RESUMO
Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compounds. Most compounds showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compound 1 and even the positive control SAHA. What's more, compared with the approved HDACs inhibitor SAHA, compounds 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compound 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N-hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compounds.
Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Domínio Catalítico , Linhagem Celular Tumoral , Cinamatos/síntese química , Inibidores de Histona Desacetilases/síntese química , Humanos , Ácidos Hidroxâmicos/síntese química , Isoenzimas/antagonistas & inibidores , Simulação de Acoplamento MolecularRESUMO
Drug discovery has always been a complex process including many phases from target validation to clinical development. Data from the Food and Drug Administration (FDA) has estimated that the elimination rate for investigational new drugs entering clinical trials is up to 80%. In recent years, many kinds of biomarkers have been used to predict response in cancer treatment and for evaluation of new drugs. By increasing the understanding of histone deactylase (HDAC) inhibitors cellular mechanism of action, we have elucidated how HDAC inhibitors exert their effect by the use of proper biomarkers. In this paper, we mainly focus on the development and potential clinical utility of HDAC inhibitor biomarkers.