RESUMO
A series of indenopyrazoles was synthesized from the corresponding indanones and phenyl isothiocyanates in two steps. Among the compounds synthesized, methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate 6m (GN39482) was found to possess a promising antiproliferative activity toward human cancer cells without affecting any antimicrobial and antimalarial activities at 100 nM. Both a methoxy group at R(1) position and a methoxycarbonyl group at R(2) position of the anilinoquinazoline framework are essential for the high cell growth inhibition. Both MorphoBase and ChemProteoBase profiling analyses suggested that compound 6m was classified as a tubulin inhibitor. Indeed, compound 6m inhibited the acetylated tubulin accumulation and the microtubule formation and induced G2/M cell cycle arrest in HeLa cells, revealing that a promising antiproliferative activity of compound 6m toward human cancer cells is probably caused by the tubulin polymerization inhibition.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Pirazóis/farmacologia , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia , meta-Aminobenzoatos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Células HeLa/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Moduladores de Tubulina/química , meta-Aminobenzoatos/químicaRESUMO
The indenopyrazole framework was investigated as a new class of HIF-1α inhibitors. Indenopyrazole 2l was found to most strongly inhibit the hypoxia-induced HIF-1α transcriptional activity (IC50 = 0.014 µM) among all of the known compounds having relatively simple structures, unlike manassantins. Indenopyrazole 2l suppressed HIF-1α transcriptional activity without affecting both HIF-1α protein accumulation and HIF-1α/HIF-1ß heterodimerization in nuclei under the hypoxic conditions, suggesting that 2l probably affected the transcriptional pathway induced by the HIF-1α/HIF-1ß heterodimer.