RESUMO
In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 µM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 µM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.
Assuntos
Antineoplásicos/farmacologia , Calônios/farmacologia , Descoberta de Drogas , Receptor X Retinoide alfa/antagonistas & inibidores , Retinoides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Calônios/síntese química , Calônios/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Receptor X Retinoide alfa/metabolismo , Retinoides/síntese química , Retinoides/química , Relação Estrutura-AtividadeRESUMO
Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities. Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0.09 to 1.30 µM. In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization. Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model. Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent.
Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Calônios/farmacologia , Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzopiranos/síntese química , Benzopiranos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Calônios/síntese química , Calônios/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias/patologia , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
In this paper, 38 millepachine derivatives have been designed, synthesized and evaluated for their in vitro and in vivo antiproliferative activity. Among these novel derivatives, 15 displayed more potent antiproliferative activity than millepachine against HepG2, K562, SK-OV-3, HCT116, HT29, and SW620 tumor cells (mean IC(50) = 0.64 vs. 2.86 µM, respectively). Furthermore, 15 could effectively inhibit tubulin polymerization in HepG2 cells, and induce the HepG2 cell cycle arrest at the G2/M phase in a concentration-dependant manner. Further studies confirmed that 15 significantly suppressed the growth of tumor volume and exerted more potent anticancer potency than millepachine and anticancer drug cisplatin in A549 lung xenograft tumor model.
