Chemical Synthesis of Novel Natural Products

描述：(由申请者提供)-本研究计划范围广泛 旨在研究化学合成的基本进展 具有生物活性的海洋天然产物。 第一部分海洋抗肿瘤大环内酯类化合物。A节高度发展的计划 劳利马利的高效、收敛和对映体控制的合成 被处死。洛利马利德的IC50与紫杉醇相当 浓度在0.01-0.05微克/毫升范围内，对广泛的选择 肿瘤细胞系。对KB细胞系表现出较高的细胞毒作用(IC50= 0.015微克/毫升)。洛伊马利特在多种药物中显著保持活性 耐药株SKVLB-1。B节综合战略 Peloruside将探索立体选择性和效率的问题 这种高氧半缩酮的组装。具有关键的结构特征和 大循环刚性，涉及有关的重要建议和研究 苔藓抑素抗肿瘤活性的性质(NCI；II期试验)， Peloruside A的研究旨在提供显著的化学进展 探讨药效团的性质及生物作用机制 这一分子家族的活性。 我们对这些目标分子的化学研究将不对称地发展 烯丙化反应。双向、发散的不对称烯丙基化策略 都经过了检查。将直接形成新的同手性烯丙基硼烷物种 通过与有机锌试剂的交叉偶联反应进行研究。 第二部分佐丹胺。我们对这一新型海洋物种的研究 生物碱描述了化学合成中具有挑战性的问题 功能化的多环系统。这个班级的成员已经展示了 重要的抗肿瘤和抗炎活性，去甲黄嘌呤是 被认为是很有前途的骨质疏松症候选人。 第三部分：澳大利亚菌素。这种独特的天然产品是一种有效的抗真菌药物。 它是第一个非鞘氨醇为基础的鞘磷脂生物合成抑制剂。 它的作用是选择性地抑制鞘氨酸N-酰基转移酶，以及 可能在脂质信号转导、细胞分化、 和细胞凋亡。 我们对佐安胺和紫草菌素的计划将探索不对称 共轭加成反应的诱导和分子内Michael基 骑自行车运动。硝基烯烃前体的分子内(4+2)环加成反应 将提供反式十连蛋白的简便构建。。

DESCRIPTION: (provided by applicant) - This research program is broadly directed to investigate fundamental advances for the chemical synthesis of biologically active marine natural products. Part I. Marine Antitumor Macrolides. Section A. A plan for the highly efficient, convergent, and enantiocontrolled synthesis of laulimalide will be executed. Laulimalide displays comparable potency to taxol with IC50 concentrations in the 0.01-0.05 mico/mL range against a broad selection of tumor cell lines. High cytotoxicity was registered toward KB lines (IC50 = 0.015 mico/mL). Significantly laulimalide retains activity in multi-drug resistant SKVLB-1 cultures. Section B. Strategies for the synthesis of peloruside will explore issues of stereoselectivity and efficiency for the assembly of this highly oxygenated hemiketal. With key structural features and macrocyclic rigidity, which address important proposals and research concerning the nature of the antitumor activity of the bryostatins (NCI; phase II trials), peloruside A studies are designed to offer a significant chemical advance for probing the nature of the pharmacophore and the mechanisms of biological activity for this family of molecules. Our chemical studies toward these target molecules will develop asymmetric allylation reactions. Bidirectional, divergent asymmetric allylation strategies are examined. Direct formation of new homochiral allylborane species will be pursued via cross coupling reactions with organozinc reagents. Part II. Zoanthamines. Our 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 osteoporotic candidate. Part III. Australifungin. This unique natural product is a potent antifungal which is the first nonsphingosine-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. Our plans toward zoanthamines and australifungin will explore asymmetric induction in conjugate addition reactions and intramolecular Michael-based cyclizations. The intramolecular (4+2) cycloadditions of nitroalkene precursors will provide facile construction of trans-decalins. .