Chemical Synthesis of Novel Natural Products

描述（由申请人提供）：这个目标驱动的发现项目广泛地指导研究合成具有生物学意义的天然产物的方法和策略的进展。第一部分：海洋抗肿瘤大环内酯类：Peloruside A.一个收敛的、对映控制的Peloruside A的合成计划将被执行。Peloruside A在细胞周期G2-M期诱导细胞凋亡，具有微管稳定活性。由于p -糖蛋白外排泵的过度表达，大环内酯对多药耐药的易感性比紫杉醇低300倍以上。此外，与紫杉醇相比，peloruside A更容易给药，并且似乎与微管蛋白上的不同位点结合。Peloruside A的研究提供了重大的化学进展，将为探索生物学研究提供天然产物和重要衍生物。第二部分。Zoanthamines。这类新型海洋生物碱的研究描述了向密集功能化多环系统化学合成的挑战性问题。这类药物已显示出重要的抗肿瘤和抗炎活性，诺佐那敏被认为是一种有前途的骨质疏松候选药物。最近，斑蝥素醇被证明对胶原诱导的血小板聚集具有特异性抑制作用。第三(a)部分。Australifungin。Australifungin是一种有效的抗真菌药物，是首个以非自旋腺苷为基础的鞘脂生物合成抑制剂。它是鞘氨氨酸n -酰基转移酶的选择性抑制剂，可能在脂质信号转导、细胞分化和细胞凋亡中起重要作用。第三(b)部分。这一最新发现揭示了一种具有显著抗肿瘤活性的新分子结构。我们的研究将探讨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.