Efficient Synthesis of the Spongistatin EF Ring Segment and Analogue SAR Study

海绵抑素EF环片段的高效合成及类似SAR研究

• 批准号: 8242086
• 负责人: Paul Steven Tanis
• 金额: $ 3.8万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2012-12-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242086
• 关键词: Acetamides; Acylation; Binding; Biological; Biological Factors; Data; Development; Goals; Hydrogen Bonding; Investigation; Macrolides; Malignant Neoplasms; Methodology; Methyl Ethers; Nitrogen; Peripheral; Property; Reporting; Role; Scheme; Source; Spongistatin; Structure; Structure-Activity Relationship; Wit; Work; analog; cancer therapy; cytotoxic; cytotoxicity; design; hydroxyl group; public health relevance; spongistatin 1; stereochemistry; three dimensional structure

DESCRIPTION (provided by applicant): The first goal is the design and development of methodology designed to accomplish a concise synthesis of the troublesome EF ring portion of the potent cytotoxic/anticancer natural product spongistatin 1. Should this approach be successful, the reduction in the synthetic step count for this portion of the molecule from approximately 30 to the proposed 11 steps would result in a much more concise synthesis of the spongistatins, one which would be amenable to a structure-activity study (SAR). The longer-term goal of this proposal is the aforementioned SAR study of the spongistatins wherein the proposed three-dimensional structure will provide the focus for this study, to wit: internal hydroxyl groups, which are hydrogen bonded to each other and are presumed to be important in the three-dimensional structure presentation, will be targeted for methyl ether formation/acylation (role will be H-bond acceptor only), inversion (examining the impact of a change in tertiary structure), inversion and substitution by nitrogen (examining tertiary structure change and atom alteration), and substitution by nitrogen with retention of absolute stereochemistry (examining the effect of the stronger H-bond donor/acceptor properties of the acetamide group). Chemically accessible exposed peripheral hydroxyl groups which might be involved in recognition/binding will be also be targeted for etherification/acylation, inversion, inversion and substitution by nitrogen and retention with replacement with nitrogen. In toto, approximately 45 analogues are envisioned; approximately 12 will be initially targeted, and the biological data garnered will inform on the suitability of the remaining 33. PUBLIC HEALTH RELEVANCE: This work will constitute a much more succinct synthesis of the important natural product spongistatin 1 than has previously been accomplished, and will enable the first meaningful study of the factors responsible for its extraordinary anticancer properties. Spongistatin 1 has been reported to be extremely potent against a broad cross-section of cancers, but low availability from both natural sources and existing syntheses has thus far hampered systematic investigations into its active components and the development of simpler derivatives for use in cancer therapy.

描述（由申请人提供）：第一个目标是设计和开发一种方法，旨在完成强效细胞毒性/抗癌天然产物海绵抑素 1 中麻烦的 EF 环部分的简洁合成。如果该方法成功，该分子这部分的合成步骤数从大约 30 步减少到建议的 11 个步骤，将导致海绵抑素的合成更加简洁，这将是 适合结构-活性研究（SAR）。该提案的长期目标是前面提到的海绵抑素的 SAR 研究，其中所提出的三维结构将为本研究提供重点，即：内部羟基基团（它们彼此之间通过氢键结合，并且被认为在三维结构呈现中很重要）将针对甲基醚形成/酰化（作用仅是氢键受体）、反转（检查影响） 三级结构变化）、氮反转和取代（检查三级结构变化和原子改变）以及保留绝对立体化学的氮取代（检查乙酰胺基团更强的氢键供体/受体特性的影响）。可能参与识别/结合的化学可接近的暴露的外围羟基也将被靶向醚化/酰化、反转、反转和氮取代以及氮取代的保留。总共设想了大约 45 个类似物；最初将大约 12 个人作为目标，收集到的生物数据将告知其余 33 个人是否适合。 公共健康相关性：这项工作将比以前完成的重要天然产物海绵抑素 1 的合成更加简洁，并将首次对其非凡抗癌特性的因素进行有意义的研究。据报道，海绵抑素 1 对多种癌症都非常有效，但天然来源和现有合成方法的可用性较低，迄今为止阻碍了对其活性成分的系统研究以及用于癌症治疗的更简单衍生物的开发。