注册 English

Facile synthesis and antitumor activity of novel 2-trifl uoromethylthieno[2,3-d]pyrimidine derivatives

Xin-Jian Song ,  Ping Yang ,  Hui Gao ,  Yan Wang ,  Xing-Gao Dong ,  Xiao-Hong Tan

downloadPDF
Citation:  Xin-Jian Song, Ping Yang, Hui Gao, Yan Wang, Xing-Gao Dong, Xiao-Hong Tan. Facile synthesis and antitumor activity of novel 2-trifl uoromethylthieno[2,3-d]pyrimidine derivatives[J]. Chinese Chemical Letters, 2014, 25(7): 1006-1010. doi: 10.1016/j.cclet.2014.05.043 shu

Facile synthesis and antitumor activity of novel 2-trifl uoromethylthieno[2,3-d]pyrimidine derivatives

    • 通讯作者: Xin-Jian Song,
    Yan Wang,
  • 基金项目:

    This work was financially supported by the National Natural Science Foundation of China (No. 21262012)  (No. 21262012)

    Utilization of Hubei Province (No. PKLHB1314). (No. PKLHB1314)

摘要: A series of novel 2-trifluoromethylthieno[2,3-d]pyrimidine derivatives were synthesized by a facile three-step procedure that afforded advantages of mild reaction conditions, simple protocol and good yields. The structures of the final compounds were confirmed by IR, NMR, EI-MS, elemental analysis, and X-ray diffraction. Preliminary bioassay results showed that some of the analogs exhibit excellent antitumor activity against MCF-7 and HepG2, especially compounds 3a, 3b, 3e and 3h exhibited higher activity than the positive control gefitinib.

English

  • 

    1. [1] R. Adepu, D. Rambabu, B. Prasad, et al., Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation, Org. Biomol. Chem. 10 (2012) 5554-5569.[1] R. Adepu, D. Rambabu, B. Prasad, et al., Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation, Org. Biomol. Chem. 10 (2012) 5554-5569.

    2. [2] J.G. Paez, P.A. Janne, J.C. Lee, et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science 304 (2004) 1497-1500.[2] J.G. Paez, P.A. Janne, J.C. Lee, et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science 304 (2004) 1497-1500.

    3. [3] B. Higgins, K. Kolinsky, M. Smith, et al., Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models, Anticancer Drugs 15 (2004) 503-512.[3] B. Higgins, K. Kolinsky, M. Smith, et al., Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models, Anticancer Drugs 15 (2004) 503-512.

    4. [4] Z.A. Liu, A. Fusi, A. Schmittel, et al., Eradication of EGFR-positive circulating tumor cells and objective tumor response with lapatinib and capecitabine, Cancer Biol. Ther. 10 (2010) 860-864.[4] Z.A. Liu, A. Fusi, A. Schmittel, et al., Eradication of EGFR-positive circulating tumor cells and objective tumor response with lapatinib and capecitabine, Cancer Biol. Ther. 10 (2010) 860-864.

    5. [5] Y. Dai, Y. Guo, R.R. Frey, et al., Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors, J. Med. Chem. 48 (2005) 6066-6083.[5] Y. Dai, Y. Guo, R.R. Frey, et al., Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors, J. Med. Chem. 48 (2005) 6066-6083.

    6. [6] J.C. Aponte, A.J. Vaisberg, D. Castillo, et al., Trypanoside, anti-tuberculosis, leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines, Bioorg. Med. Chem. 18 (2010) 2880-2886.[6] J.C. Aponte, A.J. Vaisberg, D. Castillo, et al., Trypanoside, anti-tuberculosis, leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines, Bioorg. Med. Chem. 18 (2010) 2880-2886.

    7. [7] N.S. Habib, R. Soliman, A.A. El-Tombary, S.A. El-Hawash, O.G. Shaaban, Synthesis and biological evaluation of novel series of thieno[2,3-d]pyrimidine derivatives as anticancer and antimicrobial agents, Med. Chem. Res. 22 (2013) 3289-3308.[7] N.S. Habib, R. Soliman, A.A. El-Tombary, S.A. El-Hawash, O.G. Shaaban, Synthesis and biological evaluation of novel series of thieno[2,3-d]pyrimidine derivatives as anticancer and antimicrobial agents, Med. Chem. Res. 22 (2013) 3289-3308.

    8. [8] B.Q. Cai, H.X. Jin, X.J. Yan, P. Zhu, G.X. Hu, 3D-QSAR and 3D-QSSR studies of thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as CDK4 inhibitors by CoMFA analysis, Acta Pharmacol. Sin. 35 (2014) 151-160.[8] B.Q. Cai, H.X. Jin, X.J. Yan, P. Zhu, G.X. Hu, 3D-QSAR and 3D-QSSR studies of thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as CDK4 inhibitors by CoMFA analysis, Acta Pharmacol. Sin. 35 (2014) 151-160.

