SIOC English
有机化学
高级检索

有机化学 >

2013 , Vol. 33 >Issue 02: 332 - 338

DOI: https://doi.org/10.6023/cjoc201208035

研究论文

β-咔啉衍生物的合成和初步抗肿瘤活性研究

  • 郭亮 ,
  • 范文玺 ,
  • 陈雪梅 ,
  • 马芹 ,
  • 曹日晖
展开
  • a 新疆华世丹药物研究有限责任公司 乌鲁木齐 830011;
    b 中山大学化学与化学工程学院 广州 510275

收稿日期: 2012-08-30

  修回日期: 2012-11-01

  网络出版日期: 2012-11-14

基金资助

国家“重大新药创制”科技重大专项(No. 2009ZX09401-007)资助项目.

收起

Synthesis and Antitumor Activities of β-Carboline Derivatives

  • Guo Liang ,
  • Fan Wenxi ,
  • Chen Xuemei ,
  • Ma Qin ,
  • Cao Rihui
Expand
  • a Xinjiang Huashidan Pharmaceutical Research Co., Ltd., Urumqi 830011;
    b School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275

Received date: 2012-08-30

  Revised date: 2012-11-01

  Online published: 2012-11-14

Supported by

Project supported by the National Key Program for New Drug Development (No. 2009ZX09401-007).

Fold

摘要

为了寻找更好的抗肿瘤化合物, 基于前期计算机辅助药物设计结果, 以L-色氨酸和甲醛为原料, 经过Pictet-Spengler缩合和氧化两步反应得到β-咔啉, 再经过N9-烷基化反应和N2-烷基化反应得到一系列新的β-咔啉衍生物. 合成的14个新的β-咔啉衍生物的结构经1H NMR, IR, MS及元素分析确证结构. 利用单晶X射线衍射法测定了化合物5h的晶体结构. 采用MTT法考察其对肿瘤细胞的抑制作用, 实验结果表明化合物5a～5n与先导物4相比具有明显的抗肿瘤活性; 用抑瘤率测定了化合物5e和5h对小鼠Lewis肺癌细胞的抑制作用, 体内试验表明化合物5h具有抗Lewis肺癌作用.

关键词： β-咔啉; 合成; 抗肿瘤活性; 构效关系

本文引用格式

郭亮 , 范文玺 , 陈雪梅 , 马芹 , 曹日晖 . β-咔啉衍生物的合成和初步抗肿瘤活性研究[J]. 有机化学, 2013 , 33(02) : 332 -338 . DOI: 10.6023/cjoc201208035

Abstract

In search of more effective antitumor agents, based on the previous results of computer aided drug design. The starting material L-tryptophan reacted with formaldehyde via Pictet-Spengler condensation and followed by oxidation and decarboxylation to afford the intermediate β-carboline. The intermediate was further reacted with halogenated hydrocarbon by N9-alkylation and N2-quaternarization to obtain new β-carboline derivatives. Fourteennovel β-carboline derivatives were synthesized and characterized by 1H NMR, IR, MS and elemental analysis. Compound 5h was further studied by X-ray single crystal diffraction analysis. The antitumor activity of the target compounds was studied by MTT method. The results demonstrated that N2-quaternarized compounds (5a～5n) had more remarkable cytotoxic activities in vitro than 9-phenylpropyl-β-carboline (4). The tumor inhibition rates of the selected compounds 5e and 5h in mice bearing Lewis lung cancer. The compound 9 showed inhibition activity on transplanting-tumor growth of Lewis lung cancer.

Key words： β-carboline; synthesis; antitumor activity; structure-activity relationship

参考文献

[1] Jiao, W.-H.; Gao, H.; Li, C.-Y.; Zhao, F.; Jiang, R.-W.; Wang, Y.; Zhou, G.-X.; Yao, X.-S. J. Nat. Prod. 2010, 73, 167.

[2] Takahashi, Y.; Ishiyama, H.; Kubota, T.; Kobayashi, J. Bioorg. Med. Chem. Lett. 2010, 20, 4100.

[3] Michael, C.; Robert, W. W.; Fil, G.; James, M. C.; Steven, A. B.; Kenner, C. R.; Jacqueline, N. C.; Steven, M. P.; Phil, S. J. Med. Chem. 1982, 25, 1081.

[4] Lin, W.; Xiao, S.-L.; Yang, M. J. Peking Univ. (Health Sci.) 2001, 33, 277 ( in Chinese). (林伟, 肖苏龙, 杨铭, 北京大学学报(医学版), 2001, 33, 277.)

