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1.
Postepy Biochem ; 61(3): 274-83, 2015.
Artículo en Polaco | MEDLINE | ID: mdl-26677574

RESUMEN

Thymidylate synthase ThyA (EC 2.1.1.45;-encoded by the Tyms gene), having been for 60 years a molecular target in chemotherapy, catalyses the dUMP pyrimidine ring C(5) methylation reaction, encompassing a transfer of one-carbon group (the methylene one, thus at the formaldehyde oxidation level) from 6R-N5,10-methylenetetrahydrofolate, coupled with a reduction of this group to the methyl one, with concomitant generation of 7,8-dihydrofolate and thymidylate. New facts are presented, concerning (i) molecular mechanism of the catalyzed reaction, including the substrate selectivity mechanism, (ii) mechanism of inhibition by a particular inhibitor, N4-hydroxy-dCMP, (iii) structural properties of the enzyme, (iv) cellular localization, (v) potential posttranslational modifications of the enzyme protein and their influence on the catalytic properties and (vi) non-catalytic activities of the enzyme.


Asunto(s)
Bioquímica/historia , Timidilato Sintasa/historia , Animales , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/farmacología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Cinética , Polonia , Conformación Proteica , Procesamiento Proteico-Postraduccional , Especificidad por Sustrato , Timidilato Sintasa/antagonistas & inhibidores , Timidilato Sintasa/metabolismo
2.
Postepy Biochem ; 61(3): 311-6, 2015.
Artículo en Polaco | MEDLINE | ID: mdl-26677579

RESUMEN

This article presents a brief overview of recent studies on the phenomena of halogen bonding, most of which have been done for the last 15 years in the collaboration with Prof. David Shugar. All these investigations concern reliable estimation of the thermodynamic contribution of a halogen bond to protein-ligand interactions.


Asunto(s)
Bioquímica/historia , Proteínas Quinasas/historia , Inhibidores Enzimáticos/historia , Halógenos/historia , Historia del Siglo XX , Historia del Siglo XXI , Ligandos , Polonia , Unión Proteica , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo
3.
Postepy Biochem ; 61(3): 260-73, 2015.
Artículo en Polaco | MEDLINE | ID: mdl-26677573

RESUMEN

Purine and pyrimidine nucleoside phosphorylases catalyze the reversible phosphorolytic cleavage of the glycosidic bond of purine and pyrimidine nucleosides, and are key enzymes of the nucleoside salvage pathway. This metabolic route is the less costly alternative to the de novo synthesis of nucleosides and nucleotides, supplying cells with these important building blocks. Interest in nucleoside phosphorylases is not only due to their important role in metabolism of nucleosides and nucleotides, but also due to the potential medical use of the enzymes (all phosphorylases in activating prodrugs - nucleoside and nucleic base analogs, high-molecular mass purine nucleoside phosphorylases in gene therapy of some solid tumors) and their inhibitors (as selective immunosuppressive, anticancer and antiparasitic agents, and preventing inactivation of other nucleoside drugs). Phosphorylases are also convenient tools for efficient enzymatic synthesis of otherwise inaccessible nucleoside analogues. In this paper the contribution of Professor David Shugar and some of his colleagues and coworkers in studies of these remarkable enzymes carried out over nearly 40 years is discussed on the background of global research in this field.


Asunto(s)
Bioquímica/historia , Purina-Nucleósido Fosforilasa/historia , Pirimidina Fosforilasas/historia , Bacterias/enzimología , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/farmacología , Eucariontes/enzimología , Historia del Siglo XX , Historia del Siglo XXI , Cinética , Nucleósidos/historia , Nucleósidos/metabolismo , Nucleótidos/historia , Nucleótidos/metabolismo , Polonia , Estructura Terciaria de Proteína , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Purina-Nucleósido Fosforilasa/química , Purina-Nucleósido Fosforilasa/metabolismo , Pirimidina Fosforilasas/antagonistas & inhibidores , Pirimidina Fosforilasas/química , Pirimidina Fosforilasas/metabolismo , Especificidad por Sustrato
4.
Postepy Biochem ; 61(3): 292-7, 2015.
Artículo en Polaco | MEDLINE | ID: mdl-26677576

