title: Synthesis and cytotoxic evaluation of acylated brefeldin a derivatives as potential anticancer agents.
abstract: Brefeldin A has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on brefeldin A were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of brefeldin A under mild conditions and the preparation of a series of monoacylated and diacylated brefeldin A derivatives. Their cytotoxicity, antitumor activity against TE-1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. Brefeldin A 7-O-benzoate, brefeldin A 4,7-O-dibenzoate, and brefeldin A 7-O-biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50 μm, respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anticancer agents from brefeldin A derivatives.
authors.affiliation: College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.
authors.forename: Bingyong
authors.initials: B
authors.lastname: He
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000737:chemistry / Q000378:metabolism; D000215:Acylation; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000633:toxicity; D001665:Binding Sites; D020126:Brefeldin A / Q000097:blood / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D020126:Brefeldin A; D020823:ADP-Ribosylation Factor 1
keywords: acylation; antiproliferative activity; brefeldin A derivatives; molecular modeling; prodrug