SYNTHESIS OF THE ANTITUMOR MACROLIDE SPONGISTATIN 1

描述(申请人的描述)： 从海绵Spongia sp.中分离得到海绵抑素。在……里面 微观数量，显示出特别强的生长抑制活性 抗人类黑色素瘤、肺癌、结肠癌和脑癌，并有活性 类似于微管相互作用的抗分裂模式。第一 这类大环内酯类的代表，海绵抑素1，声称是 目前已知的最特别的强效物质是针对 60个人癌细胞NCI评价组中的高耐药肿瘤类型 台词。经分离后，海绵抑素I仅在极 整个海绵的最小分离产率。实现这一综合体 项目将满足对海绵抑素1进一步材料的迫切需求 用来做生物测试。海绵抑素的高级中间体将是 提交进行生物测试，以便找到可能的药效团 单位。 该项目计划实现以海绵抑素1为基础的聚合合成 主要论述了硼试剂在立体控制中的应用 含有A/B、C4D和 E/F环路系统。这项提议的主要目的是开发一种可行的 基于试剂或试剂的海绵抑素合成方法 底物控制的不对称诱导。拟议的另一个目标 研究是对全部绝对和相对的确证。 海绵抑素1合成过程中的立体化学。 这一项目的实现将对当前的 综合方法论，进一步促进新方法的发展 提供足够数量的天然产品用于生物和 药物测试。提出的综合方法是灵活的和 将允许合成海绵抑素的各种类似物用于 构效关系研究。 该项目将在该大学化学系进行。 密歇根州的霍华德·特明奖。作为这次培训的结果， 应聘者将获得天然产品方面的高水平专业知识 综合，这将使他开始一个独立的研究生涯 学术环境。

DESCRIPTION (Applicant's Description): The spongistatins, isolated from the marine sponge Spongia sp. in microscopic quantities, show especially powerful growth inhibitory activity against human melanoma, lung, colon and brain cancers, and have an activity pattern similar to the microtubule-interactive antimitotics. The first representative of this class of macrolides, spongistatin 1, is claimed to be the most extraordinary potent substance presently known against a subset of highly chemoresistant tumor types in the NCI panel of 60 human cancer cell lines. Upon isolation, spongistatin I was obtained in only extremely minimal isolated yield from the whole sponge. Realization of this synthetic project will satisfy the urgent needs for further material of spongistatin 1 for biological testing. Advanced intermediates of spongistatin will be submitted for biological testing in order to find a possible pharmacophore unit. The project plans to achieve a convergent synthesis of spongistatin 1 based mostly on application of boron reagents for the stereocontrolled construction and coupling of smaller fragments containing the A/B, C4D, and E/F ring systems. The primary aim of this proposal is to develop a viable synthetic approach to the spongistatins based on either reagent- or substrate-controlled asymmetric induction. Another goal of the proposed research is confirmation and of the full absolute and relative stereochemistry of spongistatin 1 in the course of its synthesis. Realization of this project will provide a challenging test of current synthetic methodology and further stimulate the development of new methods for supplying sufficient quantities of natural products for biological and pharmaceutical testing. The synthetic approach presented is flexible and will allow synthesis of a variety of analogs of spongistatin for the structure-activity studies. This project will be performed at the Chemistry Department of the University of Michigan under the NCI Howard Temin Award. As a result of this training, the candidate will obtain a high level of expertise in the natural products synthesis that will allow him to start an independent research career in an academic environment.