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

• 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
• 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

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精简的方法，以含有药物孔结构的经过验证的多环丁。将在我们的实验室中开发的几种丙酰胺或propgylguanidine环化反应，以了解Naamidine A和NA22598的独特生物学活性。通过表征这些天然产品的作用方式，我们将创建工具，以进一步了解与癌症通常相关的信号通路。理解拿天过胺A与ERK 1/2的分子结合将为发展新独特的治疗剂的发展创造基础，因为变构酶在激酶信号中的作用是一个新兴的治疗区域。如果NA22598A1是MMP抑制剂，它将代表药效团设计中的重要进步，以抑制这一高度评价的靶标，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众多癌症。有了了解，这些小分子将是研究与癌症相关的信号传导过程的强大工具，我们致力于他们的公众可用性，以帮助在实验室范围之外进行研究。 公共卫生相关性：本申请的目的是开发新的化学反应以获取重要且与药物相关的自然产品架构。这种化学允许从概念上讲，新的方法可以使富含氮的异环体有望改善人类健康。具体而言，该化学将被部署，以了解两种能够选择性调节癌症信号途径的天然产品的生物学作用方式。