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: 7173416
• 负责人: Carl Lovely
• 金额: $ 24.3万
• 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/7173416
• 关键词: Agelas; Alder plant; Alkaloids; Anti-Bacterial Agents; Biological; Biological Factors; Cancer cell line; Chemistry; Chitinase; Class; Complex; Cyclin-Dependent Kinase 4; DNA Sequence Rearrangement; Diels Alder reaction; Disruption; Evaluation; Exhibits; Facility Construction Funding Category; Figs - dietary; Goals; Imidazole; Immunosuppressive Agents; Inhibitory Concentration 50; Investigation; Lead; Malignant Neoplasms; Marines; Methodology; Methods; Mixed Lymphocyte Culture Test; Nitrogen; Numbers; Outcome; Palau' amine; Peripheral; Phase; Play; Porifera; Positioning Attribute; Property; Reaction; Research; Role; Route; Saxitoxin; Time; adduct; dimethyldioxirane; imidazolone; inhibitor/antagonist; oroidin; phakellin; programs; pyridine; research study

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化，用于将简单的咪唑加工成生物相关的天然产物和同系物。提出了两个不同的项目，它们依赖于机械上不同的反应，但都以一种或另一种方式涉及咪唑环芳香性的破坏。第一个项目旨在开发 4-乙烯基咪唑的分子间和分子内 Dieis-Alder 反应，作为构建多环分子的手段，该多环分子可用于制备天然产物，特别是从海绵中分离出的 Oroidin 衍生的吡咯并咪唑类化合物。该反应预计将成为组装许多靶标的关键步骤，包括具有抗菌特性的 Agelas 生物碱（例如，ageliferin），以及更复杂的 palau'amine 和相关靶标，konbu'acidin A、styloguanidine 和 axinellamine A。 Palau'amine 是一种六环含双胍的化合物 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 癌细胞系表现出显着的活性，IC50 分别为 0.2 和 0.5 fM。相关的酰化同源物 konbu'acidin A 可抑制细胞周期蛋白依赖性激酶 4，因此可能被证明可用作抗癌先导药物，而 styloguanidine 是一种几丁质酶抑制剂。第二个项目将重点关注最近发现的二甲基二环氧乙烷诱导的双环咪唑（四氢苯并咪唑）氧化重排生成螺咪唑酮。建议调查这一潜在重要反应的范围和局限性。特别是，将研究咪唑取代基对氮和 C2 的影响，以及 C4 和 C5 的外围取代基对重排立体化学结果的作用。预计该反应将在 palau'amine、konbu'acidin A、styloguanidine 和 axinellamine A 的研究中发挥关键作用。此外，计划确定重排对咪唑并[4,5-b]吡啶的适用性，如果成功，重排产物可能作为几种单体 oroidin 衍生的方法中的关键中间体。 生物碱，例如phakellin、石房蛤毒素和鸡油碱。最终项目将把本计划探索阶段开发的方法应用于许多二聚 Oroidin 衍生的海洋生物碱（i）ageliferin、（ii）axinellamine A、（iii）palau'amine、（iv）konbu'acidin A 和（v）styloguanidine。