Synthesis of Biologically Active Macrocycle Molecules

生物活性大环分子的合成

• 批准号: 6892377
• 负责人: ROBERT E MALECZKA
• 金额: $ 26.16万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892377
• 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

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.

项目描述（由申请人提供）：本项目研究生物活性大环分子的合成，旨在在合成和研究结构复杂的生物活性天然产物的过程中，发明、发展和应用合成方法（特别是新颖的金属介导方法）。本文开发的合成方法和策略将有助于评估和研究目标分子和相关分子的生物学特性。该计划将集中在三个方面：(a)合成一类新的血小板活化因子（PAF）拮抗剂，称为效应素。PAF是一种在人体中普遍存在的化合物，与呼吸、炎症和心血管疾病有关。由于对二磷酸腺苷、花生四烯酸或胶原诱导的血小板聚集没有影响，所以这些药物是唯一的选择性PAF拮抗剂。(b)两萜内酯A及其相关分子的合成。这些结构上引人注目的化合物被认为对所有60种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化atp酶的活性。(c)合成抗人支气管肺非小细胞肺癌的海洋天然产物superstolide A。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是非常成功的。Superstolide A对耐药的小鼠白血病细胞也有活性。这种巨大的生物潜力使超stolide A成为全合成的极具吸引力的候选物。