Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (2): 776-787.DOI: 10.6023/cjoc202007006 Previous Articles     Next Articles



丛婧a, 方芳a, 薛良敏a, 王锰a, 田超a, 王孝伟a, 刘俊义a,b, 张志丽a,*()   

  1. a 北京大学药学院化学生物学系 北京 100191
    b 北京大学天然药物及仿生药物国家重点实验室 北京 100191
  • 收稿日期:2020-07-02 修回日期:2020-09-17 发布日期:2020-10-22
  • 通讯作者: 张志丽
  • 作者简介:
    * Corresponding author. E-mail:
  • 基金资助:

Synthesis and Antitumor Activity of Novel Pyrimidine Monocyclic Nonclassical Antifolates

Jing Conga, Fang Fanga, Liangmin Xuea, Meng Wanga, Chao Tiana, Xiaowei Wanga, Junyi Liua,b, Zhili Zhanga,*()   

  1. a Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191
    b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191
  • Received:2020-07-02 Revised:2020-09-17 Published:2020-10-22
  • Contact: Zhili Zhang
  • Supported by:
    the National Natural Science Foundation of China(21172014)

Regarding the nonclassical antifolates 6-(4'-methylphenethyl)-5-chloroacetyl-5,6,7,8-tetrahydropyrido[3,2-d]pyri- midine (wm-8.2) as the lead compound, in order to improve molecular flexibility and simplify molecular structure, two series of compounds were designed and synthesized according to the 6-H and 6-methyl group. And the effects of carbon chain length and aromatic heterocyclic side chain on antitumor activity were investgated. Besides, the activities of key intermediates with molecular skeleton of folic acid inhibitor were measured to study the effect of the chloroacetyl group at N(5) position. Structures of 36 target compounds and key intermediates were confirmed by 1H NMR, 13C NMR and MS. The biological activity results showed that 6-methyl-2,4-diamino-5-(N-(4-methylphenyl)propyl-N-(2-chloroacetyl))aminopyrimidine (6b-3), which had three-carbon bridge and p-methylbenzene ring side chain, exhibited the best inhibition activities against HL-60, A549 and HCT116 cells with IC50 values as 0.25, 0.83 and 0.63 μmol?L –1 respectively. 6-Methyl-2,4-diamino-5-(N-(4-methylphenyl)- propyl)aminopyrimidine (5b-3), the key intermediate of 6b-3, showed excellent dihydrofolate reductase inhibitory activity. Molecular docking studies further explored the structure-activity relationship and possible causes of the difference inhibitory activity against dihydrofolate reductase.

Key words: nonclassical antifolate, novel pyrimidine monocyclic derivative, antitumor activity, dihydrofolate reductase inhibitory activity, molecular docking