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：（主要研究者）本研究的目的 计划是发明、开发合成方法并将其应用于合成 和研究结构复杂的生物活性天然产物。 的 要研究的合成策略应该允许快速和有效的 靶向和相关分子的制备， 研究其生物学特性。 该计划将集中在三个 （a）合成一类结构独特的大环 化合物，称为phomactins。 最近从一种海洋真菌中分离出来， 这些分子已经显示出显著的生物学特性。 具体地说，磷霉素可以影响血小板活化功能， PAF因子。 PAF是一种在人体内普遍存在的化合物， 在呼吸道、炎症和心血管疾病中的应用。 虽然PAF 一直是一个激烈的研究工作的主题，许多问题， 关于它在这些疾病中的作用仍然没有答案。 有趣的是， 而phomactins抑制PAF诱导的血小板聚集，对 二磷酸腺苷、花生四烯酸和胶原诱导的血小板 已经观察到聚集。 因此，磷菌素代表了一种新型的 PAF拮抗剂。 (b)合成了一系列新的大环内酯 类似于Ampidinolides。 这些化合物具有吸引人的生物学特性， 特别是抗白血病特性以及对兔的活性 骨骼肌肌动蛋白ATP酶。 除了令人印象深刻的 抗白血病活性，这些分子具有几个显著的结构 特征，包括亲脂性和亲水性部分的对比， 以及共轭和非共轭二烯的存在。 (c)在 结合这些合成企业，计划新的 有机金属和自由基反应的设计和研究。 特别感兴趣的包括催化方法的发展， 钯，铟，锡和硅以及1，2-维蒂希的研究 复杂分子合成中的重排。