4-(甲氧基噻吩基)-3-(取代苯甲酰基)-吡咯类化合物的合成与抗肿瘤活性研究
收稿日期: 2016-10-28
修回日期: 2016-12-02
网络出版日期: 2017-01-04
基金资助
国家科技重大新药创制专项（No.2010ZX09401404-004）资助项目.
Synthesis and Anti-tumor Activity of 4-(Methoxyl thienyl)-3- (substituted benzoyl)pyrroles
Received date: 2016-10-28
Revised date: 2016-12-02
Online published: 2017-01-04
Supported by
Project supported by the National Science and Technology Major Special Drug Discovery (No. 2010ZX09401404-004).
分别以2-甲氧基噻吩、3-甲氧基噻吩、3，4-二溴噻吩和取代苯乙酮为原料，经过溴甲氧基取代反应、Vilsmeier- Hack反应、羟醛缩合和Van Leusen吡咯合成法，设计并合成了33个未见文献报道的4-取代噻吩基吡咯类化合物. 其结构均经1H NMR，13C NMR及HRMS确认，同时采用噻唑蓝（MTT）法测试了目标化合物对CHO、HCT-116、MGC80-3、SGC-7901以及HUVEC细胞增殖抑制活性. 结果显示，部分化合对MGC80-3细胞有较强（IC50≤20 μml/L）或中等（20 μmol/L < IC50≤50 μmol/L）增殖抑制作用，其中[4-（3，4-二甲氧基噻吩-2-基）-1H-吡咯-3-基]（4-苯基苯基）甲酮（4a-2）和[4-（3，4-二甲氧基噻吩-2-基）-1H-吡咯-3-基]（3-溴苯基）甲酮（4a-7）的IC50值分别为8.6和8.5 μmol/L；化合物4a-7对HCT-116细胞有中等抑制活性；化合物4a-2和4a-7对SGC-7901细胞有中等增殖抑制活性；并且几乎所有化合物对正常人体细胞HUVEC无明显抑制作用.
赵凯 , 王帅 , 詹晓平 , 刘增路 , 毛振民 . 4-(甲氧基噻吩基)-3-(取代苯甲酰基)-吡咯类化合物的合成与抗肿瘤活性研究[J]. 有机化学, 2017 , 37(4) : 943 -953 . DOI: 10.6023/cjoc201610044
33 novel 4-substituted thienyl pyrrole compounds were synthesized via replacement, Vilsmeier-Hack, aldol condensation and Van Leusen pyrrole reaction using 2-methoxythiophen, 3-methoxythiophene, 3,4-dibromothiophene and substituted acetophenone as raw materials. The structures of all target compounds were characterized by 1H NMR, 13C NMR and HRMS, meanwhile the cell proliferation inhibition efficacy was estimated against CHO, HCT-116, MGC80-3, SGC-7901 and HUVEC cell lines. The results revealed that some target compounds exhibited strong (IC50≤20 μmol/L) or moderate (20 μmol/L < IC50≤50 μmol/L) proliferation inhibition efficacy against tumor cells, meanwhile no significant inhibition activity on HUVEC, which indicated that these compounds had high selectivity. Herein, some compounds showed strong or moderate inhibition efficacy against MGC80-3. The IC50 values of [4-(3,4-dimethoxythiophen-2-yl)-1H-pyrrol-3-yl](4-phenylphenyl)-methanone (4a-2) and [4-(3,4-dimethoxythiophen-2-yl)-1H-pyrrol-3-yl](3-bromophenyl)methanone (4a-7), were 8.6 and 8.5 μmol/L against MGC80-3, respectively, and the IC50 value of 4a-7 was 20.0 μmol/L against HCT-116. Both compounds 4a-2 and 4a-7 exhibited moderate inhibition efficacy against SGC-7901.
Key words： pyrrole; thiophene; synthesis; anti-tumor activity
[1] Gholap, S. S. Eur. J. Med. Chem. 2016, 110, 13.
[2] Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402.
[3] Ma, J.; Lu, X.; Xia, Y.; Yan, F. J. Chromatogr. Sci. 2015, 53, 380.
[4] Lazerges, M.; Chane-Ching, K. I.; Aeiyach, S.; Chelli, S.; PeppinDonnat, B.; Billon, M.; Lombard, C.; Maurel, F.; Jouini, M. J. Solid State Electrchem. 2009, 13, 231.
