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SYNTHESIS OF SELECTIVELY CYTOTOXIC MARINE MACROLIDES

选择性细胞毒性海洋大环内酯的合成

基本信息

批准号：
2012346
负责人：
KAREN ERICKSON
金额：
$ 10.93万
依托单位：
CLARK UNIVERSITY (WORCESTER, MA)
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-06-01 至 2001-05-31
项目状态：
已结题

项目摘要

DESCRIPTION: The long-term objective of this research is to discover leads for the development of new anticancer and AIDS-antiviral drugs or chemicals that can serve as molecular probes in mechanistic studies of these diseases. To achieve this objective, the isolation, characterization, and biological evaluation of active compounds from selectively cytotoxic extracts of marine and terrestrial organisms is carried out. A new sponge metabolite, displaying both a unique structure and human tumor cytotoxicity profile, was recently characterized as part of this program. Further biological evaluation has not been possible because of the small amount of sample available. This proposal deals with the investigation of possible synthetic routes to this compound and its congeners in order to more fully evaluate their potential as new drug leads. The synthetic plan is a convergent one involving three fragments, one of which carries all three of the stereogenic centers. One of these centers is provided by malic acid and the remaining two are introduced stereoselectively in an Evans aldol reaction. Two of the synthons are joined by means of a modified Wittig-Horner reaction followed by macrolactonization. The introduction of the third fragment, a rather labile unsaturated amide moiety, is done at the end of the synthesis. One possible and direct method to accomplish this involves the addition of an organometallic reagent to an isocyanate. A second, but longer route utilizes more standard amide chemistry and a selenoxide elimination reaction to generate the key double bond. The synthesis of several congeners in which some of the unsaturation is removed and/or rings replace acyclic moieties, is also planned in order to make structure-activity studies possible.

描述：这项研究的长期目标是发现线索用于开发新的抗癌和艾滋病-抗病毒药物或化学品在这些疾病的机制研究中可以作为分子探针。为了实现这一目标，分离、鉴定和生物学海洋选择性细胞毒提取物中活性物质的评价和陆地上的生物被执行。一种新的海绵代谢物，显示了独特的结构和人类肿瘤的细胞毒活性最近被描述为这个项目的一部分。进一步的生物学由于样本量较少，无法进行评估可用。这项建议涉及对可能的合成材料的调查通向该化合物及其同类化合物的路线，以便更全面地评估它们作为新药线索的潜力。合成计划是一个收敛的计划，涉及三个片段，其中一个是它携带着所有三个立体中心。其中一个中心是由苹果酸提供，其余两个介绍立体选择性地在Evans Aldol反应中。其中两个合成子是通过改进的Wittig-Horner反应连接，然后大内酯化。引入第三个片段，一个相当不稳定的片段不饱和酰胺部分，在合成结束时进行。一种可能而实现这一点的直接方法涉及添加一个将有机金属试剂转化为异氰酸酯。第二条但更长的路线使用更标准的酰胺化学和氧化亚硒消除反应以生成关键的双键。几种同系物的合成，其中一些不饱和物是还计划移除和/或环取代非环部分，以便使结构-活性研究成为可能。