SYNTHESIS OF BIOLOGICALLY ACTIVE MACROCYCLIC MOLECULES

生物活性大环分子的合成

• 批准号: 2463158
• 负责人: ROBERT E MALECZKA
• 金额: $ 9.7万
• 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/2463158
• 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：（首席研究员）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 以及结构复杂的生物活性天然产物的研究。 这 待研究的合成策略应允许快速有效 制备目标分子和相关分子，以便进行评估和 研究它们的生物学特性。 该计划将集中在三个方面 领域： (a) 结构独特的一类大环化合物的合成 化合物，称为福马汀。 最近从海洋真菌中分离出来， 这些分子已表现出显着的生物学特性。 具体来说，福马汀可以影响血小板活化的功能。 因子（PAF）。 PAF 是一种人体普遍存在的化合物，与 呼吸系统、炎症和心血管疾病。 虽然PAF有 是大量研究工作的主题，存在许多问题 关于其在这些疾病中的作用仍未得到解答。 有趣的是， 虽然 phomactins 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 已观察到聚集。 因此，福马克汀代表了一种新型的 PAF拮抗剂。 (b) 一系列已知的新型大环内酯的合成 如两栖类内酯类。 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子的活性 骨骼肌肌动 ATP 酶。 除了他们令人印象深刻的 抗白血病活性，这些分子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 以及共轭二烯和非共轭二烯的存在。 (c) 在 与这些合成企业相结合，计划新的 设计和研究有机金属和自由基反应。 特别感兴趣的是涉及催化方法的开发 钯、铟、锡和硅以及 1,2-Wittig 的研究 复杂分子合成中的重排。