[5] Ishida, J.; Wang, H.-K.; Bastow, K. F.; Hu, C.-Q.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1999, 9, 3319.

[6] Rashid, M. A.; Gustafson, K. R.; Boyd, M. R. J. Nat. Prod. 2001, 64, 1454.

[7] Kuo, P.-C.; Shi, L.-S.; Damu, A. G.; Su, C.-R.; Huang, C.-H.; Ke, C.-H.; Wu, J.-B.; Lin, A.-J.; Bastow, K. F.; Lee, K.-H.; Wu, T.-S. J. Nat. Prod. 2003, 66, 1324.

[8] Rivas, P.; Cassels, B. K.; Morello, A. Comp. Biochem. Physiol., Part C 1999, 122, 27.

[9] Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatima, N.; Chatterjee, R. K. Bioorg. Med. Chem. 1999, 7, 1223.

[10] Xu, G.-Y.; Zhou, Y.; Zuo, G.-L.; Jiang, Y.-J. Chin. J. Org. Chem. 2009, 29, 1593 (in Chinese). (徐广宇, 周伊, 左高磊, 蒋勇军, 有机化学, 2009, 29, 1593.)

[11] Cao, R.-H. Ph.D. Dissertation, Sun Yat-sen University, Guangzhou, 2004 (in Chinese). (曹日晖, 博士论文, 中山大学, 广州, 2004.)

[12] Cao, R.-H.; Peng, W.-L.; Wang, Z.-H.; Xu, A.-L. Curr. Med. Chem. 2007, 14, 479.

[13] Cao, R.-H.; Peng, W.-L.; Chen, H.-X.; Hou, X.-R.; Guan, H.-J.; Ma, Y.; Xu, A.-L. Eur. J. Med. Chem. 2005, 40, 249.

[14] Cao, R.-H.; Chen, H.-X.; Peng, W.-L.; Ma, Y.; Hou, X.-R.; Guan, H.-J.; Liu, X.-D.; Xu, A.-L. Eur. J. Med. Chem. 2005, 40, 991.

[15] Cao, R.-H.; Yi W.; Wu, Q.-F.; Guan, X.-D.; Feng, M.-X.; Ma, C.-M.; Chen, Z.-Y.; Song, H.-C; Peng, W.-L. Bioorg. Med. Chem. Lett. 2008, 18, 6558.

[16] Cao, R.-H.; Guan, X.-D.; Shi, B.-X.; Chen, Z.-Y.; Ren, Z.-H.; Peng, W.-L.; Song, H.-C. Eur. J. Med. Chem. 2010, 45, 2503.

[17] Ma, C.-M.; Cao, R.-H.; Shi, B.-X.; Zhou, X.-T.; Ma, Q.; Sun, J.; Guo, L.; Yi W.; Chen, Z.-Y.; Song, H.-C. Eur. J. Med. Chem. 2010, 45, 5513.

[18] Chen, Z.-Y.; Cao, R.-H.; Shi, B.-X.; Guo, L.; Sun, J.; Ma, Q.; Fan, W.-X.; Song, H.-C. Eur. J. Med. Chem. 2011, 46, 5127.

[19] Guo, L.; Sun, J.; Fan, W.-X.; Ma, Q. Chin. J. Modern Appl. Pharm. 2012, 29, 385 (in Chinese). (郭亮, 孙洁, 范文玺, 马芹, 中国现代应用药学, 2012, 29, 385.)

[20] Zhou, S.-S.; Xue, X.; Jiang, B.; Lu, C.-H.; Tian, Y.-P.; Jiang, M.-H. Acta Chim. Sinica 2011, 69, 2335 (in Chinese). (周双生, 薛璇, 姜波, 鲁传华, 田玉鹏, 蒋明华, 化学学报, 2011, 69, 2335.)

[21] Zou, X.-J.; Liu, Y.; Liu, Z.-M.; Gao, J.-W.; Song, Q.-L.; Pan, Y.; Zhang, J.-Z.; Li, X.-J.; Lai, L.-H. Chin. J. Org. Chem. 2011, 31, 1923 (in Chinese). (邹霞娟, 刘莹, 刘振明, 高军卫, 宋前流, 潘燕, 张剑钊, 李学军, 来鲁华, 有机化学, 2011, 31, 1923.)
Options
文章导航

/

〈 〉