RESUMO
Effective inhibitors of S-adenosylhomocysteine hydrolase hold promise towards becoming useful therapeutic agents. Since most efforts have focused on the development of nucleoside analog inhibitors, issues regarding bioavailability and selectivity have been major challenges. Considering the marine sponge metabolite ilimaquinone was found to be a competitive inhibitor of S-adenosylhomocysteine hydrolase, new opportunities for developing selective new inhibitors of this enzyme have become available. Based on the activities of various hybrid analogs, SAR studies, pharmacophore modeling, and computer docking studies have lead to a predictive understanding of ilimaquinone's S-adenosylhomocysteine hydrolase inhibitory activities. These studies have allowed for the design and preparation of simplified structural variants possessing new furanoside bioisosteres with 100-fold greater inhibitory activities than that of the natural product.
Assuntos
Adenosil-Homocisteinase/antagonistas & inibidores , Adenosil-Homocisteinase/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Quinonas/química , Quinonas/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Animais , Desenho de Fármacos , Humanos , Modelos Moleculares , Ligação Proteica , S-Adenosil-Homocisteína/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-alpha, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.
Assuntos
Cumarínicos , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Proteínas ADAM/antagonistas & inibidores , Proteína ADAM17 , Ácidos Hidroxâmicos , Inibidores de Metaloproteinases de Matriz , Óxido Nítrico/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
We synthesized a series of delta-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated anti-inflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-alpha and nitric oxide by LPS-stimulated RAW264.7 cells.