School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China; Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264005, PR China.
Eur J Med Chem. 2022 Mar 15;232:114207. doi: 10.1016/j.ejmech.2022.114207. Epub 2022 Feb 19.
The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure-activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.
肿瘤多药耐药（MDR）的出现导致化疗疗效降低，而过表达 P 糖蛋白（P-gp）是 MDR 的主要原因之一。在之前的报告中，我们证明了多种羽扇豆烷（HD）衍生物可以在体内和体外逆转肿瘤的 MDR。为了进一步丰富结构类型、增强活性并改善构效关系（SARs），本研究通过 A 环融合和创新利用含氮杂环和苄基取代的结构优势设计并合成了三系列 HD 衍生物。我们评估了 21 种 HD 衍生物在 KBV（多药耐药口腔表皮样癌细胞）细胞中的 MDR 逆转活性，并对其 SARs 进行了优化。细胞实验结果表明，超过一半的化合物具有 MDR 逆转活性。其中，化合物 16 显示出相对较强的 MDR 逆转能力，因为它使 KBV 细胞对紫杉醇、长春新碱、米托蒽醌和顺铂的敏感性分别提高了 3.19、0.65、125.30 和 4.54 nM。机制分析结果表明，化合物 16 通过激活 P-gp ATPase 抑制了 P-gp 的外排功能，并增加了 KBV 细胞中罗丹明 123 的积累。重要的是，化合物 16 基于 56.24%的生长抑制率增强了紫杉醇对裸鼠 KBV 癌源性异种移植瘤的疗效。这些结果表明，引入含氮杂环可以有效提高 HD 衍生物的 MDR 逆转活性，它们似乎是肿瘤 MDR 逆转剂开发的有前途的先导化合物。
