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

描述（由申请人提供）：第一个目标是设计和开发旨在完成强效细胞毒性/抗癌天然产物spongistatin 1的麻烦EF环部分的简明合成的方法。如果这种方法是成功的，减少在合成步骤计数的这部分分子从约30至建议的11个步骤，将导致一个更简洁的合成海绵他汀，这将是一个适合的结构-活性研究（SAR）。本提案的长期目标是上述海绵他汀的SAR研究，其中所提出的三维结构将为本研究提供重点，即：内部羟基彼此氢键结合，并且被认为在三维结构呈现中是重要的，其将成为甲基醚形成/酰化的目标（作用仅为氢键受体），反转（检查三级结构变化的影响）、反转和氮置换（检查三级结构变化和原子改变），和保留绝对立体化学的氮取代（检查乙酰胺基的较强H-键供体/受体性质的影响）。可能参与识别/结合的化学上可接近的暴露的外周羟基也将被靶向醚化/酰化、转化、反转和氮取代以及氮置换保留。总共设想了大约45种类似物;大约12种最初将作为目标，收集的生物学数据将为其余33种的适用性提供信息。 公共卫生相关性：这项工作将构成一个更简洁的合成的重要天然产物spongistatin 1比以前已经完成，并将使第一个有意义的研究的因素负责其非凡的抗癌特性。据报道，Spongistatin 1对广泛的癌症具有极强的抗肿瘤作用，但天然来源和现有合成方法的低可用性迄今为止阻碍了对其活性成分的系统研究和用于癌症治疗的更简单衍生物的开发。

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.