Chemical Synthesis of Novel Natural Products

新型天然产物的化学合成

• 批准号: 6635986
• 负责人: DAVID R WILLIAMS
• 金额: $ 27万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-04-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635986
• 关键词: Diels Alder reaction; alkaloids; antifungal agents; antineoplastic antibiotics; antineoplastics; biological products; chemical structure function; cyclic compound; cyclization; drug design /synthesis /production; macrolide antibiotics; stereochemistry

DESCRIPTION: (provided by applicant) - This research program is broadly directed to investigate fundamental advances for the chemical synthesis of biologically active marine natural products. Part I. Marine Antitumor Macrolides. Section A. A plan for the highly efficient, convergent, and enantiocontrolled synthesis of laulimalide will be executed. Laulimalide displays comparable potency to taxol with IC50 concentrations in the 0.01-0.05 mico/mL range against a broad selection of tumor cell lines. High cytotoxicity was registered toward KB lines (IC50 = 0.015 mico/mL). Significantly laulimalide retains activity in multi-drug resistant SKVLB-1 cultures. Section B. Strategies for the synthesis of peloruside will explore issues of stereoselectivity and efficiency for the assembly of this highly oxygenated hemiketal. With key structural features and macrocyclic rigidity, which address important proposals and research concerning the nature of the antitumor activity of the bryostatins (NCI; phase II trials), peloruside A studies are designed to offer a significant chemical advance for probing the nature of the pharmacophore and the mechanisms of biological activity for this family of molecules. Our chemical studies toward these target molecules will develop asymmetric allylation reactions. Bidirectional, divergent asymmetric allylation strategies are examined. Direct formation of new homochiral allylborane species will be pursued via cross coupling reactions with organozinc reagents. Part II. Zoanthamines. Our investigations of this novel class of marine alkaloids describe challenging issues of chemical synthesis toward densely functionalized, polycyclic systems. Members of this class have exhibited important antitumor and anti-inflammatory activities, and norzoanthamine is considered to be a promising osteoporotic candidate. Part III. Australifungin. This unique natural product is a potent antifungal which is the first nonsphingosine-based inhibitor of sphingolipid biosynthesis. It functions as a selective inhibitor of sphinganine N-acyl transferase, and may have an important role in lipid signal transduction, cell differentiation, and apoptosis. Our plans toward zoanthamines and australifungin will explore asymmetric induction in conjugate addition reactions and intramolecular Michael-based cyclizations. The intramolecular (4+2) cycloadditions of nitroalkene precursors will provide facile construction of trans-decalins. .

描述：（由申请人提供）- 该研究计划广泛 旨在研究化学合成的基本进展 具有生物活性的海洋天然产物。 第一部分：海洋抗肿瘤大环内酯类。 A 部分：高度计划 月桂马内酯的高效、收敛和对映控制合成将是 被执行。劳利马利特显示出与紫杉醇相当的效力（IC50） 浓度在 0.01-0.05 mico/mL 范围内，针对多种选择 肿瘤细胞系。对 KB 系具有高细胞毒性（IC50 = 0.015 微/毫升）。月桂马利特在多种药物中显着保留活性 抗性 SKVLB-1 培养物。 B 节. 合成策略 peloruside 将探讨立体选择性和效率问题 这种高度氧化的半缩酮的组装。具有关键的结构特征和 大环刚性，其中涉及有关的重要提案和研究 苔藓抑素抗肿瘤活性的性质（NCI；II 期试验）， peloruside A 研究旨在为以下方面提供重大的化学进展： 探讨药效团的性质和生物机制 该分子家族的活性。 我们对这些目标分子的化学研究将发展成不对称的 烯丙基化反应。双向、不同的不对称烯丙基化策略 被检查。直接形成新的纯手性烯丙基硼烷物种将是 通过与有机锌试剂的交叉偶联反应进行。 第二部分。佐安胺。我们对这种新型海洋生物的调查 生物碱描述了化学合成的挑战性问题 功能化的多环系统。该班级成员展示了 重要的抗肿瘤和抗炎活性，去甲蒽醌是 被认为是一种有前途的骨质疏松候选药物。 第三部分。澳大利亚芬净。这种独特的天然产品是一种有效的抗真菌剂 这是第一个基于非鞘氨醇的鞘脂生物合成抑制剂。 它作为二氢鞘氨醇 N-酰基转移酶的选择性抑制剂起作用，并且 可能在脂质信号转导、细胞分化、 和细胞凋亡。 我们对 zoanthamines 和 australifungin 的计划将探索不对称 共轭加成反应和基于迈克尔的分子内诱导 环化。硝基烯烃前体的分子内 (4+2) 环加成 将提供反式十氢化萘的简便构建。 。