A Combination Strategy for Pyrrole-Containing Alkaloids

描述（由申请人提供）：本提案代表了NIH区域资助CA 67236 -02下启动的工作的继续，该资助始于2001年7月1日，将于2004年7月31日结束。以前的建议集中于使用3-取代或2，3-二取代的β-氯烯醛作为关键的取代基用于吡咯的区域选择性制备，吡咯可以作为合适的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，这属于这个迅速增长的家庭吡咯含有海洋天然产物，表现出抗肿瘤，抗艾滋病毒，免疫调节和多药耐药（MDR）逆转活动，目前正在调查的相当数量的研究小组。有趣的是，我们小组在过去几年中的研究表明，在这些2，3，4-三取代的吡咯的5位上的进一步加工是相当具有挑战性的，除了在5位上用NBS溴化之外。此外，希望创造一个快速和多样化的类似物组的生物学评价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，对称的vinamidinium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-烷氧羰基-4-取代的吡咯。我们的新策略包括在5位上的2，4-二取代吡咯的亲电取代。然后在4位用NBS溴化，然后进行交叉偶联反应（Suzuki或Heck型），得到四取代的核，其可以进一步加工成所需的吡咯。该方法的目标首先是海洋天然产物Polycitone A和B、Rigidins A-D、Permethyl Storniamide、Ningalin A及其类似物。以这种方式，可以快速组装大的、柔性的和区域选择性的吡咯阵列。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。作为本项目的一部分，还将（与合作者一起）检查行动模式和结构活动关系。

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.