Approaches to Bioactive Aminoimidazole Natural Products

描述（由申请人提供）：本申报文件中描述的研究的长期目标是提供一组合成转化，用于将简单咪唑精制成生物学相关的天然产物和同源物。我们提出了两种不同的方案，它们依赖于不同的机械反应，但都以这样或那样的方式涉及咪唑环芳香性的破坏。第一个项目旨在发展4-乙烯基咪唑分子间和分子内的Dieis-Alder反应，作为构建多环分子的一种手段，这些多环分子可能在生产天然产品的过程中有用，特别是从海洋海绵中分离出来的由罗维丁衍生的吡咯咪唑类化合物。该反应有望成为许多靶标组装的关键步骤，包括具有抗菌特性的龙珠生物碱（如龙珠素），以及更复杂的帕劳胺和相关靶标，konbu酸苷a， styloguanidine和axinellamine a。帕劳胺是一种六环双胍生物碱，是一种有效的免疫抑制剂，在混合淋巴细胞反应中显示出纳米摩尔的IC50。此外，帕劳胺对P-388和A-549癌细胞具有显著的抑制作用，IC50分别为0.2和0.5 fM。相关的酰化同系物konbu酸苷A抑制细胞周期蛋白依赖性激酶4，因此可能被证明是有用的抗癌先导物，而styloguanidine是几丁质酶抑制剂。第二个项目将重点研究最近发现的二甲二氧环诱导的双环咪唑（四氢苯并咪唑）氧化重排成螺咪唑。建议研究这一潜在重要反应的范围和局限性。特别是，咪唑取代基对氮和C2的影响，以及外围取代基在C4和C5上对重排立体化学结果的作用将被研究。预计该反应将在制备帕劳胺、孔布酸a、苯乙烯胍和辛胺a中发挥关键作用。此外，计划确定重排对咪唑[4,5-b]吡啶的适用性，如果成功，重排产物可能作为制备几种单体鸟苷类生物碱的关键中间体，如phakellin、saxitoxin和cantharelline。最后的项目将把本计划探索阶段开发的方法应用于一些二聚鱼龙葵素衍生的海洋生物碱(i) agelifin, (ii) axinellamine a, (iii) palau'amine, (iv) konbu'acidin a和(v) styloguanidine。

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.