Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
J Med Chem. 2018 Mar 22;61(6):2166-2210. doi: 10.1021/acs.jmedchem.7b00315. Epub 2017 Sep 8.
The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p K of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
gem-二甲基部分是许多具有临床意义的天然产物中经常存在的结构特征，包括但不限于紫杉烷、埃坡霉素、他汀类药物、类视黄醇、二萜/三萜、新诺糖去氧糖和β-内酰胺、大环内酯和氨基香豆素衍生的抗生素。受这一久经考验的部分的启发，药物化学家广泛探索了其在开发生物活性分子中的用途，因为有可能 (1) 通过范德华相互作用和对生物活性构象的有利熵限制来增加靶标结合、效力和选择性，(2) 减轻毒性，(3) 获得更好的 DMPK 特征，(4) 调节附近功能的 pK，(5) 在单甲基取代手性中心诱导对称，以及 (6) 在基于 o-羟基氢化肉桂酸的前药设计中应用 Thorpe-Ingold 构象效应。本文的目的是说明药物化学家如何巧妙地利用 gem-二甲基基团获得具有临床用途的药物，并提供合成方法来引入 gem-二甲基基团。
