DESIGN AND SYNTHESIS OF SELECTIVE KINASE INHIBITORS

描述：PI报告说手机信号中断 通过蛋白激酶(PK)功能障碍进行的信号转导与 出现几种疾病状态，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抑制是化疗的合理靶点 干预，阻碍了许多PK同工酶之间的结构同源性 开发特定的、因此在治疗上有用的抑制剂。它 表明在以下领域已经取得了一些特定性 吲哚咔唑，因此是典型的自然发生的同系物 星形孢菌素(1)和K252a(2)一直是相当多的 研究。国际和平倡议说，这项提案描述了：(A)初步 已实现2的简明合成的研究(11 合成运算，最长的七步线性序列)；以及(B) 该化学在合成1及其类似物(即， 3)。据报道，后一种类似物被用作探针 在耶鲁大学建立的中国仓鼠卵巢细胞分析中 组合多肽库中的试剂可用于筛选 广泛的PK同工酶特异性类似物。值得注意的是，最后， 对K252a的努力导致了新的类卡宾的开发 建议进行进一步研究的反应。

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.