DESIGN AND SYNTHESIS OF SELECTIVE KINASE INHIBITORS

描述：PI报告细胞信号中断 通过蛋白激酶（PK）功能障碍的转导与 几种疾病状态的发作，包括：类风湿性关节炎，全身性 红斑狼疮、糖尿病和阿尔茨海默病。 他指出 虽然PK抑制是化疗的逻辑目标， 由于许多PK同工酶之间的结构同源性， 开发特异性的、因此在治疗上有用的抑制剂。 它 报告指出，在下列领域取得了一些具体成果： 吲哚并咔唑，因此原型天然存在的同系物 Staurosporine（1）和K252 a（2）一直是相当多的焦点， research. PI指出，该提案描述了：（A）初步 研究，其中一个简洁的合成2已经实现（十一 合成操作，最长的线性序列的七个步骤）;和（B） 将该化学方法应用于1和2的类似物的合成（即， 3）。 据报道，后者类似物被靶向用作探针 在耶鲁大学开发的中国卵巢细胞试验中， 可以利用组合肽文库中的试剂来筛选 广泛的PK同工酶特异性类似物。 值得注意的是，最后， 对K252 a的努力导致了新类卡宾的开发 反应，建议进一步研究。

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.