A Combination Strategy for Pyrrole-Containing Alkaloids

描述(由申请人提供)：本提案是根据美国国立卫生研究院CA67236-02区域拨款发起的工作的继续，从2001年7月1日开始，到2004年7月31日结束。先前的提案侧重于使用3-取代或2，3-二取代的β-氯烯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、具有生物活性的海洋天然产物的前体，或者可能显示出它们自己的有趣的生物活性。生物碱属于含有海洋天然产物的吡咯类化合物，具有抗肿瘤、抗HIV、免疫调节和多药耐药(MDR)逆转等活性，目前正在被许多研究小组研究。有趣的是，我们小组在过去几年中的研究表明，除了与NBS在5位的溴化反应外，在5位进一步阐述这些2，3，4-三取代吡咯是相当具有挑战性的。此外，创建一组快速和多样化的类似物用于生物学评估的愿望促使我们考虑我们实验室以前的一些工作。我们已经证明，对称的乙酰胺盐可以容易和有效地制备，并与甘氨酸酯缩合，以高产率得到2-碳烷氧基-4-取代吡咯。我们的新策略包括5位2，4-二取代吡咯的亲电取代。然后在4位与NBS进行溴化反应，然后进行交叉偶联反应(Suzuki或Heck类型)，得到四取代核，可以进一步细化到所需的吡咯。这一方法学的目标首先是海洋天然产物多糖酮A和B、赤霉素A-D、全甲基斯托尼酰胺、宁林A及其类似物。以这种方式，可以快速组装大的、可弯曲的和区域选择性的吡咯阵列。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。作为该项目的一部分，还将(与合作者一起)审查行动模式和活动关系的结构。

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.