Synthesis of Pyrrole-Imidazole Alkaloids

描述（由申请人提供）：一些最有希望的强效治疗剂的先导物来自海绵。除了为这些化合物提供环境友好的途径外，化学合成还可以开发具有改善生物活性的类似物，并经常导致化学，生物学和医学的基本发现。吡咯-咪唑生物碱是海绵衍生的天然产物的不同家族，具有报道的生物活性，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病的潜在先导物。该提案涵盖了这一天然产物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，对映体选择性合成的节苷脂，oxyceptrin，nakamuric酸，ageliferin，nagelamide，axinellamine，massadine，和帕劳'amine的建议。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（埃默里大学的Raymond Schinazi教授）、神经药理学（斯克里普斯大学的乔治Siggins教授）和生理学（宾夕法尼亚州立大学医学中心的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).