, and it's possible to conclude that both of the compounds are potential reversible inhibitors.
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"Tin (II) compounds as novel catalysts for the Kabachnik-Fields reaction: Studies in the synthesis of alpha-aminophosphonates under solvent free conditions and Synthesis of phosphonates and phosphates as reversible and irreversible inhibitors of butyrylcholinesterase." CALIFORNIA STATE UNIVERSITY, LONG BEACH, 2010. http://pqdtopen.proquest.com/#viewpdf?dispub=1472277.
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Beltran, Christian Hazael Perez. "Magnetic nanoparticles for biosensing and immunoprecipitation." Master's thesis, 2019. http://hdl.handle.net/10400.1/13939.
Full textAbstract:
Our world is rapidly changing and its future is on our hands. Great effort is being done
against overexploitation of natural resources, uncontrolled hunting and pollution. A
great concerning fact is due to pollution which is causing a continuous greenhouse
effect and new cancer cases every single day. Nowadays, it is possible to improve the
detection of lethal elements in the environment, to fight against cancer in a smarter
manner, with less pain and with more efficiency but, more important, to use the same
low-cost, fast and environmentally friendly tool for these purposes and more. This
reality is thanks to previous works and findings regarding the Magnetic Nanoparticles
(MNPs), which are employable in a wide variety of applications such as magnetic
recording media, resonance imaging, heavy metals ions removal and biomedicine
(specifically in the hyperthermic treatment of malignant cells, site-specific drug delivery
and separation of proteins and cell population). MNPs have special properties such as
superparamagnetic, high field irreversibility, high saturation field, extra anisotropy
contributions or shifted loops after field cooling, biocompatibility, long durability, low
toxicity and cost.
In this context, this project intends 1) to develop through a novel synthesis method, a
biosensor capable to detect mercury in water by irreversible inhibition of the enzyme
Horseradish Peroxidase attached onto the surface of different coated MNPs being able
to approximate its detections to those limits stablished by the Environmental Protecting
Agency of the United States of America; and 2) to use these high valuable nanoparticles
as an immunoprecipitation vehicle through the attachment of a polyclonal antibody onto
the surface of functionalized MNPs, selective against a suppressor protein.
MNPs of about 10 nm were obtained within one minute via co-precipitation method
enhanced by high power ultrasound. Experimental design has been used in order to
optimize the preparation process from hours to just one minute.
The composition, structure, size and morphology analyses of these MNPs have been
carried out through X-ray diffraction, Fourier transform infrared spectroscopy,
thermogravimetric analysis and scanning electron microscopy showing the correct
achievement of the MNPs. Moreover, different coating agents have been tested in order
to functionalize MNPs surface with the aim of attaching later biomolecules, such as
enzymes and antibodies.