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环部分的简明合成。如果这种方法成功，将这部分分子的合成步骤从大约30步减少到提议的11步，将导致海绵抑素的合成更加简洁，这将适用于结构-活性研究（SAR）。本提案的长期目标是上述海绵抑制素的SAR研究，其中提出的三维结构将为本研究提供重点，即：内部羟基是相互之间的氢键，在三维结构表现中被认为是重要的，将成为甲基醚形成/酰化（作用仅为氢键受体）、反转（检查三级结构变化的影响）、反转和氮取代（检查三级结构变化和原子改变）的目标。用氮取代并保留绝对立体化学（检查乙酰胺基团较强的氢键供体/受体性质的影响）。化学上可接近的暴露在外的可能参与识别/结合的外周羟基也将成为醚化/酰化、反转、反转和氮取代以及氮取代保留的目标。总的来说，大约有45种类似物被设想；大约12个将成为最初的目标，所收集的生物学数据将为其余33个的适用性提供信息。

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.