RESUMO
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Assuntos
Antineoplásicos/síntese química , Formamidas/síntese química , Hidroxilaminas/síntese química , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Formamidas/química , Formamidas/farmacocinética , Formamidas/farmacologia , Hidroxilaminas/química , Hidroxilaminas/farmacocinética , Hidroxilaminas/farmacologia , Macaca fascicularis , Inibidores de Metaloproteinases de Matriz , Camundongos , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Cetonas/química , Cetonas/farmacologia , Acetilação , Western Blotting , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Fibrossarcoma/metabolismo , Histonas/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of succinimide hydroxamic acids was prepared and evaluated in vitro for HDAC inhibition and tumor cell antiproliferation. While the original macrocyclic analogue 6 was quite potent in both assays, several appropriately substituted non-macrocyclic succinimides, such as 23, were equipotent.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Succinimidas/síntese química , Succinimidas/farmacologia , Aminoácidos/química , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Indicadores e Reagentes , Células K562 , Conformação Molecular , Relação Estrutura-Atividade , Succinimidas/metabolismo , Células Tumorais CultivadasRESUMO
Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.