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，这些产物具有强大的药理活性，并且要么不可用，要么只能从其天然来源中获得少量。第一个靶点是螺旋螺内酯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具有纳米级的IC50值。提出了一种简明的、可能达到克级的这种化合物的合成方法，这将为进一步的生物学研究提供材料。结构生物学信息，以及对一些与螺旋藻内酯相关的化合物的化学特征的分析，也将被用于尝试和识别以选择性方式调节蛋白磷酸酶的分子。第二个目标是阿霉素，这是一种十环梯形聚醚，与腹泻性贝类中毒有关，是一种具有显著抗癌活性的化合物的类似物。本文描述了一种简洁的30步合成方法，采用了新的化学方法，合成得到的材料将用于鉴定阿霉素的分子靶标。海洋环境是药理学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，有许多障碍阻止这一潜力成为常规现实，其中两个最重要的是海洋生物产生的分子往往高度复杂，以及它们通常只产生极少量的事实。本提案研究的主要目标是为两类重要的具有强大生物活性的复杂海洋天然产物开发新的合成化学途径，并利用由此产生的材料研究其生物学。

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.