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.
Eur J Med Chem. 2021 Feb 5;211:113107. doi: 10.1016/j.ejmech.2020.113107. Epub 2020 Dec 17.
Multidrug resistance (MDR) has become a major obstacle to malignancies treatment by chemotherapeutic drugs, therefore, it is important to develop MDR reversal agents with high activity. We have previously found that the hederagenin (HD) derivative HBQ showed good tumor MDR reversal activity in vitro and in vivo but had poor solubility. In this study, to enhance the aqueous solubility and tumor MDR reversal activity of HBQ, three series of HD derivatives were designed and synthesized. Nitrogen-containing heterocyclic-substituted, PEGylated, and ring-A substituted derivatives significantly reversed the MDR phenotype of KBV (multidrug-resistant oral epidermoid carcinoma) cells toward paclitaxel at a concentration of 10 μM in MTT assays. The PEGylated derivatives 10c-10e had increased aqueous solubility compared with HBQ by 18-657 fold, while maintaining tumor MDR reversal activity. The most in vitro active compound 10c possessed good chemical stability to an esterase over 24 h and enhanced the sensitivity of KBV cells to paclitaxel and vincristine with IC values of 4.58 and 0.79 nM, respectively. Mechanism studies indicated that compound 10c increased the accumulation of P-glycoprotein (P-gp) substrates rhodamine 123 and Flutax1 in KBV cells and MCF-7T (paclitaxel-resistant breast carcinoma) cells, that is to say, compound 10c exerted the reversal effect of tumor MDR by inhibiting the efflux function of P-gp. Finally, the structure-activity relationships were further investigated by analyzing the relationship between structure and tumor MDR reversal activity of HD derivatives. This study highlights the potential of PEGylated HD derivatives such as compound 10c for the development of tumor MDR reversal agents and provides information for the further improvement of the aqueous solubility and tumor MDR reversal activity of HD derivatives in the future.
多药耐药性 (MDR) 已成为化疗药物治疗恶性肿瘤的主要障碍，因此，开发具有高活性的 MDR 逆转剂非常重要。我们之前发现，熊果酸 (HD) 衍生物 HBQ 在体外和体内均显示出良好的肿瘤 MDR 逆转活性，但溶解度较差。在这项研究中，为了提高 HBQ 的水溶解度和肿瘤 MDR 逆转活性，设计并合成了三个系列的 HD 衍生物。含氮杂环取代、聚乙二醇化和 A 环取代衍生物在 MTT 测定中，在 10μM 浓度下显著逆转了 KBV（多药耐药性口腔表皮样癌细胞）细胞对紫杉醇的 MDR 表型。与 HBQ 相比，聚乙二醇化衍生物 10c-10e 的水溶解度分别提高了 18-657 倍，同时保持了肿瘤 MDR 逆转活性。最具体外活性的化合物 10c 对酯酶具有良好的化学稳定性，超过 24 小时，将 KBV 细胞对紫杉醇和长春新碱的敏感性分别提高到 IC 值为 4.58 和 0.79 nM。机制研究表明，化合物 10c 增加了 P-糖蛋白 (P-gp) 底物罗丹明 123 和 Flutax1 在 KBV 细胞和 MCF-7T（紫杉醇耐药乳腺癌）细胞中的积累，也就是说，化合物 10c 通过抑制 P-gp 的外排功能发挥肿瘤 MDR 逆转作用。最后，通过分析 HD 衍生物的结构与肿瘤 MDR 逆转活性之间的关系，进一步研究了构效关系。本研究突出了聚乙二醇化 HD 衍生物（如化合物 10c）在开发肿瘤 MDR 逆转剂方面的潜力，并为今后进一步提高 HD 衍生物的水溶解度和肿瘤 MDR 逆转活性提供了信息。
