Synthesis of Pyrrole-Imidazole Alkaloids

吡咯咪唑生物碱的合成

基本信息

批准号：
7494188
负责人：
PHIL S BARAN
金额：
$ 13.98万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2010-04-30
项目状态：
已结题

项目摘要

Some of the most promising leads for powerful therapeutic agents have arisen from marine sponges. Aside from providing an environmentally friendly avenue to these compounds, chemical synthesis enables the development of analogs with improved bioactivity and regularly leads to fundamental discoveries in chemistry, biology and medicine. The pyrrole-imidazole alkaloids are a diverse family of marine sponge derived natural products with reported bioactivity including: anticancer, antibiotic, antiviral, antihistiminic, antimuscarinic and potential leads for cystic fibrosis and Alzheimer's disease. This proposal encompasses both the chemical and biological aspects of several members of this natural product class, including its most complex members. Thus, enantioselective syntheses of sceptrin, oxysceptrin, nakamuric acid, ageliferin, nagelamide, axinellamine, massadine, and palau'amine are proposed. The overall aim is to provide useful amounts of these natural products using concise synthetic sequences and biomimetic cascade reactions. Upon achieving practical syntheses of these compounds we will study their structure activity relationships and mechanism of action through collaborations. The biological studies will be carried out in collaboration with leaders in the fields of cancer (Professor Bob Abraham, Burnham Institute), viral (Professor Raymond Schinazi, Emory), neuropharmacology (Professor George Siggins, Scripps) and physiology (Dr. Lee Sweeny, Penn State Med. Center).

一些最有希望的强效治疗药物的线索来自于海洋生物海绵。除了为这些化合物提供环保途径之外，化学合成能够开发具有改善的生物活性的类似物，并经常导致化学、生物学和医学领域的基本发现。吡咯-咪唑生物碱是据报告具有生物活性的多种海洋海绵衍生天然产物，包括：抗癌、抗生素、抗病毒、抗组胺、抗毒蕈碱和囊性纤维化的潜在线索和阿尔茨海默病。该提案涵盖了化学和生物方面该天然产品类别的几个成员，包括其最复杂的成员。因此， sceptrin、oxyseptrin、nakamuric Acid、ageliferin、nagelamide 的对映选择性合成建议使用axinellamine、massadine 和palau'amine。总体目标是提供有用的使用简洁的合成序列和仿生级联来提取大量的这些天然产物反应。在实现这些化合物的实际合成后，我们将研究它们的结构通过协作的活动关系和作用机制。生物学研究将是与癌症领域的领导者（Burnham 的 Bob Abraham 教授）合作进行研究所）、病毒学（Raymond Schinazi 教授，埃默里大学）、神经药理学（George 教授 Siggins、Scripps）和生理学（Lee Sweeny 博士，宾夕法尼亚州立大学医学中心）。