[5] Walsh, C. T.; Garneau-Tsodikova S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517.
[6] Battilocchio, C.; Poce, G.; Alfonso, S. Bioorg. Med. Chem. 2013, 21, 3695.
[7] Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafic A.; Manettic, F. Bioorg. Med. Chem. 2004, 12, 1453.
[8] Protopopova, M.; Bogatcheva, E.; Nikonenko, B.; Hundert, S.; Einck, L.; Nacy, C. A. Med. Chem. 2007, 3, 301.
[9] Shattat, G. F.; Abuskeika, G. M.; Al-Qirim, T. M. Lat. Am. J. Pharm. 2015, 34, 1258.
[10] Dannhardt, G.; Kiefer, W.; Krämer, G.; Maehrlein, S.; Nowe U.; Fiebich, B. Eur. J. Med. Chem. 2000, 35, 499.
[11] Teixeira, C.; Barbault, F.; Rebehmed, J.; Liu, K.; Xie, L.; Lu, H.; Jiang, S.; Fan B.; Maurel, F. Bioorg. Med. Chem. 2008, 16, 3039.
[12] Lankheet, N. A. G.; Hillebrand, M. J. X.; Rosing H.; Schellens, J. H. M.; Beijnen, J. H.; Huitema, A. D. R. Biomed. Chromatogr. 2013, 27, 466.
[13] Molina, A. M.; Jia, X.; Feldman, D. R. Clin. Genitourin. Cancer 2013, 11, 297.
[14] Bailly, C. Mar. Drugs 2015, 13, 1105.
[15] Lan, L.; Zhan, X.-P.; Qin, W.-X.; Liu, Z.-L.; Mao, Z.-M. Heterocycles 2014, 89, 375.
[16] Lan, L.; Qin, W.-X.; Zhan, X.-P.; Liu, Z.-L.; Mao, Z.-M. Anti-Cancer Agents Med. Chem. 2014, 14, 994.
[17] Li, Y.-Z.; Zhao, P.; Zhan, X.-P.; Liu, Z.-L.; Mao, Z.-M. Chin. J. Org. Chem. 2015, 35(1), 167 (in Chinese).
(李衍忠, 赵萍, 詹晓平, 刘增路, 毛振民, 有机化学, 2015, 35(1), 167.)
[18] Zhan, X.-P.; Lan, L.; Zhang, Y.-K.; Chen, J.; Zhao, K.; Wang, S.; Xin, Y.-X.; Mao, Z.-M. Bull. Korean Chem. Soc. 2016, 37, 200.
[19] Zhan, X.-P.; Lan, L.; Wang, S. Chem. Biodiversity 2016, 14(2), n/a.
[20] Chen, J.; Zhang, Y.-K.; Zhan, X.-P.; Liu, Z.-L.; Mao, Z.-M. Chin. J. Org. Chem. 2016, 36, 572 (in Chinese).
(陈简, 张袁魁, 詹晓平,刘增路, 毛振民, 有机化学, 2016, 36, 572.)
[21] Chen, S.; Lu, B. Y.; Duan, X. J. Polym. Sci. Part A: Polym. Chem. 2012, 50, 1967.
[22] Shen, P.; Liu, X. P.; Jiang, S. H.; Wang, L.; Yi, L.; Ye, D. D.; Zhao, B.; Tan, S. T. Dyes Pigm. 2012, 92, 1042.
[23] Vilsmeier, A.; Haack, A. Chem. Ber. 1927, 60, 119
[24] Blockhuys, F.; Hoefnagels, R.; Peten, C.; Alsenoy, C. V.; Geise, H. J. J. Mol. Struct. 1999, 485, 87.
[25] Batista, R. M. F.; Costa, S. P. G.; Belsley, M.; Lodeiro, C.; Raposo, M. M. M. Tetrahedron 2008, 64, 9230.
[26] van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 52, 5337.
[27] Leeper, F. J.; Kelly, J. M. Org. Prep. Proced. Int. 2013, 45, 171.
[28] Zhou, J. J; Yue, X. F.; Han, J. X.; Yang, W. Y. Chin. J. Pharm. 1993, 24, 455.
[29] Chadwick, J. J. Chem. Soc., Perkin Trans. 1 1973, 2327.
/
| 〈 |
|
〉 |
