Synthesis of Biologically Active Macrocycle Molecules

生物活性大环分子的合成

基本信息

批准号：
7065264
负责人：
ROBERT E MALECZKA
金额：
$ 25.55万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-15 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7065264
关键词：
Diels Alder reaction animal extract antineoplastics aquatic organism biological products chemical addition chemical structure function chemical synthesis enzyme inhibitors leukemia method development myosins nonsmall cell lung cancer organic chemicals organometallic compounds platelet activating factor

项目摘要

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.

描述（由申请人提供）：关于生物活性大环分子合成的该项目旨在在建筑具有建筑具有复杂生物活性天然产物的合成和研究过程中发明，开发和应用合成方法（尤其是新型金属介导的方法）。本文开发的合成方法和策略将促进对靶向和盟友分子的生物学特性的评估和研究。该程序将集中在三个领域：（a）合成一类新的血小板激活因子（PAF）拮抗剂，称为phomactins。 PAF是对人体的复合无处不在，与呼吸道，炎症性和心血管疾病有关。富霉素是独特的选择性PAF拮抗剂，因为它们对二磷酸腺苷，花生四烯酸或胶原蛋白诱导的血小板聚集没有影响。（b）两栖类药物A和相关分子的合成。这些在所有60个NCI癌症筛查中都认为这些结构上的显着化合物被认为是活跃的，特别表现出急性抗白血病特性，以及对兔骨骼肌肌肉肌动症ATPase的活性。（c）对人支气管非小细胞肺癌具有出色活性的海洋天然产物的超级巨星A的合成。非小细胞肺癌占绝大多数肺癌。不幸的是，针对NSCLC的化学疗法尚未证明非常成功。超级巨星A还活跃于抗性鼠白血病细胞。如此巨大的生物学潜力使超级巨星成为完全合成的非常有吸引力的候选者。