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方法，旨在完成有效的细胞毒性/抗癌天然产物海绵抑素1的麻烦的EF环部分的简明合成。如果该方法成功，该分子这部分分子的合成步骤数将从大约30步减少到建议的11步，这将导致海绵素的合成更加简洁，这将有利于结构活性研究(SAR)。这一提议的较长期目标是前述海绵素的SAR研究，其中所提议的三维结构将为这项研究提供焦点，即：相互氢键并被认为在三维结构呈现中重要的内部羟基将被靶向于甲醚形成/酰化(作用将仅是氢键受体)、反转(检查三级结构变化的影响)、反转和被氮取代(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(考察乙酰胺基团较强的氢键供体/受体性质的影响)。可能参与识别/结合的化学上可接触的外周羟基也将成为醚化/酰化、转化、转化和氮气取代以及用氮气取代保留的目标。总而言之，设想了大约45个类似物；最初将针对大约12个类似物，获得的生物数据将告知其余33个类似物的适用性。 与公共健康相关：这项工作将比以前完成的更简洁地合成重要的天然产品海绵抑素1，并将使首次对导致其非凡的抗癌特性的因素进行有意义的研究。海绵抑素1已被报道对广泛的癌症具有极强的疗效，但天然来源和现有合成材料的低可用性迄今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品的开发。

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.