Total Synthesis of Bioactive Compounds

描述(由申请人提供)：本建议中描述的这门科学的主要目标是开发两种复杂的海洋衍生天然产品的化学和生物学，这两种产品具有强大的药理活性，并且要么无法获得，要么只能从其自然来源中获得微量。第一个靶点是螺内酯B，这是一种非常复杂的大环内酯，显示了与癌症治疗相关的蛋白质磷酸酶的纳分子IC50值。提出了一种简洁的、潜在的克级合成该化合物的方法，这将为进一步的生物学研究提供材料。结构生物学信息，以及对一些与螺杆菌内酯相关的化合物的化学特征的分析，也将被用来尝试并以选择性的方式识别调节蛋白磷酸酶的分子。第二个目标是阿德里阿托毒素，一种十环的“梯形”聚醚，与腹泻贝类中毒有关，是具有显著抗癌活性的化合物的类似物。描述了一种采用新化学方法的简明、30步的阿霉素合成方法，合成得到的材料将用于鉴定阿霉素的分子靶标。海洋环境是药理上有趣的分子的丰富来源，这些分子既有作为药物的潜力，也有作为生物系统探针的潜力。然而，有一些障碍阻碍了这种潜力成为常规现实，其中最重要的两个障碍是海洋生物产生的分子往往非常复杂，而且它们通常只产生极少量的物质。这项建议中研究的主要目标是开发新的合成化学路线，以获得两类具有强大生物活性的重要复杂海洋天然产品，并利用这一努力产生的材料来研究它们的生物学。 公共卫生相关性：长期以来，复杂的天然产品一直是药理上有趣的分子的丰富来源，这些分子具有潜在的和已证实的药物效用。在抗菌和抗癌药物领域尤其如此。阻碍这一领域进一步成功的一个关键因素是缺乏可用于彻底结构-活性研究的可靠和通用的化学路线，特别是在来自自然来源的可用材料有限的情况下。在许多情况下，这严重阻碍了对天然化合物生物学潜力的进一步研究。这项建议中描述的研究目标是开发两个复杂分子的化学和生物学：螺内酯B，一种具有强大抗癌活性的分子；以及阿霉素，一种具有从离子通道抑制到抗癌等多种生物活性的分子。

DESCRIPTION (provided by applicant): The principle objectives of this science described in this proposal are to develop the chemistry and biology of two complex marine-derived natural products that possess potent pharmacological activity, and that are either unavailable, or available only in minute amounts from their natural sources. The first target is spirastrellolide B, a very complex macrolide that displays nanomolar IC50 values against protein phosphatases of relevance to cancer therapy. A concise, potentially gram-scale, synthesis of this compound is proposed that will provide material for further biological study. Structural biology information, along with analysis of the chemical features of a number of compounds related to spirastrellolide will also be used to try and identify molecules that modulate protein phosphatases in an selective fashion. The second target is adriatoxin, a decacyclic 'ladder' polyether that has been implicated in diarrhetic shellfish poisoning and is a close analog of compounds that have remarkable anti-cancer activity. A concise, 30 step synthesis, that employs new chemistry is described for adriatoxin, and material obtained by the synthesis will be used to identify adriatoxin's molecular target. The marine environment is a prolific source of pharmacologically interesting molecules that have potential both as drugs and as probes for biological systems. However there are a number of obstacles that prevent this potential from becoming routine reality, the two most significant being the often high level of complexity among molecules produced by marine organisms and the fact that they are usually only produced in miniscule amounts. The primary goals of the research in this proposal are to develop new synthetic chemistry routes to two important classes of complex marine natural products that have potent biological activity and to use material produced by this endeavor to study their biology. PUBLIC HEALTH RELEVANCE: Complex natural products have long been a rich source of pharmacologically interesting molecules that have both potential and proven utility as drugs. This is particularly true in the realm of anti-bacterial and anti-cancer agents. One key factor that prevents further success in this arena is the lack of robust and general chemistry routes that can be adopted for thorough structure-activity investigations, particularly if there is limited material available from the natural source. In many cases this is a serious impediment to the further study of the biological potential of naturally occurring compounds. The goals of the research described in this proposal are to develop the chemistry and biology of two complex molecules: spirastrellolide B, a molecule with potent anti-cancer activity; and adriatoxin, a member of a class of molecules that possess a variety of biological activities ranging from ion-channel inhibition to anti-cancer.