ASYMMETRIC SYNTHESIS OF ANTITUMOR POLYKETIDES

拟议研究的具体目标是建立 相对和绝对配置，并执行 非常有效的抗肿瘤剂spongistatin 1。最终，也许 这种有效的抗肿瘤剂的较不复杂的衍生物， 可以制备更好的生物概况。 过程中 研究，不对称合成的一般方法， 聚乙酸酯和螺缩酮含有天然产物将是 开发 该方法也可用于抗肿瘤药物的研究 苔藓抑素11、白藜芦醇内酯A和粘液素。 非对称方法 本文所述的聚乙酸酯片段也应该 在合成多种其他生物学上重要的化合物中。 已经发现海绵抑素1对抗肿瘤非常有效。 多种高度耐药的肿瘤类型，包括NCI 一组60种人类癌细胞系。 人黑色素瘤，肺，脑和 发现结肠癌对海绵抑素特别敏感。 Spongistatin的活性与血管生成素的种类密切相关。 微管相互作用的抗有丝分裂剂。 由于极其有限的 天然来源的海绵抑素的可用性[400 kg湿重 海绵属物种仅提供13.8 mg（3.4 x 10- 7%产率） spongistatin]合成对于提供足够的 用于生物学研究的物质的量，结构-活性 关系，甚至帮助阐明完整的 这一重要化合物的相对和绝对立体化学。的 包括苔藓抑素11在内的苔藓抑素也显示出具有 显著抗肿瘤活性，包括抗淋巴细胞活性 白血病和癌肉瘤。 Leucasandrolide A显示出显著的 细胞毒性（KB和P388细胞的IC 50 =0.05和0.25 μ g/ml， 以及非常强的抑制白色念珠菌， 攻击艾滋病患者的致病酵母。

The specific objectives of the proposed research are to establish the relative and absolute configuration and to execute a synthesis of the extremely potent antitumor agent spongistatin 1. Ultimately, perhaps less complex derivatives of this potent antitumor agent with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and spiroketal containing natural products will be developed. This methodology can also be applied to the antitumor agents bryostatin 11, leucasandrolide A and mucocin. The asymmetric approaches to polyacetate fragments described herein should also find application in the synthesis of a variety of other biologically important compounds. Spongistatin 1 has been found to be extraordinarily effective against a variety of highly chemoresistant tumor types which comprise the NCI panel of 60 human cancer cell lines. Human melanoma, lung, brain and colon cancers were found to be especially sensitive to spongistatin. The activity of spongistatin correlates well with the class of microtubule interactive antimitotics. Because of the extremely limited availability of spongistatin from natural sources [400 kg wet weight of Spongia sp. provided only 13.8 mg (3.4 x 10-7 percent yield) of spongistatin] synthesis may be essential for providing adequate quantities of the substance for biological studies, structure-activity relationships and even to assist in the elucidation of the complete relative and absolute stereochemistry of this important compound. The bryostatins including bryostatin 11 have also been shown to posess significant antitumor activity including activity against lymphocytic leukemia and carcinosarcoma. Leucasandrolide A displayed significant cytotoxicity (IC50=0.05 and 0.25 mug/ml with KB and P388 cells, respectively) as well as very strong inhibition ofCandida albicans, a pathogenic yeast that attacks AIDS patients.