Synthesis of Pyrrole-Imidazole Alkaloids

说明（申请人提供）：摘要不可否认的是，大多数小分子药物是天然产物或受天然产物支架的启发。全合成通过采购天然产物（和类似物）和创造新的方法来实现未来的合成，极大地促进了这一竞技场。吡咯咪唑类天然产物具有抗肿瘤、抗菌、抗组胺、抗病毒、免疫抑制和细胞运动抑制等多种生物活性。此外，这种天然产物家族的多环成员的复杂结构促使创造新的化学方法。该提案包括化学合成的其余成员的这一类，阐述了一种新的银（II）-氧化方法，和许多合作努力，广泛调查这些分子的生物起源和结构的复杂性。还将对一类新的二聚海洋天然产品：吲哚-咪唑生物碱进行研究。该类化合物与吡咯-咪唑生物碱具有有趣的结构相似性，可以作为化学方法发明和生物学性质研究的类似平台。本文提出的研究广度是由一个广泛的合作网络，包括辉瑞公司，唐娜Blackmond教授（帝国理工学院伦敦），教授马蒂亚斯Kvck（阿尔弗雷德-韦格纳研究所f| r Polar- und Meeresforschung）、Philip威廉姆斯教授（夏威夷大学马诺阿分校）、Paul Hergenrother教授（伊利诺伊大学）和Angel Cipres教授（伯纳姆医学研究所）。 公共卫生相关性：项目叙述本提案旨在利用化学合成制备吡咯-咪唑和吲哚-咪唑生物碱家族的几种天然产物（及其类似物）。化学创新是预期的，通过与相关领域的各种专家的战略合作努力，可能会对医学做出重大贡献。

DESCRIPTION (provided by applicant): Abstract It is undeniable that a majority of small molecule medicinal agents are natural products or are inspired by natural product scaffolds. Total synthesis greatly contributes to this arena via the procurement of natural products (and analogs) and the creation of new methodologies to enable future syntheses. The pyrrole-imidazole class of natural products possesses a wealth of bioactivities including antitumor, antibiotic, antihistaminic, antiviral, immunosuppressant and cell-motility inhibition. Additionally, the complex architectures of the polycyclic members of this natural product family instigate the creation of new chemical methods. This proposal encompasses the chemical syntheses of the remaining members of this class, the elaboration of a novel silver(II)- oxidation methodology, and numerous collaborative efforts to extensively investigate the biogenesis and structural intricacies of these molecules. Research will also be conducted on a new class of dimeric marine natural products: the indole-imidazole alkaloids. This class possesses interesting architectural parallels to the pyrrole-imidazole alkaloids, and can serve as a similar platform for the invention of chemical methods and investigation of biological properties. The breadth of research proposed herein is enabled by an extensive collaboration network that includes Pfizer, Professor Donna Blackmond (Imperial College London), Professor Matthias Kvck (Alfred-Wegener-Institut f|r Polar- und Meeresforschung), Professor Philip Williams (University of Hawaii at Manoa), Professor Paul Hergenrother (University of Illinois), and Professor Angel Cipres (Burnham Institute for Medical Research). PUBLIC HEALTH RELEVANCE: Project Narrative This proposal aims at using chemical synthesis to prepare several natural products (and analogs thereof) of the pyrrole-imidazole and indole-imidazole alkaloid families. Innovations in chemistry are anticipated and substantial contributions to medicine may result through several strategic collaborative efforts with a variety of experts in related fields.