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

• Published in: European journal of medicinal chemistry Vol. 182; pp. 111668 - 111680
• Main Authors: Guo, Mengqi, Ren, Qianwen, Wang, Binghua, Ji, Wentao, Ni, Jingxuan, Feng, Yaqi, Bi, Yi, Tian, Jingwei, Wang, Hongbo
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.11.2019; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Fusidic acid; Fusidic Acid - chemical synthesis; Fusidic Acid - chemistry; Fusidic Acid - pharmacology; Humans; Life Sciences & Biomedicine; Molecular Structure; P-glycoprotein; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Synthesis; Tumor; Tumor resistance reversal activity; P-glycoprotein; Fusidic acid; Tumor; Synthesis; Tumor resistance reversal activity; IN-VITRO; ANALOGS; DOXORUBICIN; DRUG-RESISTANCE; ANTITUMOR-ACTIVITY; CANCER; H6
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111668

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. [Display omitted] •23 fusidic acid (FA) derivatives were synthesized, of which 15 were not reported.•Tumor resistance reversal activity of fusidic acid (FA) derivatives was first discovered.•Compound 1 at a concentration of 5 μM enhanced the cytotoxicity of paclitaxel in KBV cells.•The mechanism that compound 1 acting on P-gp was first proved.