The Synthesis and Biological Evaluation of Pyrrole Containing Marine Natural Prod

描述(由申请人提供)：本提案是根据美国国立卫生研究院面积拨款CA 67236 03发起的工作的继续。来自海洋的天然产品仍然是具有生物意义的化合物的丰富来源，特别是含有吡咯的海洋天然产品显示出作为抗肿瘤药物、多药耐药逆转剂和艾滋病毒整合酶抑制剂的活性。这些含有吡咯的天然产物的特征通常是位于吡咯环体系的碳3和碳4上的高氧苯基以及位于碳2和碳5上的含有羰基的官能团。我们现在建立的合成方法允许快速构建高取代和高官能化的吡咯。这种方法还允许结构活性关系(SAR)研究的结构多样性，这可能导致化疗药物具有更强的效力和减少毒副作用。新供资周期的拟议工作将涉及将这一战略以及一些新的和补充的方法应用于合成硬脂素家族(B、C和D)、宁林家族(A和C)、全甲基斯多尼胺和片麻素G三甲醚的海洋天然产物。这一新的互补策略最近得到了概念验证，涉及1)微波辅助的高取代吡咯的Vilsmeier-Haack甲酰化反应和2)芳烯酸酰胺的生成和碱基催化的环化反应。除了我们的总体战略之外，这些方法将使我们能够将我们的目标扩展到这一不断增长的具有生物活性、含有吡咯的海洋天然产品类别中的更多重要成员。除了探索这些新的方法外，我们还将继续评估我们的先导化合物的新的和新的类似物，这种化合物已经在体外和体内对各种癌细胞株进行了评估，并继续显示出有希望的结果(平均IC50=62纳摩尔)。所有目标分子、它们的前体和它们的类似物随后将由合作者和/或NCI进行生物测试。行动模式和搜救研究也将与我们的合作者一起进行。

DESCRIPTION (provided by applicant): This proposal represents a continuation of work initiated under NIH AREA grant CA 67236 03. Natural products of marine origin continue to be a rich source of biologically interesting compounds and pyrrole containing marine natural products in particular have demonstrated activity as antitumor agents, multidrug resistant reversal agents and inhibitors of HIV integrase. These pyrrole containing natural products are usually characterized by highly oxygenated phenyl groups at carbons 3 and 4 of the pyrrole ring system along with carbonyl containing functionality located at carbons 2 and 5. The synthetic methodology that we have now established allows rapid construction of highly substituted and highly functionalized pyrroles. This methodology also allows for great structural diversity for structure activity relationship (SAR) studies, which could lead to chemotherapeutic agents with increased potency and decreased toxic side effects. Work proposed for the new funding cycle will involve applying this same strategy along with some new and complimentary methodology to the synthesis of marine natural products of the rigidin family (B,C and D), the ningalin family (A and C), permethyl storniamide and lamellarin G trimethyl ether. Proof of concept has recently been established for this new and complementary strategy involving 1) the application of microwave assisted Vilsmeier Haack formylation of highly substituted pyrroles and 2) the generation and base mediated cyclization of ynenoic acid amides. These methodologies, in addition to our general strategy, will allow us to extend our targets to additional important members of this ever growing class of bioactive, pyrrole containing, marine natural products. In addition to exploring these new methodologies, we will continue to evaluate new and novel analogs of our lead compound , which has already been evaluated both in vitro and in vivo against various cancer cell lines and continues to exhibit promising results (average IC50 = 62 nanomolar). All of the target molecules, their precursors and their analogs will subsequently be bioassayed by collaborators and/or the NCI. Mode of action and SAR studies will also be carried out in conjunction with our collaborators.