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Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents
Author(s) -
He Bingyong,
Wang Yajun,
Zheng Yuguo,
Chen Wei,
Zhu Qing
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12154
Subject(s) - brefeldin a , chemistry , cytotoxicity , stereochemistry , pharmacology , biochemistry , in vitro , golgi apparatus , biology , cell
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 GI 50 values of 0.39, 0.46, and 0.50 μ m , respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF 1 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.