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有药芯结构的多环胍的简化方法。我们将利用实验室开发的几个炔丙基三聚氰胺或炔丙基胍环化反应来了解NA22598和NA22598的独特生物活性。通过表征这些天然产物的作用模式，我们将创造工具来加深我们对通常与癌症相关的信号通路的理解。了解NAK A与ERK 1/2的分子结合，将为开发新的独特的治疗药物奠定基础，因为变构在激酶信号转导中的作用是一个新兴的治疗领域。如果NA22598A1是一种基质金属蛋白酶抑制剂，它将代表着在药效团设计方面的重要进展，以抑制这一用于治疗包括胃癌和胰腺癌、多发性骨髓瘤和非小细胞肺癌在内的多种癌症的高度宝贵的靶点。了解到这些小分子将成为研究与癌症相关的信号过程的强大工具，我们致力于向公众提供它们，以帮助我们实验室范围之外的研究。 公共卫生相关性：这项应用的目的是开发新的化学物质，以获得重要的和医学上相关的天然产品架构。这种化学从概念上允许对富含氮的杂环采取新的方法，以改善人类健康。具体地说，这种化学将被用来理解两种能够选择性地调节癌症信号通路的天然产品的生物作用模式。

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.