有机化学 ›› 2016, Vol. 36 ›› Issue (3): 490-501.DOI: 10.6023/cjoc201510006 上一篇    下一篇

综述与进展

磺酰基在药物分子设计中的应用

赵飞a,b, 王江a, 丁晓a, 舒双杰a, 柳红a   

  1. a 中国科学院上海药物研究所 受体结构与功能重点实验室 上海 201203;
    b 成都大学 四川抗菌素工业研究所抗生素研究与再评价四川省重点实验室 成都 610052
  • 收稿日期:2015-10-09 修回日期:2015-11-13 发布日期:2015-12-04
  • 通讯作者: 柳红 E-mail:hliu@mail.shcnc.ac.cn
  • 基金资助:

    国家自然科学基金(No. 21372235)资助项目.

Application of Sulfonyl in Drug Design

Zhao Feia,b, Wang Jianga, Ding Xiaoa, Shu Shuangjiea, Liu Honga   

  1. a Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203;
    b Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052
  • Received:2015-10-09 Revised:2015-11-13 Published:2015-12-04
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21372235).

含磺酰基药物在临床治疗药物中占有相当比重, 将磺酰基引入到小分子中是药物分子结构改造的重要策略之一, 综述了磺酰基在药物分子设计中的应用. 就结构而言, 磺酰基和羰基、羧基、四氮唑、磷酸基具有相似的大小和电荷分布, 可以作为它们的生物电子等排体而引入到小分子中, 从而保持或增强小分子的生物活性; 磺酰基具有独特的物理化学性质, 磺酰基的引入可以调节小分子的溶解性和酸碱性; 磺酰基能提供两个氢键受体, 合理的引入磺酰基可以通过增加小分子和作用靶标的氢键相互作用而提高化合物的生物活性; 磺酰基结构较稳定, 引入磺酰基可以通过阻断易代谢位点而提高药物代谢稳定性, 延长其作用时间, 提高其生物利用度, 从而改善小分子的药代动力学性质; 磺酰基属于极性基团, 磺酰基的引入还可以增加小分子的极性从而降低hERG毒性.

关键词: 磺酰基, 药物设计, 结构优化

Sulfonyl-containing compounds comprise a substantial proportion in the therapeutic drugs. It is an important strategy to introduce sulfonyl group into the small molecules for structure-based medicinal chemistry, the application of sulfonyl group in drug design is reviewed in this paper. Structurally, sulfonyl group has similar properties in molecular size and charge distribution with carbonyl, carboxyl, tetrazolium and phosphate group, so it can be introduced into the drug molecules as their bioisostere in order to remain or improve activity. Sulfonyl group possesses unique physicochemical properties, and the introduction of sulfonyl group can also modulate the solubility and acid-base property of the drug molecules. Sulfonyl group can offer two hydrogen-bond receptors, and reasonable introduction of sulfonyl group can enhance the binding affinity of the drug molecules with the targeted proteins to improve activity through hydrogen bond interactions. What's more, sulfonyl group is relatively stable in terms of structure, the introduction of sulfonyl group can increase the metabolic stability of drugs to prolong the duration of action by blocking metabolically labile sites, improve the pharmacokinetic properties of the drug molecules to elevate the bioavailability. Sulfonyl group belongs to polar groups, which can also increase the polarity of the drug molecules to diminish hERG activity.

Key words: sulfonyl, drug design, lead optimization