RESUMEN
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.
Asunto(s)
Chalconas/química , Chalconas/farmacología , Tetrazoles/química , Tetrazoles/farmacología , Triazoles/química , Triazoles/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chalconas/síntesis química , Humanos , Modelos Moleculares , Neuroblastoma/tratamiento farmacológico , Tetrazoles/síntesis química , Triazoles/síntesis química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis químicaRESUMEN
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.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Niacinamida/farmacología , Sirtuina 1/antagonistas & inhibidores , Sirtuina 2/antagonistas & inhibidores , Sirtuina 3/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Niacinamida/síntesis química , Niacinamida/química , Especificidad por SustratoRESUMEN
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.