RESUMO
New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21â¯nM, 27â¯nM and 17â¯nM, B-RafV600E with IC50 of 29â¯nM, 28â¯nM and 16â¯nM, VEGFR-2 with IC50 of 84â¯nM, 46â¯nM and 63â¯nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sorafenibe/farmacologia , Sulfetos/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios Enzimáticos , Humanos , Ligação de Hidrogênio , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/genética , Sorafenibe/síntese química , Sulfetos/síntese químicaRESUMO
A series of novel sorafenib derivatives, 9a-w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC(50)=2.8-52.0 and 2.2-45.6 µM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by (1)H NMR, (13)C NMR and HRMS.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Compostos de Fenilureia/química , Sorafenibe , Relação Estrutura-AtividadeRESUMO
A novel series of diaryl thiourea containing sorafenib derivatives 9a-t was designed and synthesized. The structures of all the newly synthesized compounds were determined by (1)H NMR, (13)C NMR and HRMS. Their antiproliferative activities against HCT116 and MDA-MB-231 cell lines, and their inhibitory activities against the phosphorylation of VEGFR were evaluated and described. Some of the compounds showed significant activities against both cell lines and VEGFR. Compounds 9g, 9m, 9o and 9p demonstrated competitive antiproliferative activities to sorafenib, the reference standard, while compounds 9d, 9m, and 9p showed significant inhibitory activities against the phosphorylation of VEGFR.
