RESUMO
The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action. In vitro, 4bb is a significantly more potent SIRT1 inhibitor, compared to ß-naphthols such as sirtinol, cambinol. Increasing concentration of 4bb decrease viability of colon cancer cells but, does not affect the viability of normal dermal fibroblasts depicting cancer cell specificity. Further, 4bb treatment increased p53 acetylation, Bax expression and induced caspase 3 cleavage suggesting that the death of HCT116 colon cancer cells occur through intrinsic pathway of apoptosis. Overall, our results presents 4bb as a new class of human SIRT1 inhibitor and suggest that inhibition of SIRT1 by 4bb induces apoptosis of colon cancer cells at least in part via activating p53 by preventing p53 deacetylation, increasing Bax expression and inducing caspases. Therefore, this molecule provide an opportunity for lead optimization and may help in development of novel, non-toxic epigenetic therapeutics for colon cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Quinoxalinas/farmacologia , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/química , Carcinoma/patologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Células HCT116 , Humanos , Estrutura Molecular , Quinoxalinas/química , Sirtuína 1/metabolismo , Relação Estrutura-AtividadeRESUMO
A transition metal free tandem two-step strategy has been developed involving hydrolysis of 2-chloro-3-alkynyl quinoxalines/pyrazines followed by in situ cyclization of the corresponding 2-hydroxy-3-alkynyl intermediates in a single pot leading to fused furo N-heterocycles as potential inhibitors of sirtuins. A representative compound showed promising pharmacological properties in vitro and in vivo.
Assuntos
Embrião não Mamífero/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Sirtuínas/antagonistas & inibidores , Animais , Ciclização , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Hidrólise , Modelos Moleculares , Estrutura Molecular , Pirazinas/química , Quinoxalinas/química , Sirtuínas/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra/embriologiaRESUMO
An unprecedented AlCl3-mediated method has been developed involving aromatic C-H bond addition to an alkyne and heteroarylation of an arene in a single pot leading to densely functionalized novel olefins, e.g. 2-(2,2-diarylvinyl)-3-arylquinoxalines, as potential inhibitors of sirtuins.