CYTOTOXIC, COCARCINOGENIC, AND ANTILEUKEMIC AGENTS

细胞毒性剂、致癌剂和抗白血病剂

• 批准号: 3163612
• 负责人: LEO A PAQUETTE
• 金额: $ 20.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163612
• 关键词: acylation; antileukemic agent; antineoplastics; bicyclic compound; chemical carcinogen; chemical structure function; cis trans isomerization; cocarcinogen; cyclic compound; cytotoxicity; drug design /synthesis /production; epoxides; hydrocarbons; hydroxylation; paclitaxel; sesquiterpenes; stereochemistry

The principal objective of the program of research outlined herein is the development of general strategies and methods for the synthesis of complex natural products possessing cytotoxic, cocarcinogenic, and antileukemic activities. The development of concise ways to approach these diverse classes of compounds is required to permit systematic structural variation for testing structure-activity relationships and for acquiring new compounds for biological evaluation as clinical candidates. During the course of these studies, it will be necessary to extend the scope and limitations of select known reactions in utilitarian ways and to invent new ones. The synthetic approaches are designed to be adequately flexible and efficient so as to allow for all the intended applications. The targeted compounds are primarily comprised of medium-sized and/or strained ring systems. For example, the strained In,out-bicyclo[4.4.1]undecan-4-one substructure of ingenol is hopefully to be accessed by tandem [3.3] sigmatropy and WagnerMeerwein rearrangement. Seco-ent-kaurenes such as shikodomedin are to be constructed by applicability of methodology developed in a model study in which five of the six requisite steps are 100% stereocontrolled. The taxanes, members of which possess potent antitumor activity, are to be approached by a new strategy involving an anionic oxy-Cope rearrangement step followed by 1,2-shift of the gem-dimethyl substituted bridge. A totally new approach to the construction of oxygen-bridged sesquiterpenes such as zexbrevin is expected to facilitate rapid assembly of these complex molecules. Success in this area will allow for extension of our goals to the preparation of piptocarphin A and related oxagermacranolides. Our quest of the antileukemic agent jatrophatrione is to take the form of an incredibly short sequence based on anionic [3.3] sigmatropy. Synthetic entry to the highly oxygenated antitumor agents neoliacinic acid and pseudopterolide and their analogues shall rely on several interesting techniques for establishing their manifold stereogenic centers.

本文概述的研究计划的主要目标是 制定一般策略和方法来合成 具有细胞毒性，cocarcineg和 抗肿瘤活动。 开发简洁的方法 这些化合物需要这些多种类别的化合物才能允许系统 测试结构活性关系的结构变化和 获取新化合物作为临床候选者的生物学评估。 在这些研究过程中，有必要扩展 以功利主义方式的某些已知反应的范围和局限性 发明新的。 合成方法被设计为 充分灵活和高效，以允许所有预期 申请。 靶向化合物主要由中型化合物组成 和/或紧张的环系统。 例如，紧张 在，甲醇的und-bicyclo [4.4.1] undecan-4-4-4- 由串联[3.3] sigmatropy和wagnermeerwein访问 重排。 诸如shikodomedin之类的seco-ent-kaurenes将是 通过在模型研究中开发的方法的适用性构建 六个必需步骤中的五个是100％立体控制的。 这 具有强大抗肿瘤活动的成员将是 通过涉及阴离子氧化剂重排的新策略接近 步骤，然后是1,2换的宝石二甲基取代的桥。 一个 全新的氧气桥素烯烯的新方法 例如Zexbrevin有望促进这些 复杂分子。 在这一领域的成功将允许我们扩展我们 准备皮张前A和相关的目标 oxagermacranolides。 我们对抗肺化学毒剂的追求 是基于阴离子以令人难以置信的短序列的形式 [3.3] Sigmatropy。 高度充氧的抗肿瘤的合成入口 剂新糖酸和伪蝶呤及其类似物应 依靠几种有趣的技术来建立其多种多样 立体中心。