RESUMO
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Assuntos
Antimitóticos/síntese química , Antimitóticos/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animais , Antimitóticos/química , Antimitóticos/classificação , Biopolímeros/química , Biopolímeros/metabolismo , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/classificação , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.