Asymmetric Synthesis of Antitumor Agents

本研究的具体目标是合成有效的抗肿瘤药物月桂烷胺、apoptolidin和leucascandrolide a。最终，也许可以制备出这些有效抗肿瘤药物的较简单的衍生物，它们具有相似或更好的生物学特性。在研究过程中，将发展不对称合成聚乙酸酯和聚丙酸天然产物的一般方法。本文描述的聚乙酸酯和聚丙酸酯片段的不对称方法也应该在合成各种其他重要的生物化合物中找到应用。从钙质海绵Leucasandra caveolata中分离得到了Leucasandra androliide A。在广泛的二维核磁共振实验的基础上，确定了其总体结构和相对立体化学。用Mosher法用C5羟基的Mosher酯确定了绝对构型。在体外实验中，白花楸内酯显示出显著的细胞毒性（在KB和P388细胞中，IC50分别为0.05和0.25马克/毫升），并且对白色念珠菌（一种攻击艾滋病患者的致病酵母菌）有很强的抑制作用来自Norcardiopsis sp.的Apoptolidin在腺病毒E1A癌基因转化的大鼠神经胶质细胞中诱导凋亡细胞死亡（IC50为11ng/mL），但在正常神经胶质细胞或正常成纤维细胞中没有（IC50大于100 μ g/mL）。Laulimalide是一种有效的细胞生长抑制剂，具有低纳摩尔IC50值，从冲绳海绵筋膜海绵中分离出来。Laulimalide显示紫杉醇样微管稳定，然而，与紫杉醇相反，Laulimalide抑制SKVLB-1细胞（一种多药耐药细胞系）的增殖。月桂酰胺比紫杉醇更有效地刺激微管蛋白聚合。Laulimalide是一类具有治疗潜力的新型微管稳定剂的代表。

The specific objectives of the proposed research are to execute a synthesis of the potent antitumor agents laulimalide, apoptolidin and leucascandrolide A. Ultimately, perhaps less complex derivatives of these potent antitumor agents with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and and polypropionate natural products will be developed. The asymmetric approaches to polyacetate and polypropionate fragments described herein should also find application in the synthesis of a variety of other biologically important compounds. Leucasandrolide A was isolated from the calcareous sponge Leucasandra caveolata. The gross structure and relative stereochemistry was assigned based on extensive two dimensional NMR experiments. The absolute configuration was assigned by Mosher's method using the Mosher's ester of the C5 hydroxyl. Leucasandrolide displayed significant cytotoxicity in vitro (IC50 = 0.05 and 0.25 mug/ml with KB and P388 cells, respectively) as well as very strong inhibition of Candida albicans, a pathogenic yeast that attacks AIDS patients.3 Apoptolidin, from Norcardiopsis sp. induced apoptotic cell death in rat glia cells transformed with the adenovirus E1A oncogene (IC50 11ng/mL) but not in normal glia cells or normal fibroblasts (IC50 greater than 100 mug/mL). Laulimalide is a potent inhibitor of cell growth with low, nanomolar IC50 values which was isolated from an Okinawan sponge Fasciospongia rimosa. Laulimalide shows paclitaxel-like microtubule stabilization, however, in contrast to paclitaxel, laulimalide inhibits proliferation of SKVLB-1 cells, a multidrug resistant cell line. Laulimalide stimulates tubulin polymerization more effectively than paclitaxel. Laulimalide is a representative of a new class of microtubule stabilizing agents with promise for therapeutic potential.