SYNTHESIS OF THE ANTITUMOR MACROLIDE SPONGISTATIN 1

抗肿瘤大环内酯海绵抑素1的合成

• 批准号: 6174233
• 负责人: ANATOLY N PINCHUK
• 金额: $ 6.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174233
• 关键词: Porifera; animal extract; antineoplastics; biotechnology; chemical synthesis; conformation; drug design /synthesis /production; stereochemistry

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.

描述（申请人的描述）： 海绵抑素，从海洋海绵 Spongia sp 中分离出来。 在 微观量，显示出特别强大的生长抑制活性 对抗人类黑色素瘤、肺癌、结肠癌和脑癌，并具有活性 模式类似于微管相互作用的抗有丝分裂剂。 第一个 此类大环内酯类的代表海绵抑素 1 据称是 目前已知的对抗一小部分最有效的物质 NCI 60 人类癌细胞组中高度耐药的肿瘤类型 线。 分离后，海绵抑素 I 仅在极其 整个海绵的最小分离产量。 这种合成的实现 项目将满足对海绵抑素1进一步原料的迫切需求 用于生物测试。 海绵抑素高级中间体将 提交生物测试以寻找可能的药效团 单元。 该项目计划实现基于海绵抑素1的聚合合成 主要研究硼试剂在立体控制中的应用 包含 A/B、C4D 和 的较小片段的构建和耦合 E/F 环系统。 该提案的主要目的是制定可行的 海绵抑素的合成方法基于试剂或 底物控制的不对称诱导。 拟议的另一个目标 研究是对完全绝对和相对的确认 海绵抑素 1 在其合成过程中的立体化学。 该项目的实现将对当前的 合成方法学并进一步刺激新方法的开发 为生物和生物制品供应足够数量的天然产物 药物测试。 所提出的合成方法灵活且 将允许合成多种海绵抑素类似物 结构-活性研究。 该项目将在大学化学系进行 密歇根州国家癌症研究所霍华德特明奖。 通过这次培训， 候选人将获得天然产品方面的高水平专业知识 综合，这将使他能够在一个领域开始独立的研究生涯 学术环境。