Chemical Synthesis of Novel Natural Products

描述：（由申请人提供）-本研究计划广泛 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品。 第一部分.海洋抗肿瘤大环内酯类。a节一个计划，为高度 有效的，收敛的，和对映体控制的合成laulimalide将是 处决了被Laulimalide显示出与紫杉醇相当的功效，IC 50 浓度范围为0.01 - 0.05 mico/mL， 肿瘤细胞系对KB系记录了高细胞毒性（IC50 = 0.00000）。 0.015 mico/mL）。值得注意的是，laulimalide在多种药物中保留活性， 耐SKVLB-1培养物。B部分。综合战略 peloruside将探讨立体选择性和效率的问题， 这种高度氧化的半缩酮的组装。具有关键的结构特征， 大循环刚性，解决重要的建议和研究， 苔藓抑素的抗肿瘤活性的性质（NCI; II期试验）， peloruside A研究旨在提供一个显着的化学进步， 探索药效团的性质和生物学作用机制 这个分子家族的活性。 我们对这些目标分子的化学研究将发展出不对称的 烯丙基化反应双向发散不对称烯丙基化策略 进行检查。直接形成新的同手性烯丙基硼烷物种将是可行的。 通过与有机锌试剂的交叉偶联反应进行。 第二部分. Zoanthamines。我们对这种新型海洋生物的研究 生物碱描述了化学合成的挑战性问题， 功能化的多环系统。这个班的成员表现出了 重要的抗肿瘤和抗炎活性，去甲虫胺是 被认为是一个有前途的候选人。 第三部分.澳大利亚芬净这种独特的天然产品是一种有效的抗真菌剂 它是第一个非鞘氨醇基鞘脂生物合成抑制剂。 它作为鞘氨醇N-酰基转移酶的选择性抑制剂发挥作用， 可能在脂质信号转导，细胞分化， 和凋亡。 我们对zoanthamines和australifungin的计划将探索不对称 共轭加成反应中诱导和分子内Michael基 循环硝基烯烃前体的分子内（4 + 2）环加成反应 将提供容易的反式十氢化萘结构。.

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. .