Design and synthesis of brefeldin A sulfide derivatives as prodrug candidates with enhanced aqueous solubilities
Design and synthesis of brefeldin A sulfide derivatives as prodrug candidates with enhanced aqueous solubilities
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DOI：
10.1021/jm970746g
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发表时间：
1998-08-27
影响因子：
7.3
通讯作者：
Cushman, M
中科院分区：
文献类型：
--
作者：
Argade, AB;Devraj, R;Cushman, M
已经进行了将各种硫醇加成到布雷菲德菌素A中存在的α，β-不饱和内酯官能团上，并且所得硫化物已经氧化成相应的亚砜。这些亚砜具有经历顺式消除以再生布雷菲德菌素A的潜力。亚砜比硫化物作为细胞毒性剂在各种人类癌细胞培养物中更活跃，亚砜的活性接近布雷菲德菌素A本身的活性。亚砜的细胞毒性可能是由于它们转化回布雷菲德菌素A。在四种情况下研究了亚砜消除形成布雷菲德菌素A的动力学，结果表明，在亚砜衍生物的细胞毒性试验期间可能会产生大量的布雷菲德菌素A。由于硫化物氧化成亚砜是常见的代谢反应，因此可将源自布雷菲德菌素A的硫化物视为潜在的布雷菲德菌素A前药。几种硫化物衍生物被确定为相对于布雷菲德菌素A本身具有增强的水溶性。还制备了许多布雷菲德菌素A琥珀酸酯、戊二酸酯、氧化产物和砜衍生物，并在舞蹈细胞培养物中评价了细胞毒性。在体内动物模型中测试了一些更有活性的布雷菲德菌素A衍生物，其中皮下（SC）和腹膜内（IF）植入含有癌细胞培养物的中空纤维，并IP施用化合物。对于大多数这些化合物，在SC部位观察到比在IP部位更大的细胞毒性活性，这一观察结果与它们在体内充当布雷菲德菌素A前药的假设一致。
The addition of a variety of thiols to the alpha,beta-unsaturated lactone functionality present in brefeldin A has been carried out, and the resulting sulfides have been oxidized to the corresponding sulfoxides. These sulfoxides have the potential to undergo syn elimination to regenerate brefeldin A. The sulfoxides were more active than the sulfides as cytotoxic agents in a variety of human cancer cell cultures with the activities of the sulfoxides approaching that of brefeldin A itself. The cytotoxicities of the sulfoxides may be due to their conversion back to brefeldin A. The kinetics of sulfoxide elimination to form brefeldin A were studied in four cases, and the results indicate that substantial amounts of brefeldin A are likely to be generated during the cytotoxicity assays of the sulfoxide derivatives. Since the oxidation of sulfides to sulfoxides is a common metabolic reaction, the sulfides derived from brefeldin A can be considered as potential brefeldin A prodrugs. Several of the sulfide derivatives were determined to have enhanced aqueous solubilities relative to brefeldin A itself, A number of brefeldin A succinates, glutarates, oxidation products, and sulfone derivatives were also prepared and evaluated for cytotoxicity in dancer cell cultures. Some of the more active brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing cancer cell cultures were implanted subcutaneously (SC) and intraperitoneally (IF), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majority of these compounds, an observation which is consistent with the hypothesis that they are acting as brefeldin A prodrugs in vivo.