Chemical Synthesis of Novel Natural Products

描述(由申请人提供)：这个以目标为导向的发现计划广泛地针对研究合成具有生物意义的天然产品的方法和策略的进展。第一部分海洋抗肿瘤大环内酯类化合物：Peloruside A将执行一项收敛的、对映体控制合成Peloruside A的计划。Peloruside A诱导G2-M期细胞周期中的细胞凋亡，具有稳定微管的活性。由于P-糖蛋白外排泵的过度表达，大环内酯对多药耐药的敏感性比紫杉醇低300倍以上。此外，红景天苷A更容易给药，与紫杉醇相比，它似乎结合到微管蛋白上不同的位置。Peloruside A的研究提供了重大的化学进展，这将为探测生物学研究提供天然产物和重要的衍生品。第二部分佐丹胺。对这类新型海洋生物碱的研究描述了向稠密官能化的多环系统进行化学合成的挑战性问题。这类化合物显示出重要的抗肿瘤和抗炎活性，去甲苯并三胺被认为是一种很有前途的骨修复候选药物。最近，偶氮苯酚表现出对胶原诱导的血小板聚集的特异性抑制作用。第III(A)部。澳大利亚的真菌素。澳大利亚真菌素是一种有效的抗真菌药物，是第一种非鞘氨醇为基础的鞘脂生物合成抑制剂。它是鞘氨酸N-酰基转移酶的选择性抑制因子，在脂质信号转导、细胞分化和细胞凋亡中可能发挥重要作用。第III(B)部。这一最新发现揭示了一种新的分子结构，它具有显著的抗肿瘤活性。我们的研究将探索这些复杂的多环体系的化学合成策略。

DESCRIPTION (provided by applicant): This program of target-driven discovery is broadly directed to investigate advances of methodologies and strategies for the synthesis of biologically significant natural products. Part I. Marine Antitumor Macrolides: Peloruside A. A plan for the convergent, enantiocontrolled synthesis of peloruside A will be executed. Peloruside A induces apoptosis in the G2-M phase of the cell cyclic with microtubule-stabilizing activity. The macrolide is more than 300 X less susceptible than paclitaxel to multi-drug resistance due to the over-expression of the P-glycoprotein efflux pump. Additionally, peloruside A is more readily administered, and appears to bind to a different site on tubulin compared to paclitaxel. Peloruside A studies offer significant chemical advancements, which will supply natural product and important derivatives for probing biological investigations. Part II. Zoanthamines. Investigations of this novel class of marine alkaloids describe challenging issues of chemical synthesis toward densely functionalized, polycyclic systems. Members of this class have exhibited important antitumor and anti-inflammatory activities, and norzoanthamine is considered to be a promising osteoporetic candidate. Recently, zoanthenol has demonstrated specific inhibition of collagen-induced platelet aggregation. Part III (a). Australifungin. Australifungin is a potent antifungal which is the first nonspingosine-based inhibitor of sphingolipid biosynthesis. It functions as a selective inhibitor of sphinganine N-acyl transferase, and may have an important role in lipid signal transduction, cell differentiation, and apoptosis. Part III (b). Daphnicyclidin A. This recent discovery has revealed a new molecular architecture which exhibits significant antitumor activity. Our research will investigate strategies for chemical synthesis of these complex polycyclic systems.