Synthesis of Pyrrole-Imidazole Alkaloids

吡咯咪唑生物碱的合成

基本信息

批准号：
7616104
负责人：
PHIL S BARAN
金额：
$ 28.22万
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

DESCRIPTION (provided by applicant): 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).

描述（由申请人提供）：一些最有希望的强效治疗剂先导化合物来自海绵。除了为这些化合物提供环境友好的途径之外，化学合成还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础发现。吡咯-咪唑生物碱是一个多样化的海绵衍生天然产物家族，据报道其生物活性包括：抗癌、抗生素、抗病毒、抗组胺、抗毒蕈碱以及囊性纤维化和阿尔茨海默氏病的潜在线索。该提案涵盖了该天然产品类别的几个成员的化学和生物学方面，包括其最复杂的成员。因此，提出了sceptrin、oxysceptrin、nakamuric Acid、ageliferin、nagelamide、axinellamine、massadine和palau'amine的对映选择性合成。总体目标是使用简洁的合成序列和仿生级联反应提供有用量的这些天然产物。在实现这些化合物的实际合成后，我们将通过合作研究它们的结构活性关系和作用机制。生物学研究将与癌症（伯纳姆研究所的 Bob Abraham 教授）、病毒学（埃默里大学的 Raymond Schinazi 教授）、神经药理学（斯克里普斯的 George Siggins 教授）和生理学（斯克里普斯大学的 Lee Sweeny 博士）等领域的领导者合作进行。宾夕法尼亚州立大学医学中心）。