RESUMEN

Therapy for hepatitis C virus (HCV) initially consisted on administering ribavirin - having a broad spectrum of action - and pegylated interferon, and was only effective in 40-50% of patients. Appropriate was to find effective inhibitors of viral replication e.g. by inhibition of a viral enzyme, NTPase/helicase required in the process of translation and RNA replication of the HCV. We developed methods of synthesis of many compounds belonging to different groups - derivatives of nucleosides, benzotriazole, benzimidazole, tropolone and epirubicine. Some of the derivatives inhibit HCV helicase activity at low concentrations and reduces replication of the viral RNA in subgenomic replicon system. In the process of HCV replication casein kinase CK2 plays an important role. It regulates the level of phosphorylation of HCV protein NS5A, which affects the production of infectious virions of HCV. Effective and selective inhibitors of kinase CK2 could be of use in the treatment of HCV in combination with other drugs. CK2 kinase phosphorylates approximately 300 proteins that affect the growth, differentiation, proliferation or apoptosis. Elevated CK2 kinase activity has been observed in several types of cancer and other diseases, therefore, inhibitors of this enzyme are potential therapeutic importance, particularly for anti-cancer treatment. Research carried out in collaboration with prof. Shugar led to the synthesis of one of the most selective inhibitors of this enzyme which is 4,5,6,7-tetrabromo-1H-benzotriazole, used for the study of the role of kinase CK2 in a number of metabolic processes in tumor cells.


Asunto(s)
Bioquímica/historia , Inhibidores Enzimáticos/historia , Hepacivirus/efectos de los fármacos , Hepatitis C/historia , Proteínas no Estructurales Virales/historia , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Farmacología/historia , Polonia , ARN Viral/historia , ARN Viral/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
5.
Mov Disord ; 26(6): 1072-82, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21626552

RESUMEN

In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions.


Asunto(s)
Antiparkinsonianos/historia , Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/historia , Enfermedad de Parkinson/terapia , Amantadina/historia , Amantadina/uso terapéutico , Estimulación Encefálica Profunda/historia , Estimulación Encefálica Profunda/métodos , Dopaminérgicos/historia , Dopaminérgicos/uso terapéutico , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/uso terapéutico , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Palidotomía/historia , Palidotomía/métodos , Enfermedad de Parkinson/complicaciones
6.
J Thromb Thrombolysis ; 31(4): 478-92, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21318583

RESUMEN

Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 µM⁻¹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.


Asunto(s)
Descubrimiento de Drogas/historia , Inhibidores Enzimáticos , Inhibidores del Factor Xa , Fibrinolíticos , Pirazoles , Piridonas , Animales , Evaluación Preclínica de Medicamentos/historia , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Fibrinolíticos/química , Fibrinolíticos/historia , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapéutico , Historia del Siglo XX , Humanos , Pirazoles/química , Pirazoles/historia , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Piridonas/química , Piridonas/historia , Piridonas/farmacocinética , Piridonas/uso terapéutico , Tromboembolia/tratamiento farmacológico
7.
DNA Repair (Amst) ; 6(8): 1161-9, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17485250

RESUMEN

The DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase (MGMT) can confer resistance to the cancer chemotherapeutic effects of the class of DNA damaging drugs generally referred to as the O(6)-alkylating agents. Inactivation of MGMT is thus a practical approach to improving the efficacy of such agents. An account is given of the collaboration between groups at Trinity College, Dublin and the Paterson Institute, Manchester which led to the development of the MGMT inactivating drug, Patrin (PaTrin-2, Lomeguatrib). The development of a simpler method of synthesis of O(6)-arylmethylguanines opened up the way to make a series of O(6)-heteroalkylmethyl analogues of the archetypal MGMT pseudosubstrate, O(6)-methylguanine. Of these, the furfuryl and thenyl compounds were the most active against recombinant Human MGMT in an in vitro assay. The 4-bromothenyl derivative was chosen for clinical trial as the most active compound. The MGMT active site tolerates O(6)-substituted guanines where the side chain can be quite large, but does not tolerate those with an aromatic or heteroaromatic ring with an 'ortho' substituent.


