Synthesis of Biologically Active Macrocycle Molecules

描述(申请人提供)：这项关于合成生物活性大环分子的项目旨在发明、开发和应用合成方法(特别是新型金属介导法)，用于合成和研究具有复杂结构的生物活性天然产物。本文开发的合成方法和策略将有助于评价和研究靶向分子和缔合分子的生物学性质。该计划将集中在三个领域：(A)合成一类新的血小板激活因子(PAF)拮抗剂，称为Pomactins。PAF是一种对人体普遍存在的化合物，与呼吸道、炎症和心血管疾病有关。由于它们对二磷酸腺苷、花生四烯酸或胶原诱导的血小板聚集没有影响，因此是唯一具有选择性的PAF拮抗剂。(B)两性内酯A及其相关分子的合成。这些结构惊人的化合物被认为对所有60个NCI癌症筛查都有活性，并表现出特别的急性抗白血病特性，以及对兔骨骼肌肌动肌动蛋白ATPase的活性。(C)具有良好抗人支气管肺非小细胞肺癌活性的海洋天然产物Superstolide A的合成。非小细胞肺癌占肺癌的绝大多数。不幸的是，针对非小细胞肺癌的化疗尚未证明非常成功。Superstolide A对耐药的小鼠白血病细胞也有活性。如此巨大的生物学潜力使Superstolide A成为非常有吸引力的全合成候选者。

DESCRIPTION (provided by applicant): This project on the synthesis of biologically active macrocyclic molecules aims to invent, develop, and apply synthetic methods (particularly novel metal mediated methods) during the synthesis and study of architecturally complex bioactive natural products. The synthetic methods and strategies developed herein will facilitate the evaluation and study of the biological properties of the targeted and allied molecules. The program will concentrate in three areas: (a) Synthesis of a new class of platelet activating factor (PAF) antagonists known as the phomactins. PAF is a compound ubiquitous to the human body and implicated in respiratory, inflammatory, and cardiovascular diseases. The phomactins are uniquely selective PAF antagonists as they have no effect on adenosine diphosphate, arachidonic acid, or collagen-induced platelet aggregation. (b) Synthesis of amphidinolide A and allied molecules. These structurally striking compounds are deemed active against all 60 NCI cancer screens and exhibit especially acute antileukemic properties, as well as activity towards rabbit skeletal muscle actomysion ATPase. (c) Synthesis of superstolide A, a marine natural product with excellent activity against human bronchpulmonary non-small cell lung carcinoma. Non-small cell lung carcinoma accounts for the large majority of lung cancers. Unfortunately chemotherapy against NSCLC has yet to prove very successful. Superstolide A is also active against resistant murine leukemia cells. Such tremendous biological potential makes superstolide A a very attractive candidate for total synthesis.