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: 7338677
• 负责人: Carl Lovely
• 金额: $ 17.54万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338677
• 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）：本申报资料中描述的研究的长期目标是提供一套合成转化方法，将简单的咪唑类化合物转化为生物相关的天然产物和同系物。提出了两个不同的项目，依赖于机械上不同的反应，但都涉及，以这样或那样的方式，破坏咪唑环的芳香性。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，作为构建多环分子的手段，这些多环分子可能在天然产物的制备过程中有用，特别是从海绵中分离的oroidin衍生的吡咯并咪唑类化合物。该反应预计将作为组装包括Agelas生物碱（例如，ageliferin），其具有抗菌特性，以及更复杂的帕劳'amine和相关靶标，konbu'acidin 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摩尔IC 50。此外，帕劳胺对P-388和A-549癌细胞系表现出显着的活性，IC 50分别为0.2和0.5 fM。相关的酰化同源物konbu'acidin 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。第二个项目将集中在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）的氧化重排螺咪唑酮。建议调查这一潜在重要反应的范围和局限性。特别是，氮和在C2的咪唑取代基的影响将被研究沿着的作用，周边取代基在C4和C5的立体化学重排的结果。预计该反应将在帕劳'amine、konbu'acidin A、styloguanidine和axinellamine A的合成中发挥关键作用。此外，还计划建立重排对咪唑并[4，5-B]吡啶的适用性，如果成功的话，重排产物可能作为关键中间体用于制备几种单体的oroidin衍生的生物碱，如phakellin，saxitoxin和quarararelline。最后的项目将应用在该计划的探索阶段开发的方法，以一些二聚体oroidin衍生的海洋生物碱（i）ageliferin，（ii）axinellamine A，（iii）帕劳'amine，（iv）konbu'acidin A和（v）styloguanidine。

项目成果

Total synthesis and cytotoxicity of Leucetta alkaloids.

• DOI: 10.1016/j.bmc.2017.01.024
• 发表时间: 2017-03-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Koswatta PB;Kasiri S;Das JK;Bhan A;Lima HM;Garcia-Barboza B;Khatibi NN;Yousufuddin M;Mandal SS;Lovely CJ
• 通讯作者: Lovely CJ

Total synthesis of 7'-desmethylkealiiquinone, 4'-desmethoxykealiiquinone, and 2-deoxykealiiquinone.

• DOI: 10.1021/jo4027337
• 发表时间: 2014-03-21
• 期刊: The Journal of organic chemistry
• 作者: Lima HM;Sivappa R;Yousufuddin M;Lovely CJ
• 通讯作者: Lovely CJ

Diversity-oriented approach to pyrrole-imidazole alkaloid frameworks.

吡咯 - 咪唑生物碱框架的多样性方法。

• DOI: 10.1021/ol200067e
• 发表时间: 2011-03-18
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Bhandari, Manojkumar R.;Yousufuddin, Muhammed;Lovely, Carl J.
• 通讯作者: Lovely, Carl J.

Total syntheses of kealiinines A-C.

• DOI: 10.1021/ol302958e
• 发表时间: 2012-12-21
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Das, Jayanta;Koswatta, Panduka B.;Jones, J. Daniel;Yousufuddin, Muhammed;Lovely, Carl J.
• 通讯作者: Lovely, Carl J.

Preparation and Diels-Alder reactions of 1'-heterosubsituted vinylimidazoles.

1-杂取代乙烯基咪唑的制备和 Diels-Alder 反应。

• DOI: 10.1016/j.tetlet.2015.01.190
• 发表时间: 2015
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Ray,Abhisek;Mukherjee,Sabuj;Das,Jayanta;Bhandari,ManojK;Du,Hongwang;Yousufuddin,Muhammed;Lovely,CarlJ
• 通讯作者: Lovely,CarlJ