高等学校化学学报 ›› 2019, Vol. 40 ›› Issue (10): 2111-2120.doi: 10.7503/cjcu20190108

• 有机化学 • 上一篇    下一篇

2-位或4-位取代吡啶并嘧啶类非经典叶酸拮抗剂的合成及抗肿瘤活性

方芳1,薛良敏1,丛婧1,田超1,王孝伟1,刘俊义1,2,张志丽1,*()   

  1. 1. 北京大学药学院化学生物学系
    2. 天然药物及仿生药物国家重点实验室, 北京 100191
  • 收稿日期:2019-02-17 出版日期:2019-10-08 发布日期:2019-06-01
  • 通讯作者: 张志丽 E-mail:Lilybmu@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(No.21172014)

Synthesis and Anti-tumor Activity Evaluation of a Series of 2- or 4-Substituted Pyrido[3,2-d]pyrimidines as Nonclassical Antifolates

FANG Fang1,XUE Liangmin1,CONG Jing1,TIAN Chao1,WANG Xiaowei1,LIU Junyi1,2,ZHANG Zhili1,*()   

  1. 1. Department of Chemical Biology, School of Pharmaceutical Sciences
    2. State Key Labroatory of Natural and Biomimetic Drugs, Peking University, Beijing 100191
  • Received:2019-02-17 Online:2019-10-08 Published:2019-06-01
  • Contact: ZHANG Zhili E-mail:Lilybmu@bjmu.edu.cn
  • Supported by:
    † Supported by the National Nature Science Foundation of China(No.21172014)

摘要:

以非经典叶酸拮抗剂2,4-二氨基-6-(4-甲基苯基)乙基吡啶并[3,2-d]嘧啶(wm-5b)及其侧链简化产物2,4-二氨基吡啶并[3,2-d]嘧啶为先导化合物, 选取具有抗肿瘤活性的基团, 通过微波法高效合成了2-位或4-位取代吡啶并嘧啶类非经典叶酸拮抗剂, 研究了2-位及4-位取代基对抗肿瘤活性的影响, 为非经典叶酸拮抗剂的设计合成提供了更多的理论依据. 目标化合物的结构均经核磁共振波谱(NMR)和质谱(MS)确证. 生物活性测定结果表明, 所有目标化合物均具有抗肿瘤活性, 其中, 6-(4-甲基苯基)乙基-4-氨基-2-(3-氯-4-氟苯基)氨基吡啶并[3,2-d]嘧啶(6b)对HL-60细胞的IC50=(4.09±0.48) μmol/L, 对A549细胞的IC50=(17.99±7.20) μmol/L, 而对HCT116细胞的IC50=(14.52±4.74) μmol/L; 部分目标化合物具有二氢叶酸还原酶抑制活性. 此外, 对部分目标化合物和先导物进行了二氢叶酸还原酶晶体结构的分子对接, 对活性结果和构效关系从分子水平上进行解释.

关键词: 非经典叶酸拮抗剂, 吡啶并[3,2-d]嘧啶类衍生物, 抗肿瘤活性, 二氢叶酸还原酶抑制活性

Abstract:

Using compounds 2,4-diamino-6-(4-methylphenethyl)pyrido [3,2-d] pyrimidine(wm-5b) and 2,4-diaminopyrido [3,2-d] pyrimidine as the lead compounds, a series of 2- or 4-substituted pyrido[3,2-d]pyrimidines was synthesized as potential nonclassical antifolates by means of microwave efficiently. Besides, the effects of different substituted positions which provides more theoretical basis for the design and synthesis of nonclassical antifolates can be explored. The target compounds were characterized by 1H NMR, 13C NMR as well as MS. All compounds showed certain anti-tumor activity[compound 6b, the most potent one, has IC50 values of (4.09±0.48) μmol/L against HL-60 cells, IC50 value of (17.99±7.20) μmol/L against A549 cells and IC50 value of (14.52±4.74) μmol/L against HCT116 cells], while some of them exhibited certain inhibition of recombinant human DHFR(rhDHFR). Some compounds and the lead were applied to molecular docking of the crystal structure of dihydrofolate reductase, and the activity results and structure-activity relationship were explained at the molecular level.

Key words: Nonclassical antifolate, Pyrido[3,2-d]pyrimidine derivative, Antitumor activity, Inhibition of dihydrofolate reductase

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