SYNTHESIS OF BIOLOGICALLY ACTIVE MACROCYCLIC MOLECULES

生物活性大环分子的合成

• 批准号: 6076901
• 负责人: ROBERT E MALECZKA
• 金额: $ 0.67万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-15 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6076901
• 关键词: antineoplastic antibiotics; biological products; carbopolycyclic compound; catalyst; chemical synthesis; drug design /synthesis /production; lactones; molecular rearrangement; organometallic compounds; platelet aggregation inhibitors

DESCRIPTION: (Principal Investigator's) The purpose of this research program is to invent, develop, and apply synthetic methods to the synthesis and study of architecturally complex bioactive natural products. The synthetic strategies to be studied should allow for the rapid and efficient preparation of targeted and allied molecules allowing for the evaluation and study of their biological properties. The program will concentrate in three areas: (a) The synthesis of a structurally unique class of macrocyclic compounds, known as the phomactins. Recently isolated from a marine fungus, these molecules have demonstrated marked biological properties. Specifically, the phomactins can effect the function of platelet-activating factor (PAF). PAF is a compound ubiquitous to the human body and implicated in respiratory, inflammatory, and cardiovascular diseases. While PAF has been the subject of an intense research effort, numerous questions concerning its role in these diseases remain unanswered. Interestingly, while the phomactins inhibit PAF-induced platelet aggregation, no effect on adenosine diphosphate, arachidonic acid, and collagen-induced platelet aggregation has been observed. Thus the phomactins represent a new type of PAF antagonist. (b) The synthesis of a series of novel macrolactones known as the amphidinolides. These compounds have attractive biological features, especially antileukemic properties as well as activity towards rabbit skeletal muscle actomysion ATPase. In addition to their impressive antileukemic activity, these molecules have several striking structural features, including the contrast of lipophilic and hydrophilic moieties as well as the presence of both conjugated and non-conjugated dienes. (c) In conjunction with these synthetic ventures it is planned that new organometallic and free radical reactions be designed and investigated. Particular interests include the development of catalytic methods involving palladium, indium, tin, and silicon as well as a study of the 1,2-Wittig rearrangement in complex molecule synthesis.

描述：（主要研究者）这项研究的目的 程序是发明，开发和应用合成方法 并研究建筑复杂的生物活性天然产品。 这 要研究的合成策略应允许快速有效 制备有针对性和相关分子，允许评估和 研究其生物学特性。 该计划将集中在三个 区域：（a）合成结构独特的大环类 化合物，称为富霉素。 最近与海洋真菌分离 这些分子表现出明显的生物学特性。 具体而言，phomactins可以影响血小板激活的功能 因子（PAF）。 PAF是人体无处不在的复合物，牵连 在呼吸道，炎症和心血管疾病中。 而PAF拥有 是一项激烈的研究工作的主题，许多问题 关于其在这些疾病中的作用仍然没有解决。 有趣的是， phomactins抑制PAF诱导的血小板聚集，但对 腺苷二磷酸腺苷，花生四烯酸和胶原蛋白诱导的血小板 已经观察到聚集。 因此，phomactins代表一种新型的 PAF拮抗剂。 （b）一系列新的大花生酮已知的合成 作为两栖类药物。 这些化合物具有吸引人的生物学特征， 尤其是抗肺的特性以及对兔子的活性 骨骼肌肌动症ATPase。 除了令人印象深刻 抗白血病活性，这些分子具有几个引人注目的结构 特征，包括亲脂性和亲水性部分的对比度 以及共轭和非混合二烯的存在。 （c）IN 与这些合成企业的结合计划是新的 设计和研究有机金属和自由基反应。 特定兴趣包括开发涉及的催化方法 钯，inim，锡和硅以及对1,2-Wittig的研究 复杂分子合成中的重排。