Total Synthesis of Bioactive Compounds

描述（由申请人提供）：本提案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物的化学和生物学，这两种天然产物具有强大的药理活性，并且从其天然来源中无法获得或仅以微量获得。第一个靶点是螺环内酯B，这是一种非常复杂的大环内酯，对与癌症治疗相关的蛋白磷酸酶显示出纳摩尔IC 50值。一个简洁的，潜在的克级，合成这种化合物的建议，将提供材料，为进一步的生物学研究。结构生物学信息，沿着与螺旋霉素相关的许多化合物的化学特征的分析也将用于尝试和鉴定以选择性方式调节蛋白磷酸酶的分子。第二个目标是adriatoxin，一种十环“梯形”聚醚，与贝类中毒有关，是具有显着抗癌活性的化合物的类似物。一个简洁的，30步的合成，采用新的化学描述阿霉素，和材料的合成将被用来确定阿霉素的分子目标。海洋环境是一个多产的有趣的分子，有潜力作为药物和生物系统的探针来源。然而，有一些障碍阻止这种潜力成为常规现实，其中两个最重要的障碍是海洋生物产生的分子往往高度复杂，而且它们通常只产生极少量。这项研究的主要目标是开发新的合成化学路线，以获得两类重要的具有强大生物活性的复杂海洋天然产物，并使用通过这一奋进产生的材料来研究它们的生物学。 公共卫生相关性：复杂的天然产物长期以来一直是一个丰富的来源，有趣的分子，既有潜力和证明效用作为药物。在抗菌剂和抗癌剂领域尤其如此。阻碍在这一竞技场取得进一步成功的一个关键因素是缺乏可用于彻底结构-活性研究的稳健和通用化学路线，特别是如果从天然来源获得的材料有限。在许多情况下，这严重阻碍了对天然存在的化合物的生物潜力的进一步研究。本提案中描述的研究目标是开发两种复杂分子的化学和生物学：螺旋霉素B，一种具有强效抗癌活性的分子;以及阿霉素，一类具有从离子通道抑制到抗癌等多种生物活性的分子的成员。

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.