Synthetic and biological investigations of 2-aminoimidazole derived natural produ

2-氨基咪唑衍生天然产物的合成和生物学研究

基本信息

批准号：
8136414
负责人：
Ryan Edward Looper
金额：
$ 2.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136414
关键词：
Aldehydes Alkaloids Alkynes Allosteric Regulation Amines Anchorage-Independent Growth Architecture Area Binding Biological Biological Factors Biological Process Cells Chemistry Commit Core Assembly Cyanamide Cyclization Development Extracellular Signal Regulated Kinases Family Foundations Guanidines Health Human In Vitro Investigation Ions Laboratories Malignant Neoplasms Marines Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Metalloproteases Methodology Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Mitotic Molecular Molecular Target Multiple Myeloma Nitrogen Non-Small-Cell Lung Carcinoma Pancreatic carcinoma Phosphotransferases Porifera Positioning Attribute Preparation Prize Reaction Reagent Research Role Route Saxitoxin Signal Pathway Signal Transduction Stomach Structure Suspension substance Suspensions Therapeutic analog base batzelladine D computerized data processing design improved in vivo inhibitor/antagonist kinase inhibitor metalloenzyme naamidine A novel strategies pharmacophore pre-clinical propargylamine public health relevance skeletal small molecule tool

项目摘要

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.

描述（由申请人提供）：本申请的目的是开发经过验证的含有多环胍的药效核心结构的简化方法。我们实验室开发的几种炔丙基氰酰胺或炔丙基胍环化反应将用于了解 naamidine A 和 NA22598 的独特生物活性。通过表征这些天然产物的作用模式，我们将创建工具来进一步了解通常与癌症相关的信号通路。了解 naamidine A 与 ERK 1/2 的分子结合将为开发新的独特疗法奠定基础，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 NA22598A1 是一种 MMP 抑制剂，那么它将代表药效基团设计的重要进步，以抑制这一高度珍贵的靶标，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。我们认识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，因此我们致力于向公众提供这些小分子，以帮助我们实验室范围之外的研究。公共卫生相关性：该应用的目的是开发新的化学物质，以获取重要且与医学相关的天然产物结构。这种化学方法在概念上允许采用新的方法来制备富氮杂环化合物，从而改善人类健康。具体来说，这种化学反应将用于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。