SYNTHESIS OF BIOLOGICALLY ACTIVE MACROCYCLIC MOLECULES

生物活性大环分子的合成

• 批准号: 2857929
• 负责人: ROBERT E MALECZKA
• 金额: $ 10.83万
• 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/2857929
• 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：(主要调查者)本研究的目的 计划是发明、开发并将合成方法应用于合成 以及研究具有复杂建筑结构的生物活性天然产物。这个 需要研究的综合策略应该考虑到快速和有效的 靶向和缔合分子的制备，允许评价和 研究它们的生物学特性。该计划将集中在三个方面 领域：(A)一类结构独特的大环化合物的合成 化合物，也就是所谓的褐马菌素。最近从一种海洋真菌中分离出来， 这些分子已显示出显著的生物学特性。 具体地说，Pomactins可以影响血小板激活功能。 系数(PAF)。PAF是一种对人体普遍存在的化合物，与 在呼吸系统、炎症和心血管疾病中。而PAF则拥有 一直是紧张研究的主题，无数的问题 关于它在这些疾病中的作用的问题仍未得到答复。有趣的是， 虽然假单胞菌素抑制PAF诱导的血小板聚集，但对 二磷酸腺苷、花生四烯酸和胶原诱导的血小板 观察到了聚集现象。因此，Pomactins代表了一种新型的 PAF拮抗剂。(B)一系列已知的新型大内酯的合成 就像双宾内酯一样。这些化合物具有诱人的生物学特性， 尤其是抗白血病特性以及对兔的活性 骨骼肌肌动肌动蛋白ATPase。除了令人印象深刻的 抗白血病活性，这些分子有几个惊人的结构 特征，包括亲油性和亲水性部分的对比 以及共轭和非共轭双烯的存在。(C)在 与这些合成企业相结合，计划推出新的 有机金属和自由基反应的设计和研究。 特别感兴趣的是开发催化方法，包括 钯、铟、锡和硅以及1，2-Wittig的研究 复杂分子合成中的重排。