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已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丙基氰胺或丙基胍环化反应来了解萘脒A和NA22598的独特生物活性。通过描述这些天然产物的作用模式，我们将创造工具来进一步了解通常与癌症相关的信号通路。由于变构在激酶信号传导中的作用是一个新兴的治疗领域，因此了解naamidine A与erk1 /2的分子结合将为开发新的独特治疗方法奠定基础。如果NA22598A1是一种MMP抑制剂，那么它将代表药效团设计的重要进展，可以抑制这一高度珍贵的靶点，用于治疗包括胃癌、胰腺癌、多发性骨髓瘤和非小细胞肺癌在内的许多癌症。认识到这些小分子将成为研究与癌症相关的信号过程的有力工具，我们致力于将它们的公开可用性用于我们实验室范围之外的研究。

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.