Hulme Christopher, Lee Yeon-Sun
Division of Medicinal Chemistry & Organic Chemistry, BIO5 Institute, University of Arizona, Tucson, Arizona, USA.
Mol Divers. 2008 Feb;12(1):1-15. doi: 10.1007/s11030-008-9072-1. Epub 2008 Apr 12.
Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a 'drug hunters' quest to discover new leads and a chemical biologists search for effective molecular tools in 'cell perturbation' studies. At the front end of the drug discovery flow chart, the last 5-10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 10(7) derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis.
咪唑并-[1,2-x]杂环是多功能的结构单元，可用于“药物猎手”寻找新线索的探索过程，也可用于化学生物学家在“细胞扰动”研究中寻找有效的分子工具。在药物发现流程图的前端，过去5到10年见证了新的高通量方法的发现，这些方法很快就能在10⁷种衍生物的范围内获取这些化学类型的虚拟库。有趣的是，这些在专利合作条约（PCT）申请中常常被忽视的核心结构出现在几种高效的上市药物中，为药物化学家寻找临床成功画上了句号。这些刚性的化学类型都含有一个桥头氮原子，因此对新分子疗法的发现和开发的影响将不断增加。以下小型综述将简要介绍为以高通量方式制备这些化学类型的阵列而开发的治疗用途、化学方法和自动化技术。合成重点是基于异腈的三组分三中心多组分反应（IMCR），它涵盖了溶液、固相、氟相和微波辅助有机合成。
