The Synthesis and Biological Evaluation of Pyrrole Containing Marine Natural Prod

含吡咯海洋天然产物的合成及生物学评价

• 批准号: 7354888
• 负责人: JOHN T. GUPTON
• 金额: $ 20.26万
• 依托单位: UNIVERSITY OF RICHMOND
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354888
• 关键词: Acids; Adverse effects; Amides; Biological; Biological Assay; Biological Factors; Cancer cell line; Carbon; Class; Cyclization; Evaluation; Exhibits; Facility Construction Funding Category; Family; Funding; Generations; Grant; HIV Integrase Inhibitors; In Vitro; Inhibitory Concentration 50; Lead; Marines; Mediating; Methodology; Multi-Drug Resistance; Pyrroles; Scheme; Source; Structure-Activity Relationship; System; United States National Institutes of Health; Work; analog; antitumor agent; base; chemotherapeutic agent; concept; glycine methyl ester; in vivo; interest; lamellarin G trimethyl ether; marine natural product; member; microwave electromagnetic radiation; novel

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.

描述（由申请人提供）：本提案代表了NIH区域资助CA 67236 03下启动的工作的延续。海洋来源的天然产物仍然是生物学上令人感兴趣的化合物的丰富来源，特别是含有吡咯的海洋天然产物已被证明具有作为抗肿瘤剂、多药耐药逆转剂和HIV整合酶抑制剂的活性。这些含吡咯的天然产物的特征通常在于在吡咯环系统的碳3和碳4处的高度氧化的苯基以及位于碳2和碳5处的含羰基官能团沿着。我们现在已经建立的合成方法允许快速构建高度取代和高度官能化的吡咯。该方法还允许用于结构活性关系（SAR）研究的大的结构多样性，这可能导致具有增加的效力和降低的毒副作用的化学治疗剂。为新的供资周期提议的工作将涉及沿着一些新的补充方法，将这一战略应用于合成刚性蛋白家族（B、C和D）、宁加林家族（A和C）、全甲基storniamide和片螺素G三甲基醚的海洋天然产品。最近已经建立了这种新的互补策略的概念验证，包括1）应用微波辅助的Vilsmeier Haack双链反应（Vilsmeier Haack dichrooms）高度取代的吡咯和2）炔酸酰胺的产生和碱介导的环化。这些方法，除了我们的一般战略，将使我们能够扩展我们的目标，以额外的重要成员，这类不断增长的生物活性，含吡咯，海洋天然产品。除了探索这些新方法外，我们还将继续评估我们的先导化合物的新的和新颖的类似物，该化合物已经在体外和体内针对各种癌细胞系进行了评估，并继续显示出有希望的结果（平均IC 50 = 62纳摩尔）。所有靶分子、其前体及其类似物随后将由合作者和/或NCI进行生物测定。还将与我们的合作者一起进行行动模式和SAR研究。