Argade A B, Devraj R, Vroman J A, Haugwitz R D, Hollingshead M, Cushman M
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1998 Aug 27;41(18):3337-46. doi: 10.1021/jm970746g.
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 cancer 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 (IP), 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.
已将多种硫醇添加到布雷菲德菌素A中存在的α,β-不饱和内酯官能团上，并将所得的硫化物氧化为相应的亚砜。这些亚砜有可能进行顺式消除以再生布雷菲德菌素A。在多种人类癌细胞培养物中，亚砜作为细胞毒性剂比硫化物更具活性，其活性接近布雷菲德菌素A本身。亚砜的细胞毒性可能是由于它们转化回布雷菲德菌素A。研究了四例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测定过程中可能会产生大量的布雷菲德菌素A。由于硫化物氧化为亚砜是一种常见的代谢反应，源自布雷菲德菌素A的硫化物可被视为潜在的布雷菲德菌素A前药。相对于布雷菲德菌素A本身，已确定几种硫化物衍生物具有增强的水溶性。还制备了多种布雷菲德菌素A琥珀酸酯、戊二酸酯、氧化产物和砜衍生物，并在癌细胞培养物中评估了它们的细胞毒性。一些活性更强的布雷菲德菌素A衍生物在体内动物模型中进行了测试，在该模型中，将含有癌细胞培养物的中空纤维皮下（SC）和腹腔内（IP）植入，化合物通过腹腔内给药。对于大多数这些化合物，在皮下部位观察到的细胞毒性活性高于腹腔内部位，这一观察结果与它们在体内作为布雷菲德菌素A前药起作用的假设一致。
