Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 29(3): 466-470, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579797

RESUMO

Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.

2.
J Med Chem ; 59(3): 1041-51, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26751161

RESUMO

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.


Assuntos
Encéfalo/metabolismo , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Niacinamida/administração & dosagem , Niacinamida/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 25(9): 1856-63, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25845281

RESUMO

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3ß. We identified several series of promising new GSK-3ß inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3ß inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.


Assuntos
Aminopiridinas/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Pirróis/química , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
4.
Proteins ; 83(2): 331-50, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25401969

RESUMO

HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure-activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel ß20-ß21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the "open state" four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development.


Assuntos
Proteína gp120 do Envelope de HIV/química , Inibidores da Fusão de HIV/química , Piperazinas/química , Triazóis/química , Sítios de Ligação , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Ligação Proteica , Homologia Estrutural de Proteína , Relação Estrutura-Atividade
5.
Bioorg Med Chem ; 22(5): 1782-90, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24495863

RESUMO

Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Iminas/farmacocinética , Receptores de Serotonina/uso terapêutico , Animais , Humanos , Iminas/farmacologia , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade
6.
Mol Inform ; 33(9): 610-26, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27486080

RESUMO

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. GSK-3ß, also known as tau protein kinase I (TPK-I), is one of the most important kinases implicated in the hyperphosphorylation of tau that leads to neurodegenerative diseases. Hence, GSK-3ß has emerged as an important therapeutic target. To identify compounds that are structurally novel and diverse compared to previously reported ATP-competitive GSK-3ß inhibitors, we performed virtual screening by implementing a mixed ligand/structure-based approach, which included pharmacophore modeling, diversity analysis, and ensemble docking. The sensitivities of different docking protocols to induced-fit effects were explored. An enrichment study was employed to verify the robustness of ensemble docking, using 13 X-ray structures of GSK-3ß, compared to individual docking in terms of retrieving active compounds from a decoy dataset. A total of 24 structurally diverse compounds obtained from the virtual screening underwent biological validation. The bioassay results showed that 15 out of the 24 hit compounds are indeed GSK-3ß inhibitors, and among them, one compound exhibiting sub-micromolar inhibitory activity is a reasonable starting point for further optimization.

7.
J Chem Inf Model ; 49(7): 1787-96, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19588935

RESUMO

Drug resistance acquired by Plasmodium falciparum (Pf) is a major problem in the treatment and control of malaria. One of the major examples of drug resistance is that caused by mutations in the active site of dihydrofolate reductase (DHFR) of Pf (PfDHFR-TS). A double mutation, A16V+S108T, is specific for resistance to the marketed drug cycloguanil. In this study, we used 58 cycloguanil (2,4-diamino-1,6-dihydro-1,3,5-triazine) derivatives to explore the relationship between various physicochemical properties and reported binding affinity data on wild-type and mutant-type A16V+S108T. Using the Hansch 2D-quantitative structure-activity relationship method, we obtained a parabolic relationship of hydrophobicity of substituents at the N1-phenyl ring with the wild-type binding affinity data. Hydrophobicity being a key property for wild-type binding affinity data, we found steric factors to be crucial for A16V+S108T mutant resistance. We investigated FlexX, GOLD, Glide and Molegro virtual docking programs and 13 different scoring functions on 10 of the cycloguanil derivatives to evaluate which program was best for reproducing the experimental binding mode and correlating the docking scores with the reported binding affinity data. We identified GOLD, using its GoldScore fitness function, as the most accurate docking program for predicting binding affinity data of cycloguanil derivatives to DHFR and Molegro virtual docker, with its template docking algorithm and MolDock [GRID] scoring function, as most accurate for reproducing the experimental binding mode of a reference ligand that is structurally similar to the cycloguanil derivatives studied. We also report an interaction index which best describes the structure-activity relationships exhibited by these analogs in terms of PfDHFR-TS active site interactions.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/enzimologia , Proguanil/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Triazinas/farmacologia , Animais , Antimaláricos/química , Resistência a Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Mutação , Proguanil/química , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Triazinas/química
8.
Bioorg Med Chem ; 14(24): 8210-8, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17010615

RESUMO

Glycogen synthase kinase-3alpha (GSK-3alpha) was recently found to be an attractive target for the treatment of Alzheimer's disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3alpha binding. Using Fujita-Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3alpha inhibition.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/metabolismo , Relação Quantitativa Estrutura-Atividade , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Maleimidas/química , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 14(21): 7311-23, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16837204

RESUMO

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r(2)=0.94, q(2)=0.63, and r(pred)(2)=0.63. The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Benzofenonas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Animais , Ligações de Hidrogênio , Modelos Moleculares , Conformação Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA