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 非常有效的抗肿瘤药物海绵抑素1。最终，也许 这种有效的抗肿瘤药物的不太复杂的衍生物具有类似的或 可以制备更好的生物图谱。在这个过程中， 不对称合成的一般方法学研究 含有聚乙酸酯和螺环酮的天然产品将 发展起来的。该方法学也适用于抗肿瘤药物。 Bryostatin 11，Leucasandrode A和Mucocin。不对称的方法 在此描述的聚醋酸酯碎片也应该找到应用 用于合成各种其他重要的生物化合物。 海绵抑素1已被发现对 构成NCI的多种高度耐药的肿瘤类型 由60个人类癌细胞株组成的研究小组。人类黑色素瘤，肺，脑和 研究发现，结肠癌对海绵抑素特别敏感。 海绵抑素的活性与血管紧张素转换酶的分类密切相关 微管相互作用的抗分裂。因为极其有限的 天然来源的海绵抑素的可用性[400千克湿重 海绵属Spongia sp.仅提供13.8毫克(3.4x10-7%)的 海绵抑素]的合成可能是必不可少的，以提供足够的 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。这个 包括Bryostatin 11在内的苔藓类药物也被证明具有 显著的抗肿瘤活性，包括对淋巴细胞的活性 白血病和癌肉瘤。银杏内酯A显示出显著的意义 对KB和P388细胞的IC50分别为0.05和0.25mug/ml， 对白色念珠菌有很强的抑制作用，a 攻击艾滋病患者的致病酵母菌。

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.