Synthesis of Pyrrole-Imidazole Alkaloids

描述(由申请人提供)：一些最有希望成为有效治疗剂的线索来自海洋海绵。除了为这些化合物提供环境友好的途径外，化学合成还使开发具有更高生物活性的类似物成为可能，并经常导致化学、生物和医学方面的基础发现。吡咯咪唑生物碱是一类从海绵中提取的多种天然产物，据报道具有生物活性，包括：抗癌、抗生素、抗病毒、抗组织、抗肌肉瘤以及可能导致囊性纤维化和阿尔茨海默病。该提案涵盖了这一天然产品类别的几个成员的化学和生物方面，包括其最复杂的成员。因此，我们提出了对映体选择性的合成方法，包括麦角苷、氧化麦角苷、那卡尿酸、洋参皂苷、橙皮酰胺、青蒿胺、马萨定和帕劳胺。总体目标是利用简明的合成序列和仿生级联反应提供有用数量的这些天然产物。在实现这些化合物的实际合成后，我们将通过合作来研究它们的结构、活性、关系和作用机理。生物学研究将与以下领域的领导人合作进行：癌症(伯纳姆研究所鲍勃·亚伯拉罕教授)、病毒(雷蒙德·斯奇纳齐教授，埃默里)、神经药理学(乔治·西金斯教授，斯克里普斯)和生理学(宾夕法尼亚州立大学李·斯威尼博士)。居中)。

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).