Asunto(s)
Metilasas de Modificación del ADN/antagonistas & inhibidores , Enzimas Reparadoras del ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Animales , Conducta Cooperativa , Diseño de Fármacos , Inglaterra , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Técnicas In Vitro , Irlanda , Purinas/síntesis química , Purinas/química , Purinas/historia , Purinas/farmacología , Relación Estructura-Actividad
8.
Ann N Y Acad Sci ; 1122: 231-44, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18077576

RESUMEN

Methylene blue (MB), generic name methylthioninium (C(16)H(18)ClN(3) S . 3H(2)O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well-known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S-100beta, as well as troponin I and creatine kinase isoenzyme MB, respectively.


Asunto(s)
Isquemia Encefálica/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Azul de Metileno/administración & dosificación , Isquemia Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Circulación Cerebrovascular/efectos de los fármacos , Forma MB de la Creatina-Quinasa/metabolismo , Dinoprost/sangre , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/historia , Historia del Siglo XIX , Azul de Metileno/química , Azul de Metileno/historia , Isquemia Miocárdica/tratamiento farmacológico , Reperfusión Miocárdica/métodos , Factores de Crecimiento Nervioso/sangre , Distribución Aleatoria , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/sangre , Análisis de Supervivencia , Porcinos , Factores de Tiempo , Troponina I/metabolismo
9.
Mini Rev Med Chem ; 6(6): 657-65, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16787376

RESUMEN

This review provides a chronological account of the identification and refinement of the pharmacophore for inhibition of two key serine/threonine protein phosphatases, PP1 and PP2A. The dramatic impact of natural product isolation, molecular modeling, analogue design, biochemical studies, and crystallography on the evolution of the pharmacophore will be described.


Asunto(s)
Inhibidores Enzimáticos/historia , Fosfoproteínas Fosfatasas/historia , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Serina/química , Relación Estructura-Actividad , Treonina/química
10.
Chem Biol Interact ; 111-112: 239-54, 1998 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-9679558

RESUMEN

L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines. Phase I clinical trials of BSO + melphalan (L-PAM)have been carried out and observed little toxicity with BSO alone and increased myelosuppression with BSO + L-PAM. Consistent and profound (< 10% of control) GSH depletion was observed in serial determinations of tumor GSH levels in patients receiving continuous infusion (CI) BSO. Evidence of clinical activity has been observed in patients with alkylating or platinating agent-refractory tumors. Phase II evaluation of CI BSO with L-PAM is in progress.


Asunto(s)
Butionina Sulfoximina/historia , Animales , Antimetabolitos Antineoplásicos/historia , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Butionina Sulfoximina/uso terapéutico , Resistencia a Medicamentos , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/uso terapéutico , Femenino , Glutamato-Cisteína Ligasa/antagonistas & inhibidores , Historia del Siglo XX , Humanos , Masculino , Melfalán/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo
11.
J Ethnopharmacol ; 51(1-3): 239-53; discussion 253-4, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9213622

RESUMEN

Camptothecin (CPT) and taxol are secondary metabolites found in the stembark of Camptotheca acuminata, a native of China, and Taxus brevifolia, found in the northwest Pacific coastal region of the USA, respectively. The compounds were isolated through bioassay-guided fractionation of various extracts and through chromatographic fractions. Their unique and hitherto unknown structures were elucidated by nuclear magnetic resonance, mass spectrometry and X-ray analysis. Both compounds have unique mechanisms of antitumor activity; CPT uniquely inhibits an enzyme, topoisomerase I, involved in DNA replication, while taxol binds to a protein, tubulin, thus inhibiting cell division. Taxol has been called the best new anticancer agent developed from natural products, showing particular efficacy against ovarian cancer. CPT and analogs singly or combined with cisplatinum show efficacy against solid tumors, breast, lung, and colorectal, which hitherto have been unaffected by most cancer chemotherapeutic agents.


