Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents

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.