A Combination Strategy for Pyrrole-Containing Alkaloids

含吡咯生物碱的组合策略

• 批准号: 6848378
• 负责人: JOHN T. GUPTON
• 金额: $ 19.1万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848378
• 关键词: alkaloids; analog; biological products; calmodulin; chemical substitution; drug design /synthesis /production; drug screening /evaluation; esters; inhibitor /antagonist; phosphodiesterase inhibitors; pyrroles

DESCRIPTION (provided by applicant): This proposal represents a continuation of work initiated under NIH AREA grant CA67236-02, which began July 1, 2001 and will end July 31,2004. The previous proposal focused on using 3-substituted or 2,3- disubstituted beta-chloroenals as key synthons for the regioselective preparation of pyrroles, which could function as precursors to appropriate, bioactive, marine natural products or might exhibit interesting bioactivity of their own. Alkaloids, which belong to this rapidly growing family of pyrrole containing marine natural products, exhibit anti-tumor, anti-HIV, immunomodulatory and multidrug resistance (MDR) reversal activities and are under current investigation by a significant number of research groups. Interestingly, studies in our group during the last several years indicate that further elaboration at the 5 position of these 2,3,4-trisubstituted pyrroles is quite challenging, with the exception of the bromination at the 5 position with NBS. In addition, the desire to create a rapid and diverse group of analogs for biological evaluation prompted us to consider some previous work in our laboratory. We have demonstrated that symmetrical vinamidinium salts can be readily and efficiently prepared and condensed with glycinate esters to give 2-carboalkoxy-4- substituted pyrroles in high yields. Our new strategy involves the electrophilic substitution of the 2,4- disubstituted pyrroles at the 5 position. This is followed by bromination with NBS at the 4-position and then a cross-coupling reaction (Suzuki or Heck type) to give the tetrasubstituted core, which can be further elaborated to the desired pyrroles. The targets of this methodology will initially be the marine natural products Polycitone A and B, Rigidins A-D, Permethyl Storniamide, Ningalin A and their analogs. In this manner, a large, flexable and regioselective array of pyrroles can be rapidly assembled. All of the target molecules, their precursors and their analogs will subsequently be bioassayed by collaborators and/or the NCI. Mode of action and structure activity relationships will also be examined (in conjunction with collaborators) as part of this project.

描述（由申请人提供）：本提案代表了在NIH AREA拨款CA67236-02下启动的工作的延续，该工作始于2001年7月1日，将于2004年7月31日结束。先前的建议侧重于使用3-取代或2,3-二取代的-氯烯醛作为区域选择性制备吡咯的关键合成子，这些吡咯可以作为适当的生物活性海洋天然产物的前体，或者可能表现出自己有趣的生物活性。生物碱是一种快速发展的含吡咯的海洋天然产物，具有抗肿瘤、抗艾滋病毒、免疫调节和逆转多药耐药（MDR）的活性，目前正受到许多研究小组的研究。有趣的是，我们小组在过去几年的研究表明，除了NBS在5位的溴化外，进一步阐述这些2,3,4-三取代吡咯的5位是相当具有挑战性的。此外，创建一组快速和多样化的生物评价类似物的愿望促使我们考虑一些以前的工作在我们的实验室。我们已经证明了对称的vinamidinium盐可以很容易和有效地制备，并与甘氨酸酯缩合得到高收率的2-碳烷氧基-4-取代吡咯。我们的新策略是在5位上亲电取代2,4-二取代吡咯。接下来是溴化反应，NBS在4位，然后交叉偶联反应（Suzuki或Heck型）得到四取代核，这可以进一步阐述到所需的吡咯。该方法的目标最初将是海洋天然产物聚柠檬酸酮A和B， Rigidins A- d, Permethyl Storniamide， Ningalin A及其类似物。通过这种方式，可以快速组装出大量灵活且具有区域选择性的吡咯。所有的靶分子、它们的前体和类似物随后将由合作者和/或NCI进行生物测定。作为该项目的一部分，还将（与合作者一起）检查作用模式和结构活动关系。