化学学报 ›› 2004, Vol. 62 ›› Issue (7): 703-712. 上一篇    下一篇

研究论文

甲氨蝶呤与一氧化氮供体或一氧化氮合酶抑制剂组合物的合成

姚其正1, 张志祥1, PFLEIDERER Wolfgang2, 郑国海3, 徐进宜1, 唐锋1, 华维一1   

  1. 1. 中国药科大学药学院, 南京, 210009;
    2. Department of Chemistry, University of Konstanz, P.O.Box 5560, D-78457 Konstanz, Germany;
    3. 中国人民解放军第105医院, 合肥, 230031
  • 收稿日期:2003-08-16 修回日期:2003-10-10 出版日期:2004-04-14 发布日期:2014-02-18
  • 通讯作者: 姚其正,E-mail:qz-yao@yahoo.com. E-mail:qz-yao@yahoo.com
  • 基金资助:
    国家自然科学基金(No.39870882)资助项目.

Synthesis of Methotrexates Combined with Nitric Oxide Donor or Nitric Oxide Synthase Inhibitor

YAO Qi-Zheng1, ZHANG Zhi-Xiang1, PFLEIDERER Wolfgang2, ZHENG Guo-Hai3, XU Jin-Yi1, TANG Feng1, HUA Wei-Yi1   

  1. 1. School of Pharmacy, China Pharmaceutical University, Nanjing 210009;
    2. Department of Chemistry, University of Konstanz, P. O. Box 5560, D-78457 Konstanz, Germany;
    3. 105th Hospital, the People's Liberation Army, Hefei 230031
  • Received:2003-08-16 Revised:2003-10-10 Online:2004-04-14 Published:2014-02-18

一氧化氮(nitric oxide, NO)在肿瘤病理生理过程中产生多方面的生化作用,诸如引起的某些核苷酸碱基的羟基化,参与免疫系统清除肿瘤细胞,促进肿瘤细胞凋亡和调节血管生成等.在此基础上,首次提出将NO供体(NO donor)或一氧化氮合酶(nitric oxide synthase, NOS)抑制剂分别连接到甲氨蝶呤(methotrexate, MTX, MTX本身就是NOS抑制剂)的α或γ位羧基上的设想,设计并合成出:(1) MTX-NO供体(3-羟甲基-4-苯基-1,2,5-二唑-2-氧化物,属于Furoxan 衍生物,缩写为FU): 1a (MTX-α-FU), 2a (MTX-γ-FU);(2) MTX-NOS抑制剂(L-Nω-硝基精氨酸或L-Nω-硝基精氨酸甲酯): 1b (MTX-α-L-Nω-NO2-Arg), 2b (MTX-γ-L-Nω-NO2-Arg), 1c (MTX-α-L-Nω-NO2-Arg-OMe), 2c (MTX-γ-L-Nω-NO2-Arg-OMe).在生物活性测试中,我们选择耐MTX细胞株K-562(慢性粒细胞性白血病急性病变细胞株),进行抗肿瘤活性测试,得到以下结果:(1) 脂溶性差的MTX衍生物1b, 2b抗肿瘤活性低于MTX,其它1a, 2a; 1c, 2c均优于MTX;(2) 连接有NO供体的MTX明显增强了MTX衍生物的抗肿瘤活性;(3) MTX中谷氨酸γ位组合物抗肿瘤活性均高于相应的α位异构体的活性.以上初步结果,将对进一步研究NO抗肿瘤作用以及新的抗肿瘤药物设计提供新的思路,对肿瘤临床化疗也有一定的参考价值.

关键词: 甲氨蝶呤衍生物, 一氧化氮供体, 一氧化氮合酶抑制剂, 抗肿瘤

Nitric oxide (NO) is an important messenger molecule with multiple biological activities in blood vessels, neurons, macrophages, and other cells. NO is a ubiquitous modulator of both physiological and pathophysiological functions that is generated endogenous by the enzyme nitric oxide synthase of which 3 isoforms are known. NO appears critical for the tumoricidal activity of the immune system, modulates apoptosis of tumors and has other effects on tumor biology, including angiogenesis and metestasis. On the basis of the multifaceted roles of NO in cancer and the fact that methotrexate (MTX) is a very active anticancer drug and one of the nitric oxide synthase (NOS) inhibitors, new conjugates of MTX with NO donors or NOS inhibitors have been synthesized hoping that MTX functions as an active carrier. Methotrexate was coupled with 3-hydroxymethyl-4-phenyl-1,2,5-oxadiazole-N-oxide (an NO donor) at the α- and γ-carboxyl groups to give 1a and 2a. Analogously reacted MTX with N-nitro-L-arginine to 1b and 2b and with N-nitro-L-arginine methyl ester to 1c and 2c. In the biological assay the MTX-conjugates were tested against K-562 human leukemia cells which are resistant to MTX. Increasing in lipiphobicity as shown by 1b and 2b reduced the activity of K-562 cell-killing in culture and contrarily, compounds 1a, 2a, 1c and 2c inhibited the growth of K-562 cells superior to MTX due to their higher lipiphilicity. In general, the MTX-NO-donors enhance tumoricidal activity significantly and the γ-substituted conjugates are more effective than the α-isomers.

Key words: methotrexate derivatives, nitric oxide donor, inhibitor of nitric oxide synthase, antineoplastic