RESUMO
Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
Assuntos
Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Feminino , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos SCID , Modelos Moleculares , Oxidiazóis/química , Oxidiazóis/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Especificidade por SubstratoRESUMO
A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a structure-activity study on this compound with respect to its antimicrobial activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Indicadores e Reagentes , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A practical total synthesis of Bengamides B, E, and Z from a common polyol intermediate is described. Consecutive aldol condensations afford a protected polyol thioester side chain suitable for coupling to the Bengamides. A novel chiral phase transfer catalyzed enantioselective alkylation affords the more highly functionalized amino caprolactams required for Bengamides B and Z. Use of the 2-naphthylmethyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to Bengamide B.
