Divergent C-H Functionalizations Directed by Sulfonamide Pharmacophores: Late-Stage Diversification as a Tool for Drug Discovery
Divergent C-H Functionalizations Directed by Sulfonamide Pharmacophores: Late-Stage Diversification as a Tool for Drug Discovery
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DOI：
10.1021/ja201708f
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发表时间：
2011-05-11
影响因子：
15
通讯作者：
Yu, Jin-Quan
中科院分区：
文献类型：
--
作者：
Dai, Hui-Xiong;Stepan, Antonia F.;Yu, Jin-Quan
现代药物的发现取决于先导化合物的鉴定和类似物的快速合成。使用共同的药效团来指导先导化合物的多重和不同的C-H官能化是特别有吸引力的方法。在本文中，我们通过磺胺类药物的不同C-H官能化证明了后期多样化的可行性，磺胺类药物是目前市场上近200种药物中发现的一类重要药效团，包括非甾体抗炎药塞来昔布。我们开发了一组六种不同的磺酰胺C-H官能化反应（烯化、芳基化、烷基化、卤化、羧基化和羰基化），每种反应都代表了进一步多样化以获得大量类似物的独特方法。然后，我们进行了后期，位点选择性多样化的磺胺类药物候选人含有多个潜在的反应性C-H键，直接合成新的塞来昔布类似物作为潜在的环加氧酶-II（考克斯-2）特异性抑制剂。与最近开发的其他实用导向基团，如CONHOMe和CONHC 6F5，磺酰胺导向基团表明，在不对称催化中建立的辅助方法在开发广泛有用的C-H活化反应中同样有效。
Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC6F5, sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions.