School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
Eur J Med Chem. 2019 Jan 1;161:118-130. doi: 10.1016/j.ejmech.2018.10.038. Epub 2018 Oct 16.
Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer.
多药耐药（MDR）是癌症治疗失败的主要原因，其中 P-糖蛋白（Pgp）的过度表达起着关键作用。本文设计、合成了一类新型的 25-羟基羽扇豆醇型酰胺衍生物，并评价了它们逆转多药耐药的能力。分析了逆转活性的构效关系。十种化合物表现出有希望的化疗逆转能力，其中具有 N-Boc-己酰基单元的 24R-25-羟基羽扇豆醇型酰胺衍生物 6c 在逆转 KBV 细胞紫杉醇耐药方面表现出最强的活性。化合物 6c 通过刺激 Pgp-ATP 酶活性抑制 Pgp 介导的罗丹明 123 外排功能，并在分子对接研究中显示与 Pgp 具有高结合亲和力。重要的是，化合物 6c 经口服给药后增强了紫杉醇对裸鼠 KBV 癌细胞衍生异种移植肿瘤的疗效。这些结果表明，25-羟基羽扇豆醇型酰胺衍生物是克服癌症多药耐药性的有前途的先导化合物。
