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  3. Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles

Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles

  • Eur J Med Chem. 2022 Mar 15;232:114207. doi: 10.1016/j.ejmech.2022.114207.
Wentao Huang 1,  Yingjie Wang 1,  Si Xu 1,  Hui Qiao 1,  Haoran Cheng 1,  Linxu Wang 1,  Shuqi Liu 2,  Qingjian Tian 1,  Ruodong Wang 1,  Hongbo Wang 3,  Yi Bi 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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. Electronic address: hongbowangyt@gmail.com.
  • 4 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. Electronic address: beeyee_413@163.com.
PMID: 35219948 DOI: 10.1016/j.ejmech.2022.114207
Abstract

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 IC50 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.

Keywords

Drug resistance reversal activity; Hederagenin; Nitrogen-containing heterocycle; P-glycoprotein; Synthesis.

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