Synthesis of Pyrrole-Imidazole Alkaloids

描述（由申请人提供）：一些最有希望的强力治疗剂的线索来自海洋海绵。除了为这些化合物提供一种环境友好的途径外，化学合成还可以开发具有更好生物活性的类似物，并经常导致化学，生物学和医学的基础发现。吡咯-咪唑类生物碱是一种从海绵中提取的天然产物，具有抗癌、抗生素、抗病毒、抗组氨酸、抗蛇毒碱等生物活性，并可能导致囊性纤维化和阿尔茨海默病。该提案涵盖了该天然产物类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，提出了对映选择性合成sceptrin， oxysceptrin, nakamuric acid, agelifin, nagelamide, axinellamine， massadine和palau’amine。总的目标是利用简明的合成序列和仿生级联反应提供这些天然产物的有用量。在实现这些化合物的实际合成后，我们将通过协作研究它们的结构、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（埃默里大学的Raymond Schinazi教授）、神经药理学（Scripps大学的George Siggins教授）和生理学（宾夕法尼亚州立医学中心的Lee Sweeny博士）领域的领导者合作进行。

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).