Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences , Zhengzhou University , Zhengzhou 450001 , P. R. China.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
J Med Chem. 2018 Jul 26;61(14):5988-6001. doi: 10.1021/acs.jmedchem.8b00335. Epub 2018 Jul 18.
P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has become a major obstacle in successful cancer chemotherapy, which attracted much effort to develop clinically useful compounds to reverse MDR. Here, we designed and synthesized a novel series of derivatives with a 5-cyano-6-phenylpyrimidine scaffold and evaluated their potential reversal activities against MDR. Among these compounds, 55, containing an acylurea appendage, showed the most potent activity in reversing paclitaxel resistance in SW620/AD300 cells. Further studies demonstrated 55 could increase accumulation of PTX, interrupt ABCB1-mediated Rh123 accumulation and efflux, stimulate ABCB1 ATPase activity, and especially have no effect on CYP3A4 activity, which avoid drug interaction caused toxicity. More importantly, 55 significantly enhanced the efficacy of PTX against the SW620/AD300 cell xenograft without obvious side effects for orally intake. Given all that, the pyrimidine-acylurea based ABCB1 inhibitor may be a promising lead in developing new efficacious ABCB1-dependent MDR modulator.
P-糖蛋白（ABCB1）介导的多药耐药（MDR）已成为癌症化疗成功的主要障碍，这促使人们努力开发临床有用的化合物来逆转 MDR。在这里，我们设计并合成了一系列具有 5-氰基-6-苯基嘧啶骨架的新型衍生物，并评估了它们对 MDR 的潜在逆转活性。在这些化合物中，含有酰脲附加物的 55 在逆转 SW620/AD300 细胞紫杉醇耐药方面表现出最强的活性。进一步的研究表明，55 可以增加 PTX 的积累，中断 ABCB1 介导的 Rh123 积累和外排，刺激 ABCB1 ATP 酶活性，特别是对 CYP3A4 活性没有影响，从而避免了由药物相互作用引起的毒性。更重要的是，55 显著增强了 PTX 对 SW620/AD300 细胞异种移植物的疗效，而口服无明显副作用。综上所述，基于嘧啶-酰脲的 ABCB1 抑制剂可能是开发新的有效 ABCB1 依赖性 MDR 调节剂的有前途的先导化合物。
