Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents
Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents
复制标题
酰化 Brefeldin A 衍生物作为潜在抗癌药物的合成及细胞毒性评价
DOI：
10.1111/cbdd.12154
复制
发表时间：
2013-09-01
影响因子：
3
通讯作者：
Zhu, Qing
中科院分区：
文献类型：
--
作者：
He, Bingyong;Wang, Yajun;Zhu, Qing
Brefeldin A因其在癌症预防方面的潜在功能而引起了广泛的关注。然而，其治疗用途因其较差的生物利用度而受到限制。布雷菲德菌素 A 的修饰很困难，因为它的稳定性和对同一分子内两个羟基的选择性较低。在本研究中，我们报道了布雷菲德菌素A在温和条件下的选择性酰化，并制备了一系列单酰化和二酰化布雷菲德菌素A衍生物。评估了它们的细胞毒性、对 TE-1 细胞的抗肿瘤活性以及吸附、分布、代谢和消除的分子特性。布雷菲德菌素 A 7-O-苯甲酸酯、布雷菲德菌素 A 4,7-O-二苯甲酸酯和布雷菲德菌素 A 7-O-生物素羧酸盐表现出最强的细胞毒活性，GI50 值分别为 0.39、0.46 和 0.50m。这些类似物的分子对接表明，这些衍生物在 ARF1 及其鸟嘌呤核苷酸交换因子 ARNO 之间的界面处具有良好的耐受性。我们的结果可以作为从布雷菲德菌素 A 衍生物中开发新型潜在抗癌药物的基础。
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 0.50m, 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.