    9. [9] W.K. Hagmann, The many roles for fluorine in medicinal chemistry, J. Med. Chem. 51 (2008) 4359-4369.[9] W.K. Hagmann, The many roles for fluorine in medicinal chemistry, J. Med. Chem. 51 (2008) 4359-4369.

    10. [10] X.J. Song, Z.C. Duan, Y. Shao, X.G. Dong, Facile synthesis of novel fluorinated thieno[2,3-d]pyrimidine derivatives containing 1,3,4-thiadiazole, Chin. Chem. Lett. 23 (2012) 549-552.[10] X.J. Song, Z.C. Duan, Y. Shao, X.G. Dong, Facile synthesis of novel fluorinated thieno[2,3-d]pyrimidine derivatives containing 1,3,4-thiadiazole, Chin. Chem. Lett. 23 (2012) 549-552.

    11. [11] T. Horiuchi, M. Nagata, M. Kitagawa, K. Akahane, K. Uoto, Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of Cyclin D1-CDK4: synthesis, biological evaluation and structure-activity relationships. Part 2, Bioorg. Med. Chem. Lett. 17 (2009) 7850-7860.[11] T. Horiuchi, M. Nagata, M. Kitagawa, K. Akahane, K. Uoto, Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of Cyclin D1-CDK4: synthesis, biological evaluation and structure-activity relationships. Part 2, Bioorg. Med. Chem. Lett. 17 (2009) 7850-7860.

    12. [12] A.G. Golub, V.G. Bdzohla, N.V. Briukhovetska, et al., Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2, Eur. J. Med. Chem. 46 (2011) 870-876.[12] A.G. Golub, V.G. Bdzohla, N.V. Briukhovetska, et al., Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2, Eur. J. Med. Chem. 46 (2011) 870-876.

    13. [13] T. Beckers, A. Sellmer, E. Eichhorn, et al., Novel inhibitors of epidermal growth factor receptor: (4-(arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones, Bioorg. Med. Chem. 20 (2012) 125-136.[13] T. Beckers, A. Sellmer, E. Eichhorn, et al., Novel inhibitors of epidermal growth factor receptor: (4-(arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones, Bioorg. Med. Chem. 20 (2012) 125-136.

    14. [14] S.E. Abbas, N.M.A. Gawad, R.F. George, Y.A. Akar, Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives, Eur. J. Med. Chem. 65 (2013) 195-204.[14] S.E. Abbas, N.M.A. Gawad, R.F. George, Y.A. Akar, Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives, Eur. J. Med. Chem. 65 (2013) 195-204.

    15. [15] P. Yang, Y. Wang, Z.C. Duan, et al., Synthesis, crystal structure, and biological activity of 4-chlorobenzaldehyde (2-trifluoromethyl-5,6,7,8-tetrahydrobenzo[ 4,5]thieno[2,3-d]pyrimidin-4-yl)hydrazone monohydrate, Chin. J. Struct. Chem. 32 (2013) 1023-1030.[15] P. Yang, Y. Wang, Z.C. Duan, et al., Synthesis, crystal structure, and biological activity of 4-chlorobenzaldehyde (2-trifluoromethyl-5,6,7,8-tetrahydrobenzo[ 4,5]thieno[2,3-d]pyrimidin-4-yl)hydrazone monohydrate, Chin. J. Struct. Chem. 32 (2013) 1023-1030.

    16. [16] T. Horiuchi, J. Chiba, K. Uoto, T. Soga, Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of Cyclin D1-CDK4: synthesis, biological evaluation, and structure-activity relationships, Bioorg. Med. Chem. Lett. 19 (2009) 305-308.[16] T. Horiuchi, J. Chiba, K. Uoto, T. Soga, Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of Cyclin D1-CDK4: synthesis, biological evaluation, and structure-activity relationships, Bioorg. Med. Chem. Lett. 19 (2009) 305-308.

    17. [17] R.J. Gillespie, D.R. Adams, D. Bebbington, et al., Antagonists of the human adenosine A2A receptor. Part 1: discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives, Bioorg. Med. Chem. Lett. 18 (2008) 2916-2919.[17] R.J. Gillespie, D.R. Adams, D. Bebbington, et al., Antagonists of the human adenosine A2A receptor. Part 1: discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives, Bioorg. Med. Chem. Lett. 18 (2008) 2916-2919.

    18. [18] M. Hayakawa, H. Kaizawa, H. Moritomo, et al., Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110a inhibitors, Bioorg. Med. Chem. 14 (2006) 6847-6858.[18] M. Hayakawa, H. Kaizawa, H. Moritomo, et al., Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110a inhibitors, Bioorg. Med. Chem. 14 (2006) 6847-6858.

    19. [19] M.R. Prasad, D.P. Kishore, Multistep, microwave assisted, solvent free synthesis and antibacterial activity of 6-substituted-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]thieno[3,2-e]pyrimidines, Chem. Pharm. Bull. 55 (2007) 776-779.[19] M.R. Prasad, D.P. Kishore, Multistep, microwave assisted, solvent free synthesis and antibacterial activity of 6-substituted-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]thieno[3,2-e]pyrimidines, Chem. Pharm. Bull. 55 (2007) 776-779.

