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 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. An efficient strategy for the construction of different acylated brefeldin A derivatives was developed using a mild and selective method. The inhibitory activity against TE‐1 was obtained, and certain compounds were identified as potential prodrugs. Docking study was carried out to demonstrate the binding mode between these compounds and ARF1‐GDP/GEF, and the result was coincident with the cytotoxicity activity.