Asymmetric Synthesis of Antitumor Agents

拟议研究的具体目标是合成有效的抗肿瘤药物劳利马利德、凋亡素和亮氨酸内酯A。最终，也许可以制备出具有相似或更好生物学特性的这些有效抗肿瘤药物的较不复杂的衍生物。在研究过程中，将开发不对称合成聚乙酸酯和聚丙酸酯天然产物的一般方法。这里描述的聚醋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生物重要化合物中得到应用。银杏内酯A是从钙质海绵新银莲花中分离得到的。通过大量的二维核磁共振实验，对其大体结构和相对立体化学进行了指认。绝对构型由Mosher方法指定，使用C5羟基的Mosher酯。银杏内酯具有显著的体外细胞毒性(对KB和P388细胞的IC_(50)分别为0.05和0.25µg/ml)，对攻击艾滋病患者的致病酵母菌白色念珠菌也有很强的抑制作用。对转腺病毒E1a癌基因的大鼠胶质细胞(IC50为11 ng/m L)，对正常胶质细胞和正常成纤维细胞(IC50大于100µg/m L)均无明显的诱导凋亡作用。劳利马利德是一种有效的细胞生长抑制物质，具有低的纳摩尔IC50值，它是从冲绳海绵中分离出来的。劳利马利德表现出紫杉醇样的微管稳定，然而，与紫杉醇相反，劳利马利德抑制多药耐药细胞株SKVLB-1的增殖。洛利马利比紫杉醇更有效地促进微管蛋白聚合。洛利马利是一类具有潜在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.