Asunto(s)
Antineoplásicos Fitogénicos , Camptotecina , Paclitaxel , Antineoplásicos Fitogénicos/historia , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/historia , Camptotecina/aislamiento & purificación , Camptotecina/farmacología , Camptotecina/uso terapéutico , División Celular/efectos de los fármacos , Química Analítica/métodos , Química Farmacéutica/métodos , Ensayos Clínicos como Asunto , Distribución en Contracorriente , Inhibidores Enzimáticos/historia , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Historia del Siglo XX , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Paclitaxel/historia , Paclitaxel/aislamiento & purificación , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I , Moduladores de Tubulina , Estados Unidos
13.
J Antibiot (Tokyo) ; 62(1): 17-26, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19132059

RESUMEN

Staurosporine was discovered at the Kitasato Institute in 1977 while screening for microbial alkaloids using chemical detection methods. It was during the same era that protein kinase C was discovered and oncogene v-src was shown to have protein kinase activity. Staurosporine was first isolated from a culture of Actinomyces that originated in a soil sample collected in Mizusawa City, Japan. Thereafter, indolocarbazole compounds have been isolated from a variety of organisms. The biosynthesis of staurosporine and related indolocarbazoles was finally elucidated during the past decade through genetic and biochemical studies. Subsequently, several novel indolocarbazoles have been produced using combinatorial biosynthesis. In 1986, 9 years since its discovery, staurosporine and related indolocarbazoles were shown to be nanomolar inhibitors of protein kinases. They can thus be viewed as forerunners of today's crop of novel anticancer drugs. The finding led many pharmaceutical companies to search for selective protein kinase inhibitors by screening natural products and through chemical synthesis. In the 1990s, imatinib, a Bcr-Abl tyrosine kinase inhibitor, was synthesized and, following human clinical trials for chronic myelogenous leukemia, it was approved for use in the USA in 2001. In 1992, mammalian topoisomerases were shown to be targets for indolocarbazoles. This opened up new possibilities in that indolocarbazole compounds could selectively interact with ATP-binding sites of not only protein kinases but also other proteins that had slight differences in ATP-binding sites. ABCG2, an ATP-binding cassette transporter, was recently identified as an important new target for indolocarbazoles.


Asunto(s)
Carbazoles/historia , Inhibidores Enzimáticos/historia , Estaurosporina/historia , Actinobacteria/metabolismo , Animales , Antimaláricos/farmacología , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Historia del Siglo XX , Humanos , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/historia , Inhibidores de Proteínas Quinasas/farmacología , Estaurosporina/análogos & derivados , Estaurosporina/biosíntesis , Estaurosporina/farmacología , Inhibidores de Topoisomerasa I
15.
J Nat Prod ; 67(2): 129-35, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14987046

RESUMEN

The research team of Dr. Monroe E. Wall and Dr. Mansukh C. Wani of Research Triangle Institute discovered two first-in-class life-saving chemotherapeutic agents. Camptothecin, first isolated and identified from Camptotheca acuminata, was found to kill cancer cells uniquely via topoisomerase I poisoning. Presently, two first-generation analogues of camptothecin are used to treat ovarian, colorectal, and small-cell lung cancers, and several second-generation analogues are in clinical trials. Taxol, first isolated and identified by Wall and Wani from Taxus brevifolia, was found to inhibit cancer cell growth via the stabilization of microtubules. In 1992, taxol was approved for refractory ovarian cancer and today is used against breast and non-small cell lung cancers and in Kaposi's sarcoma. While there have been numerous reviews of these molecules individually, this review offers an integrated account of the research team of "Wall and Wani" and the significance of their discoveries to chemistry, biology, and clinical medicine.


Asunto(s)
Antineoplásicos Fitogénicos/historia , Productos Biológicos/historia , Camptotecina/historia , Paclitaxel/historia , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Camptotheca/química , Camptotecina/química , Camptotecina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/historia , Historia del Siglo XX , Humanos , Paclitaxel/química , Paclitaxel/farmacología , Taxus/química , Inhibidores de Topoisomerasa I
18.
FASEB J ; 7(5): 486-7, 1993 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8462790
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