Synthesis of Lactonamycin and Related Polyketides

乳霉素及相关聚酮化合物的合成

• 批准号: 7087034
• 负责人: SEIICHI P.T. MATSUDA
• 金额: $ 24.99万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087034
• 关键词: drug design /synthesis /production; glycosylation; macrolide antibiotics; method development

DESCRIPTION (provided by applicant): Lactonamycin was isolated by Matsumoto and coworkers in 1996 from Streptomyces rishiriensis in a screen for new antibiotics active against drug resistant bacterial strains. Lactonamycin exhibits potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Structurally related polyketides including the tetracenomycins and elloramycin display potent antitumor activity. The goals of this research program are as follows: 1) Development of general synthetic methods to access lactonamycin, elloramycin, saintopin E, and the numerous tetracenomycin structures. In particular the construction of the ABCD-ring systems through a strategy of tandem 1,4-addition-Dieckmann ring closure will provide access to the natural product targets as well as analogs. 2) Construct advanced synthetic intermediates postulated as biosynthetic precursors of lactonamycin as part of elucidating the biosynthetic pathway to lactonamycin. 3) Construct an appropriate form of the carbohydrate L-rhodinose for completion of a chemical synthesis of lactonamycin. 4) Expand and define the scope of the tandem 1,4-addition-Dieckmann ring closure for applications to related type II polyketide natural products. Further expansion of the methodology to the synthesis of condensed polycyclic heterocycles. 5) Expand the [3+2] cycloaddition reaction of quinones with nitrile oxides to gain access to diverse type II polyketide structures such as DNA helicase inhibitor heliquinomycin.

描述（由申请人提供）：松本及其同事于 1996 年从利希里链霉菌中分离出乳霉素，用于筛选对耐药细菌菌株具有活性的新型抗生素。 Lactonamycin 对耐甲氧西林金黄色葡萄球菌 (MRSA) 和耐万古霉素肠球菌 (VRE) 表现出有效的抗菌活性。结构相关的聚酮化合物，包括四烯霉素和埃罗霉素，显示出有效的抗肿瘤活性。该研究计划的目标如下： 1) 开发获得内霉素、埃罗霉素、圣托平 E 和众多四烯霉素结构的通用合成方法。特别是通过串联 1,4-加成-迪克曼闭环策略构建 ABCD 环系统将提供获得天然产物目标以及类似物的途径。 2) 构建被假定为内托霉素生物合成前体的先进合成中间体，作为阐明内托霉素生物合成途径的一部分。 3)构建适当形式的碳水化合物L-罗迪糖以完成内托霉素的化学合成。 4) 扩展并定义了串联 1,4-加成-Dieckmann 闭环的范围，以应用于相关的 II 型聚酮化合物天然产物。该方法进一步扩展到稠合多环杂环的合成。 5) 扩展醌与氧化腈的[3+2]环加成反应以获得多种II型聚酮化合物结构，例如DNA解旋酶抑制剂海喹霉素。