NEW STRATEGIES FOR THE SYNTHESIS OF BIOACTIVE MOLECULES

生物活性分子合成的新策略

• 批准号: 2175233
• 负责人: RAYMOND L. FUNK
• 金额: $ 22.07万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2175233
• 关键词: DNA damage; chemical cleavage; chemical synthesis; cyclic compound; cyclization; diterpenes; drug design /synthesis /production; heterocyclic compounds; molecular rearrangement; paclitaxel; photoactivation; tumor promoters

The primary objective of this research is to continue to develop new strategies of the construction of complex carbocyclic or heterocyclic ring systems. It is expected that this new methodology will expedite the syntheses of biologically active natural products and /or analogs as well as de novo bioactive compounds. Analogs of the promising anticancer agent taxol will be prepared via two complementary Claisen-rearrangement-based strategies for taxane synthesis. Each of these approaches involves successive ring annelations (CyieldsCByieldsCBA and AyieldsAByieldsABC) and features a stereocontrolled cyclooctane annexation. The taxane ring system will also be constructed ba route which exploits a titanium-promoted eight- membered ring closure reaction. These new taxane derivatives will feature highly variable substitution patterns along the lower periphery of the molecule and will further elucidate which functional groups are required for biological activity. Hopefully, a simplified, biologically active analog of taxol will be discovered. The first total synthesis of ingenol will be complected. More importantly, the tumor promoter analogs, 4.5-dideoxyingenol-3 tetradecanoate and 5-deoxyingenol-3-tetradecanoate will also be prepared. These analogs will permit the several conflicting tumor promoter pharmacophore hypotheses to be rigorously tested. Delineation of the tumor promoter pharmacophore could facilitate the development of new signal transduction-based chemotherapeutic agents. A new class of DNA photocleaving agents will be developed by exploiting recently discovered photochemical Bergman reactions of ortho- dialkynylarenes. These new DNA photocleaving agents are novel in that the binding and photoactive domains are consolidated and , moreover, generate two reactive sites for subsequent ribose hydrogen atom abstraction(s). attachment of these DNA photocleaving agents to DNA recognition domains such as antisense oligonucleotides or protein scaffolds could result in novel anticancer and/or antiviral photo- therapeutic agents and new tools for biotechnology (photonucleases or protein footprinting). Finally, the carbon-carbon bond forming potential of the Bergman cyclization reaction will be examined in the context of a natural products synthesis, specifically, lysergic acid.

这项研究的主要目的是继续开发新的 复杂的碳环或杂环的建造策略 环系统。 预计这种新方法将加快 生物活性天然产物和 /或类似物的合成 作为从头生物活性化合物。 有希望的抗癌剂紫杉醇的类似物将通过两个 基于紫外线的基于互补的克莱森重态策略 合成。 这些方法中的每一种都涉及连续的环形电an （CanieldScbyieldScba和AyieldSabyieldSabc），并具有 立体控制的环销吞并。 紫杉烷环系统将 还可以构建BA路线，该路线利用钛促进的八 成员环闭合反应。 这些新的紫杉烷衍生物将 沿下部外围的特征高度可变的替代模式 分子的属性，并将进一步阐明哪些官能团是 生物活性所必需的。 希望一个简化的生物学 将发现紫杉醇的主动类似物。 Ingenol的第一个总合成将被批准。 更多的 重要的是，肿瘤启动子类似物，4.5-脱氧烯醇-3 还将准备四核酸酯和5-脱氧烯醇-3-四烷酸盐。 这些类似物将允许几个冲突的肿瘤启动子 药效假设将进行严格测试。 描述 肿瘤启动子药片学可以促进新的发展 基于信号转导的化学治疗剂。 通过利用将开发一类新的DNA光接种剂 最近发现了正骨的光化学伯格曼反应 Dialkynylarenes。 这些新的DNA光裂解剂是新颖的 结合和光活性域是合并的，此外， 生成两个反应性位点，用于随后的核糖氢原子 抽象（S）。 这些DNA光裂解剂与DNA的附着 识别域，例如反义寡核苷酸或蛋白质 脚手架可能会导致新颖的抗癌和/或抗病毒照片 - 生物技术的治疗剂和新工具（光核酸或 蛋白质足迹）。 最后，碳碳键形成潜力 将在 天然产物合成，特别是脂肪酸。