Department of Ophthalmology, Columbia University Medical Center, 635 W 165th St., New York, NY, 10032 (USA).
Angew Chem Int Ed Engl. 2013 Nov 18;52(47):12256-67. doi: 10.1002/anie.201303207. Epub 2013 Oct 22.
The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of CH to CMe improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp(2) )H and C(sp(3) )H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new CH methylation reactions.
甲基是小分子药物中最常见的碳片段之一。这种最简单的烷基片段出现在超过 67%的 2011 年最畅销药物中，并且可以调节分子的生物和物理性质。本综述重点介绍了所谓的结合效力的“神奇甲基效应”，其中看似平凡的 CH 到 CMe 的变化使药物候选物的 IC50 值提高了 100 多倍。这一讨论之后是对允许直接甲基化 C(sp(2) )H 和 C(sp(3) )H 键的合成化学最新进展的调查。我们希望本文中呈现的微不足道的甲基对药物发现的相关性将激励有关新的 CH 甲基化反应的报告。