    20. [20] A.E. Kassab, E.M. Gedawy, Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives, Eur. J. Med. Chem. 63 (2013) 224-230.[20] A.E. Kassab, E.M. Gedawy, Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives, Eur. J. Med. Chem. 63 (2013) 224-230.

    21. [21] M. Sridhar, R.M. Rao, N.H.K. Baba, R.M. Kumbhare, Microwave-accelerated Gewald reaction: synthesis of 2-aminothiophenes, Tetrahedron Lett. 48 (2007) 3171-3172.[21] M. Sridhar, R.M. Rao, N.H.K. Baba, R.M. Kumbhare, Microwave-accelerated Gewald reaction: synthesis of 2-aminothiophenes, Tetrahedron Lett. 48 (2007) 3171-3172.

    22. [22] R. Rajagopal, T.M. Jyothi, T. Daniel, K.V. Srinivasan, B.S. Rao, Calcined Mg-Al hydrotalcite as a heterogeneous base catalyst for Gewald aminothiophene synthesis, Synth. Commun. 31 (2001) 3113-3117.[22] R. Rajagopal, T.M. Jyothi, T. Daniel, K.V. Srinivasan, B.S. Rao, Calcined Mg-Al hydrotalcite as a heterogeneous base catalyst for Gewald aminothiophene synthesis, Synth. Commun. 31 (2001) 3113-3117.

    23. [23] T. Wang, X.G. Huang, J. Liu, et al., An efficient one-pot synthesis of substituted 2-aminothiophenes via three-component Gewald reaction catalyzed by L-proline, Synlett (2010) 1351-1354.[23] T. Wang, X.G. Huang, J. Liu, et al., An efficient one-pot synthesis of substituted 2-aminothiophenes via three-component Gewald reaction catalyzed by L-proline, Synlett (2010) 1351-1354.

    24. [24] D.D. Zhao, L. Li, F. Xu, Q. Wu, X.F. Lin, Bovine serum albumin-catalyzed one-pot synthesis of 2-aminothiophenes via Gewald reaction, J. Mol. Catal. B-Enzym. 95 (2013) 29-35.[24] D.D. Zhao, L. Li, F. Xu, Q. Wu, X.F. Lin, Bovine serum albumin-catalyzed one-pot synthesis of 2-aminothiophenes via Gewald reaction, J. Mol. Catal. B-Enzym. 95 (2013) 29-35.

    25. [25] R. Tayebee, F. Javadi, G. Argi, Easy single-step preparation of ZnO nano-particles by sedimentation method and studying their catalytic performance in the synthesis of 2-aminothiophenes via Gewald reaction, J. Mol. Catal. A-Chem. 368-369 (2013) 16-23.[25] R. Tayebee, F. Javadi, G. Argi, Easy single-step preparation of ZnO nano-particles by sedimentation method and studying their catalytic performance in the synthesis of 2-aminothiophenes via Gewald reaction, J. Mol. Catal. A-Chem. 368-369 (2013) 16-23.

    26. [26] E. Rezaei-Seresht, R. Tayebee, M. Yasemi, KG-60-piperazine as a new heterogeneous catalyst for Gewald three-component reaction, Synth. Commun. 43 (2013) 1859-1864.[26] E. Rezaei-Seresht, R. Tayebee, M. Yasemi, KG-60-piperazine as a new heterogeneous catalyst for Gewald three-component reaction, Synth. Commun. 43 (2013) 1859-1864.

    27. [27] P. Malherbe, R. Masciadri, R.D. Norcross, H. Ratni, A.W. Thomas, Thieno-pyridine derivatives as allosteric enhancers of the GABAB receptors, US2006135552 (2006).[27] P. Malherbe, R. Masciadri, R.D. Norcross, H. Ratni, A.W. Thomas, Thieno-pyridine derivatives as allosteric enhancers of the GABAB receptors, US2006135552 (2006).

    28. [28] G.M. Sheldrick, A short history of SHELX, Acta Cryst. A64 (2008) 112-122.[28] G.M. Sheldrick, A short history of SHELX, Acta Cryst. A64 (2008) 112-122.

    29. [29] M.C. Alley, D.A. Scudiero, A. Monks, et al., Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay, Cancer Res. 48 (1988) 589-601.[29] M.C. Alley, D.A. Scudiero, A. Monks, et al., Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay, Cancer Res. 48 (1988) 589-601.

  • 加载中
WeChat 扫一扫看文章
计量
  • PDF下载量:  0
  • 文章访问数:  1399
  • HTML全文浏览量:  46
文章相关
  • 收稿日期:  2014-04-09
  • 网络出版日期:  2014-05-21
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章

All Rights Reserved by the Chinese Chemical Society   中国化学会 版权所有 京ICP备05002797号

本系统由北京仁和汇智信息技术有限公司开发    技术支持: info@rhhz.net