Synthetic and biological investigations of 2-aminoimidazole derived natural produ

描述（由申请人提供）：本申请的目的是开发经证实的含多环胍的药效学核心结构的简化方法。几个炔丙基氰胺或炔丙基胍环化反应，在我们的实验室开发将部署了解独特的生物活性naamidine A和NA 22598。通过表征这些天然产物的作用模式，我们将创建工具，以进一步了解通常与癌症相关的信号通路。了解纳脒A与ERK 1/2的分子结合将为开发新的和独特的治疗方法奠定基础，因为变构在激酶信号传导中的作用是一个新兴的治疗领域。如果NA 22598 A1是MMP抑制剂，则其将代表药效团设计的重要进展，以抑制用于治疗多种癌症（包括胃癌和胰腺癌、多发性骨髓瘤和非小细胞肺癌）的这种高度珍贵的靶标。了解到这些小分子将成为研究与癌症相关的信号传导过程的强大工具，我们致力于将其公开，以帮助我们实验室范围以外的研究。 公共卫生相关性：本申请的目的是开发新的化学物质，以获得重要的和医学相关的天然产品结构。这种化学允许概念上的新方法，以富氮杂环准备更好的人类健康。具体来说，这种化学将被部署来了解两种能够选择性调节癌症信号通路的天然产物的生物学作用模式。

DESCRIPTION (provided by applicant): The purpose of this application is to develop streamlined approaches to proven polyclic guanidine containing pharmacopcore structures. Several propargylcyanamide or propargylguanidine cyclization reactions developed in our laboratory will be deployed to understand the unique biological activities of naamidine A and NA22598. By characterizing the mode of action of these natural products we will create tools to further our understanding of signaling pathways commonly associated with cancer. Understanding the molecular binding of naamidine A to ERK 1/2, will create the foundation for the development of new and unique therapeutics as the role of allostery in kinase signaling is an emerging therapeutic area. If NA22598A1 is an MMP inhibitor it would represent an important advance in pharmacophore design to inhibit this highly prized target for the treatment of numerous cancers including gastric and pancreatic carcinomas, multiple myeloma and non-small cell lung cancer. With the understanding that these small molecules will be powerful tools to study signaling processes associated with cancer, we are committed to their public availability to aid in studies outside the scope of our laboratory. PUBLIC HEALTH RELEVANCE: The purpose of this application is to develop new chemistry to access important and medicinally relevant natural product architectures. This chemistry permits conceptually new approaches to nitrogen rich heterocycles poised to better human health. Specifically, this chemistry will be deployed to understand the biological mode of action of two natural products capable of selectively modulating cancer-signaling pathways.