RESUMO
As part of an effort to identify novel selective modulators of sirtuins, we synthesized and tested several isosteres and constrained analogues of nicotinamide. Biological data suggest that compound 2 is selective for Sirt3 over Sirt1 and Sirt2.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Niacinamida/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Niacinamida/síntese química , Niacinamida/química , Especificidade por SubstratoRESUMO
Tubulin inhibition represents an established target in the field of anticancer research, and over the last 20 years, an intensive search for new antimicrotubule agents has occurred. Indeed, in silico models have been presented that might aid the discovery of novel agents. Among these, a 7-point pharmacophore model has been recently proposed. As a formal proof of this model, we carried out a ligand-based virtual screening on the colchicine-binding site. In vitro testing demonstrated that two compounds displayed a cytotoxic profile on neuroblastoma cancer cells (SH-SY5H) and one had an antitubulinic profile.
Assuntos
Colchicina/química , Bases de Dados Factuais , Modelos Moleculares , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Sítios de Ligação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologiaRESUMO
In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.