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Eur J Med Chem. 2019 Aug 31;182:111668. doi: 10.1016/j.ejmech.2019.111668. [Epub ahead of print]

Discovery and synthesis of 3- and 21-substituted fusidic acid derivatives as reversal agents of P-glycoprotein-mediated multidrug resistance.

Author information

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; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, 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: beeyee_413@163.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: hongbowangyt@gmail.com.

Abstract

In this study, we synthesized 23 fusidic acid (FA) derivatives and screened them for tumor drug resistance reversal activity and cytotoxicity toward the KBV (multidrug-resistant oral epidermoid carcinoma) cell line based on MTT assay. Tumor resistance reversal activity of fusidic acid (FA) derivatives was discovered for the first time. Our results showed that compound 1 enhanced the cytotoxicity of paclitaxel toward the drug-resistant KBV cells at a concentration of 5 μM. And compound 1 sensitized KBV cells toward paclitaxel in arresting cells in the G2/M phase and inducing cell apoptosis. Further researches showed that compound 1 inhibited the drug efflux activity of P-glycoprotein (P-gp) by increasing the ATPase activity of P-gp without affecting its expression. The structure-activity relationships (SARs) of the FA derivatives were also preliminarily investigated. Our findings indicate that compound 1 is a promising lead compound for designing FA derivatives with improved tumor drug resistance reversal activity in the future.

KEYWORDS:

Fusidic acid; P-glycoprotein; Synthesis; Tumor; Tumor resistance reversal activity

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