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: 6376809
• 负责人: ANATOLY N PINCHUK
• 金额: $ 12.34万
• 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 2002-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376809
• 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（申请人描述）： spongistatin是从海绵Spongia sp.中分离出来的， 微观量，显示出特别强大的生长抑制活性 抗人黑色素瘤、肺癌、结肠癌和脑癌， 类似于微管相互作用的抗有丝分裂剂的模式。 第一 这类大环内酯的代表，海绵抑素1，被声称是 目前已知的最特别有效的物质， 在NCI的60个人类癌细胞组中的高度化学抗性肿瘤类型 线 在分离时，仅在极低浓度下获得海绵抑素I。 从整个海绵中分离出的产量最小。 实现这种合成 项目将满足对spongistatin 1进一步材料的迫切需求 进行生物测试 海绵他汀的高级中间体将是 提交进行生物学测试，以找到可能的药效团 单位 该项目计划实现基于spongistatin 1的聚合合成 主要是关于硼试剂在立体控制中的应用 构建和偶联含有A/B、C4 D和 E/F环系统。 这项建议的主要目的是制定一项可行的 基于试剂-或 底物控制的不对称诱导。 拟议的另一个目标是 研究是确认和充分的绝对和相对 在其合成过程中观察到海绵抑素1的立体化学。 该项目的实现将对现有的 综合方法，并进一步促进新方法的发展 提供足够数量的天然产品， 药物测试 所提出的合成方法是灵活的， 将允许合成多种海绵抑素类似物， 构效关系研究 该项目将在大学化学系进行 获得NCI霍华德·泰明奖。 由于这次培训， 候选人将获得高水平的专业知识，在天然产品 综合，这将使他开始一个独立的研究生涯， 学术环境。