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

Mengqi Guo; Qianwen Ren; Binghua Wang; Wentao Ji; Jingxuan Ni; Yaqi Feng; Yi Bi; Jingwei Tian; Hongbo Wang

doi:10.1016/j.ejmech.2019.111668

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

Eur J Med Chem. 2019 Nov 15:182:111668. doi: 10.1016/j.ejmech.2019.111668. Epub 2019 Aug 31.

Authors

Mengqi Guo¹, Qianwen Ren², Binghua Wang¹, Wentao Ji¹, Jingxuan Ni¹, Yaqi Feng¹, Yi Bi³, Jingwei Tian¹, Hongbo Wang⁴

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; 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.

PMID: 31505451
DOI: 10.1016/j.ejmech.2019.111668

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.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Fusidic Acid / chemical synthesis
Fusidic Acid / chemistry
Fusidic Acid / pharmacology*
Humans
Molecular Structure
Structure-Activity Relationship

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Fusidic Acid