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laulimalide，acetolidin和leucascandrolide A。 最终，可能可以制备具有相似或更好生物学特性的这些有效抗肿瘤剂的较不复杂的衍生物。 在研究过程中，将发展聚乙酸酯和聚丙酸酯天然产物的不对称合成的一般方法。 本文所述的聚乙酸酯和聚丙酸酯片段的不对称方法也应该应用于合成多种其他生物学重要的化合物。Leucasandrolide A是从石灰质海绵Leucasandra caveolata中分离得到的。 基于广泛的二维NMR实验，指定了总体结构和相对立体化学。 通过Mosher方法使用C5羟基的Mosher酯指定绝对构型。Leucasandrolide在体外具有明显的细胞毒性（对KB和P388细胞的IC 50分别为0.05和0.25 μ g/ml）以及对白色念珠菌（一种攻击AIDS患者的致病酵母）的非常强的抑制作用。拟诺卡氏菌诱导腺病毒E1 A癌基因转化的大鼠胶质细胞凋亡（IC 50 11 ng/mL），但在正常神经胶质细胞或正常成纤维细胞中不存在（IC 50大于100 μ g/mL）。Laulimalide是一种有效的细胞生长抑制剂，具有低的纳摩尔IC 50值，其分离自冲绳海绵Fasciospongia rimosa。 Laulimalide显示紫杉醇样微管稳定性，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。 月桂酰马来酸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.