喹唑啉-4-酮衍生物的合成及抗肿瘤活性
收稿日期: 2016-07-29
修回日期: 2016-09-13
网络出版日期: 2016-10-09
基金资助
国家自然科学基金（No.21372060）、河北省自然科学杰出青年基金（培育）（No.B2015201005）资助项目.
Synthesis and Anti-tumor Activity of Novel Quinazolin-4-one Derivatives
Received date: 2016-07-29
Revised date: 2016-09-13
Online published: 2016-10-09
Supported by
Project supported by the National Natural Science Foundation of China (No. 21372060), the Hebei Provincal Natural Science Fund for Distinguished Young Scholars (Incubation) (No. B2015201005).
以邻氨基苯甲酸、芳醛和甘氨酸乙酯为原料，利用亚胺和亚胺烯酮的加成反应，芳构化合成了系列含氨基酸链的C-2和N-3双取代的喹唑啉-4-酮衍生物5.酸性条件下脱除羧甲基，设计合成了连有氨基侧链的喹唑啉酮衍生物9，并评价了化合物的抗肿瘤细胞增殖活性.化合物9ba和9bc具有较好的抗Hela细胞增殖活性，IC50值分别为8.16和7.47 μmol/L，而9bc和9bd具有较好的抗A549细胞增殖活性，IC50值分别为5.62和9.54 μmol/L.构效关系表明，C-2位香豆素（较大的π平面芳环）取代以及氨基侧链的引入有利于化合物的抗肿瘤活性.
孙佳婧 , 周利凯 , 谭官海 , 李帅 , 王淑霞 , 陈华 , 李小六 . 喹唑啉-4-酮衍生物的合成及抗肿瘤活性[J]. 有机化学, 2017 , 37(2) : 455 -461 . DOI: 10.6023/cjoc201607045
A series of novel C-2 and N-3 disubstituted quinazolin-4(3H)-one derivatives 5 possessing amino acid chain were synthesized by the addition reaction of imine with iminoketene and aromatization using anthranilic acid, aromatic aldehyde and glycine ethyl ester as starting materials. After elimination of carboxymethyl in the acidic condition, novel quinazolin-4(3H)-one derivatives 9 bearing amino side chain were designed and synthesized by SN2 substitution reaction. The compounds were evaluated for their anti-proliferation activities against four tumor cells. The results showed that some of the compounds, such as 9ba and 9bc showed significantly anti Hela activity with the IC50 values of 8.16 μM and 7.47 μM, respectively, while 9bc and 9bd against A549 with the IC50 values of 5.62 μM and 9.54 μM, respectively. Structure activity relationship analysis of these analogues suggested that coumarin substituent (extended π planar aromatic ring) on C-2 position and the introduction of amino side chain should be favorable to their anti-tumor activities.
[1] Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.; Saeed, A. Bioorg. Med. Chem. 2016, 24, 2361.
[2] Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur. J. Med. Chem. 2014, 76, 193.
[3] Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur. J. Med. Chem. 2015, 90, 124.
[4] Ou, J. J.; Liu, K. C.; Wang, Y.; Zhang, H.; Liu, R. Q.; Li, Q. B.; Wang, Q. M.; Li, Y. Q.; Rui, C. H.; Liu S. Z. Chin. J. Org. Chem. 2014, 34, 526 (in Chinese).(欧俊军, 刘克昌, 王毅, 张浩, 刘瑞全, 李奇博, 汪清民, 李永强, 芮昌辉, 刘尚钟, 有机化学, 2014, 34, 526.)
[5] Wang, Z.-Z.; Tang, Y. Tetrahedron 2016, 72, 1330.
[6] Kim, N. Y.; Cheon, C.-H. Tetrahedron Lett. 2014, 55, 2340.
[7] Yu, C. W.; Chang, P. T.; Hsin, L. W.; Chern, J. W. J. Med. Chem. 2013, 56, 6775.
[8] Deepak, G.; Kumar, R.; Roy, R. K.; Sharma, A.; Ali, I. Med. Chem. Res. 2013, 22, 3282.
[9] Johannes, K.; Martens, J. Tetrahedron 2010, 66, 242.
[10] Unsworth, W. P.; Coulthard, G.; Kitsiou, C.; Taylor, R. J. K. J. Org. Chem., 2014, 79, 1368.
[11] Kametani, T.; Van LoC C.; Higa, T.; Koizumi, M.; Ihara, M.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99, 2306.
[12] Xu, S.; Xu, S. P.; Li, L. M. Acta Pharm. Sin. 2002, 37, 113 (in Chinese).(徐嵩, 徐世平, 李兰敏, 药学学报, 2002, 37, 113.)
[13] Hou, B. L.; Ai, Y.; Wang, C. L.; Zhang, N.; Yang, L.; Liu, Z. L.; Liu, J. L. Chin. J. Org. Chem. 2016, 36, 121 (in Chinese).(侯宝龙, 艾芸, 王翠玲, 张宁, 杨柳, 刘竹兰, 刘建利, 有机化学, 2016, 36, 121.)
[14] Nacro, K.; Charles, Z.; Guzzo, P. R.; Herr, R. J.; Peace, D.; Friedrich, T. D. Bioorg. Med. Chem. 2007, 15, 4237.
[15] Mayer, J. P.; Lewis, G. S.; Curtis, M. J.; Zhang, J. W. Tetrahedron Lett. 1997, 38, 8445.
[16] Chen, H.; Li, S.; Yao, Y. C.; Zhou, L. K.; Zhao, J. P.; Gu, Y. J.; Wang, K. R.; Li, X. L. Bioorg. Med. Chem. Lett. 2013, 23, 4785.
[17] Gunaratnam, M.; Swank, S.; Haider, S. M.; Galesa, K.; Reszka, A. P.; Beltran, M.; Cuenca, F.; Fletcher, J. A.; Neidle, S. J. Med. Chem. 2009, 52, 3774.
[18] Chen, G. S.; Kalchar, S.; Kuo, C.-W.; Chang, C.-S.; Usifoh, C. O.; Chern, J.-W. J. Org. Chem. 2003, 68, 2502.
[19] Venkata Sairam, K.; Gurupadayya, B. M.; Chandan, R. S.; Nagesha, D. K.; Vishwanathan, B. Curr. Drug Delivery 2016, 13, 186.
[20] Mosmann, T. J. Immunol. Methods 1983, 65, 55.
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