DESIGN AND SYNTHESIS OF SELECTIVE KINASE INHIBITORS

选择性激酶抑制剂的设计与合成

• 批准号: 2883041
• 负责人: JOHN L WOOD
• 金额: $ 22.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2883041
• 关键词: CHO cells; autoimmune disorder; carbazoles; drug design /synthesis /production; enzyme inhibitors; isozymes; peptide library; protein kinase; staurosporine

DESCRIPTION: The PI reports that the disruption of cellular signal transduction via protein kinase (PK) malfunction has been related to the onset of several disease states, including: rheumatoid arthritis, systemic lupus erythematosis, diabetes mellitus, and Alzheimer's disease. He notes that while PK inhibition is a logical target for chemotherapeutic intervention, the structural homology among the many PK isozymes has impeded the development of specific and hence therapeutically useful inhibitors. It is indicated that some specificity has been achieved in the area of indolocarbazoles and hence the archetypal naturally occurring congeners staurosporine (1) and K252a (2) have been the focus of considerable research. The PI states that this proposal describes: (A) preliminary studies in which a concise synthesis of 2 has been achieved (eleven synthetic operations, longest linear sequence of seven steps); and (B) the application of this chemistry to the synthesis of 1 and analogs of 2 (i.e., 3). It is reported that the latter analogs are targeted for use as probes in a Chinese Hamster Ovary Cell assay developed at Yale and the capping agent in a combinatorial peptide library that can be utilized to screen a wide range of analogs for PK isozyme specificity. It is noted that finally, efforts toward K252a have resulted in the development of novel carbenoid reactions for which further research is proposed.

描述：PI报告了蜂窝信号的中断

项目成果

Rhodium carbenoid-initiated Claisen rearrangement: scope and mechanistic observations.

• DOI: 10.1021/ol990697x
• 发表时间: 1999-07
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: J. Wood;G. Moniz