RESUMO
AIM: Discovery of novel series of colchicine binding site inhibitors (CBSIs). MATERIALS & METHODS: Isoxazoline 3a-d, pyrazoline 4a-b, 7a-f and 8a-f, cyclohexenone 9a-b and 10a-b or pyridine derivatives 11a-b were synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity. Most of the compounds displayed potent to moderate antitumor activity against leukemia SR cell line.7c, 7e and 11a were more potent than colchicine with IC50 of 0.09, 0.05 and 0.06 µM, and percentage inhibition in tubulin polymerization of 95.2, 96.0 and 96.3%, respectively. Compounds 7c and 11a showed cell-cycle arrest at G2/M phase and induced apoptosis and were able to bind the colchicine binding site of tubulin with comparable affinity to colchicine. Docking study showed that these compounds may interact with tubulin exploiting a binding cavity not commonly reported in the binding of CBSI. CONCLUSION: Compounds 7c and 11a may be considered as promising CBSI based on their excellent activity and favorable drug likeness profile.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Furanos/química , Furanos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Sítios de Ligação/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colchicina/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Halogenação , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Polimerização/efeitos dos fármacos , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese químicaRESUMO
AIM: Novel quinazolinone and triazinoquinazolinone derivatives were designed and synthesized as apoptotic inducers. METHODOLOGY/RESULTS: Most of the synthesized compounds showed excellent antiproliferative activity against MCF-7 and HCT-116 cell lines, respectively. Compounds 7a, 8a, 8d, 14a and 14d were superior to doxorubicin as activators of caspases 3, 8 and 9 in HCT-116 cell line. The most potent caspase inducers, 8d and 14a showed cell cycle arrest mainly in G1 and S phase, respectively and increased the levels of p53, Bax and the Bax/Bcl-2 ratio compared with doxorubicin in HCT-116 cells with excellent selectivity against CCD-18Co human colon normal cell line. CONCLUSION: The synthesized compounds can be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways.
