Approaches to Bioactive Aminoimidazole Natural Products

生物活性氨基咪唑天然产物的研究方法

• 批准号: 6837732
• 负责人: Carl Lovely
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837732
• 关键词: Diels Alder reaction; antibacterial agents; artificial immunosuppression; biological products; biotherapeutic agent; chemical synthesis; drug design /synthesis /production; guanidines; imidazole; method development

DESCRIPTION (provided by applicant): The long-term goals of the research described in this submission are to provide a set of synthetic transformations for elaborating simple imidazoles into biologically relevant natural products and congeners. Two distinct projects are proposed that rely on mechanistically diverse reactions, but all involve, in one way or another, the disruption of the aromaticity of the imidazole ring. The first project seeks to develop the inter- and intramolecular Dieis-Alder reaction of 4-vinylimidazoles as a means to construct polycyclic molecules that may be useful en route to natural products, in particular the oroidin derived pyrroloimidazole class of compounds isolated from marine sponges. This reaction is expected to feature as the key step in the assembly of a number of targets including the Agelas alkaloids (e.g., ageliferin), which possess antibacterial properties, and the more complex palau'amine and related targets, konbu'acidin A, styloguanidine and axinellamine A. Palau'amine, a hexacyclic, bisguanidine-containing alkaloid, is a potent immunosuppressant, exhibiting a nanomolar IC50 in the mixed lymphocyte reaction. Furthermore, palau'amine showed significant activity against P-388 and A-549 cancer cell lines, with IC50's of 0.2 and 0.5 fM respectively. The related acylated congener, konbu'acidin A, inhibits cyclin dependent kinase 4 and thus may prove useful as an anti-cancer lead, whereas styloguanidine is a chitinase inhibitor. The second project will focus on the recently discovered dimethyldioxirane induced oxidative rearrangement of bicyclic imidazoles (tetrahydrobenzimidazoles) to spiro imidazolones. It is proposed to investigate the scope and limitations of this potentially important reaction. In particular, the influence of both imidazole substituents on nitrogen and at C2 will be investigated along with the role of peripheral substituents at C4 and C5 on the stereochemical outcome of the rearrangement. It is anticipated that this reaction will play a pivotal role in approaches to palau'amine, konbu'acidin A, styloguanidine and axinellamine A. Also, it is planned to establish the applicability of the rearrangement to imidazo[4,5-b]pyridines, if successful, the rearranged products might function as key intermediates in approaches to several monomeric oroidin-derived alkaloids, such as phakellin, saxitoxin and cantharelline. The final projects will apply the methodology developed during the exploratory phases of this program to a number of the dimeric oroidin-derived marine alkaloids (i) ageliferin, (ii) axinellamine A, (iii) palau'amine, (iv) konbu'acidin A and (v) styloguanidine.

描述（由申请人提供）：本提交中描述的研究的长期目标是提供一组合成转换，以将简单的咪唑详细介绍到生物学相关的天然产品和同类物中。提出了两个不同的项目，这些项目依赖于机械上的反应，但都以一种或另一种方式涉及咪唑环的芳香性的破坏。第一个项目旨在开发4-乙烯基咪唑的分子间和分子内的DIEIS - alder反应，作为构建可能在天然产物途径的多环分子的一种手段，尤其是Oroidin衍生的吡洛洛咪唑类化合物类别从海洋sponges分离出来的多吡罗莫唑类。 This reaction is expected to feature as the key step in the assembly of a number of targets including the Agelas alkaloids (e.g., ageliferin), which possess antibacterial properties, and the more complex palau'amine and related targets, konbu'acidin A, styloguanidine and axinellamine A. Palau'amine, a hexacyclic, bisguanidine-containing生物碱是一种有效的免疫抑制剂，在混合淋巴细胞反应中表现出纳摩尔IC50。此外，Palau'amine对P-388和A-549癌细胞系的活性显着，IC50分别为0.2和0.5 FM。相关的酰化同类物konbu'acidin A抑制了细胞周期蛋白依赖性激酶4，因此可能被证明是抗癌铅，而Styloguanidine是几数数蛋白酶抑制剂。第二个项目将集中于最近发现的二甲基二氧化烷诱导的双环咪唑（四氢苯甲酰二唑唑）氧化重排向Spiro Imidazolones。提议研究这种潜在重要反应的范围和局限性。特别是，将研究两种咪唑取代基对氮和在C2处的影响，以及C4和C5处外周取代基对重排的立体化学结果的作用。可以预见，这种反应将在palau'amine，konbu'acidin A，Styloguanidine和axinellamine A中起关键作用生物碱，例如phakellin，saxitoxin和cantharelline。最终项目将应用在该程序的探索阶段开发的方法，用于许多二聚体核苷衍生的海洋生物碱（i）Ageliferin，（ii）axinellamine a，（iii）palau'amine，（iii）palau'amine，（iv）konbu'acidin a和（v）stylogunidine。