具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究
收稿日期: 2023-11-22
修回日期: 2023-12-20
网络出版日期: 2024-01-18
基金资助
广东省自然科学基金(2021A1515011238)
Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities
Received date: 2023-11-22
Revised date: 2023-12-20
Online published: 2024-01-18
Supported by
Natural Science Foundation of Guangdong Province(2021A1515011238)
以4-氨基苯甲酸为原料, 经重氮化反应后与甲基烷基胺反应构建三氮烯骨架, 随后将羧基与2-二乙基氨基乙氨缩合, 合成了11个1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)苯基-3-甲基-3-烷基(R2)三氮烯化合物1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-环己基三氮烯(6a)~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-硝基)苄基三氮烯(6k), 3步反应的总收率为46.5%~68.3%. 噻唑蓝(MTT)比色法检测发现, 6a、1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-苯基三氮烯(6e)~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-甲氧基)苄基三氮烯(6j)对人肝癌细胞(HepG-2)、大鼠胶质瘤细胞(C6)、人结肠癌细胞(SW620)、人前列腺癌细胞(PC-3)、小鼠黑色素瘤细胞(B16)和人非小细胞肺癌细胞(A549)共六株肿瘤细胞都有良好的抗肿瘤活性, 显示出广谱的抗癌特性; 其中, 1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-氯)苯基三氮烯(6g)的抗癌活性最为突出, 对C6、SW620、PC-3和B16的IC50值均小于10 μmol/L, 抗癌活性远优于阳性对照药达卡巴嗪. 研究发现, 当R2为具有适当吸电子效应的芳基时, 化合物的抗癌活性较高. 药物安全性评价发现, 6e、6g、1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-氯)苄基三氮烯(6h)对C6、SW620、PC-3, 6g~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-甲氧基)苯基三氮烯(6i)对B16, 6e、6h、6i对HepG-2, 6i对C6、SW620, 其安全指数(SI)均大于2.0, 其安全性高于达卡巴嗪. 化合物6e、6g~6i的油水分布系数(lg P)为3.0~4.0, 具有较高的膜渗透性. 所有数据证实, 新型三氮烯化合物6e、6g~6i具有更佳的成药性.
许芹芳 , 胡健灵 , 刘园林 , 张超 , 李明月 , 彭姝羚 , 刘志军 , 陈河如 . 具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究[J]. 有机化学, 2024 , 44(5) : 1606 -1619 . DOI: 10.6023/cjoc202311020
Eleven novel 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-alkyl (R2) triazenes have been designed and synthesized. Firstly, 4-aminobenzoic acid, as starting material, underwent diazo reaction following the reaction with methyl alkylamine to build the triazene scaffold. Condensation of carboxylic group with 2-diethylaminoethylamine resulted in all the title compounds. The overall yield of these 3-step reactions was between 46.5% and 68.3%. By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl- 3-methyl-3-cyclohexyltriazene (6a), 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-phenyltriazene (6e)~1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)benzyltriazene (6j) were confirmed as good broad-spectrum anti-cancer agents again/st human liver cancer cells (HepG-2), rat glioma cells (C6), human colon cancer cells (SW620), human prostate cancer cells (PC-3), murine melanoma cells (B16), and human non-small-cell lung cancer cells (A549). Among them, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene (6g) show- ed as the most active agent, where IC50 values of 6g against C6, SW620, PC-3, and B16 cell lines are less than 10 μmol/L, which is far better than the positive dacarbazine. It was found that when R2 is aryl group with propriate electron-withdrawal intensity, the triazene will have good even excellent anti-cancer activity. Through drug safety evaluation, the safety indexes (SI) of 6e, 6g, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene (6h) against C6, SW620, and PC-3 cell lines, respectively; 6g, 6h, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4- methoxyl)phenyltriazene (6i) against B16 cell line respectively; 6e, 6h, and 6i against HepG-2 cell line respectively; 6i against C6, and SW620 cell lines, respectively; were identified more than 2.0, implied better drug safety than dacarbazine. The partition coefficient (lg P) of 6e, 6g~6i lied between 3.0 and 4.0, meaning good membrane permeability. All the data support that the novel triazenes 6e, 6g~6i have better druggability.
Key words： triazenes; anti-cancer; drug safety evaluation; druggability; drug design-synthesis
| [1] | Griess, P. Justus Liebigs Ann. Chem. 1862, 121, 258. |
| [2] | Connors, T. A.; Goddard, P. M.; Merai, K.; Ross, W. C. J.; Wilman, D. E. V. Biochem. Pharmacol. 1976, 25, 241. |
| [3] | Clarke, D. A.; Barclay, R. K.; Stock, C. C.; Rondestvedt, C. S. Jr. Proc. Soc. Expt. Biol. Med. 1955, 90, 484. |
| [4] | Shealy, Y. F.; Krauth, C. A.; Montgomery, J. A. J. Org. Chem. 1962, 27, 2150. |
| [5] | Wexler, P. In Encyclopedia of Toxicology, 3rd ed., Ed.: Andrea, M., Academic Press, Lundon, 2014, pp. 1132-1134. |
| [6] | Ege, G.; Gilbert, K. Tetrahedron Lett. 1979, 20, 4253. |
| [7] | Clark, A. S.; Deans, B.; Stevens, M. F. G.; Tisdale, M. J.; Wheelhouse, R. T.; Denny, B. J.; Hartley, J. A. J. Med. Chem. 1995, 38, 1493. |
| [8] | Saunders, P. P.; Schultz, G. A. Biochem. Pharmacol. 1970, 19, 911. |
| [9] | Skibba, J. L.; Beal, D. D.; Ramirez, G.; Bryan, G. T. Cancer Res. 1970, 30, 147. |
| [10] | Denny, B. J.; Wheelhouse, R. T.; Stevens, M. F.; Tsang, L. L.; Slack, J. A. Biochemistry 1994, 33, 9045. |
| [11] | Lei, Q.; Zhang, S. Y.; Liu, M. L.; Li, J.; Zhang, X.; Long, Y. Mol. Diversity 2017, 21, 957. |
| [12] | Wei, G. P.; Zhang, X.; Lei, Q.; Xu, M.; Zhang, M. Q.; Long, Y. Chin. J. Org. Chem. 2018, 38, 2137 (in Chinese). |
| [12] | ( 魏光璞, 张茜, 雷强, 徐淼, 张明千, 龙跃, 有机化学, 2018, 38, 2137.) |
| [13] | Ge, Y.; Ren, T.; Cui, X.; Zhao, L. J.; Zhong, R. G. Chem. Reagents 2018, 40, 707 (in Chinese). |
| [13] | ( 葛瑶, 任婷, 崔鑫, 赵丽娇, 钟儒刚, 化学试剂, 2018, 40, 707.) |
| [14] | Matheson, S. L.; Mcnamee, J. P.; Wang, T. Q.; Alaoui-Jamali, M. A.; Tari, M. A.; Jean-Claude, B. J. J. Pharmacol. Exp. Ther. 2004, 311, 1163. |
| [15] | Monteiro, A. S.; Almeida, J.; Cabral, G.; Severino, P.; Videira, P. A.; Sousa, A.; Nunes, R.; Pereira, J. D.; Francisco, A. P.; Jesus Perry, M.; Mendes, E. Eur. J. Med. Chem. 2013, 70, 1. |
| [16] | Lei, Q.; Qin, S.; Feng, C.; Li, P.; Zhang, X.; Long, Y. Chin. J. Org. Chem. 2016, 36, 406 (in Chinese). |
| [16] | ( 雷强, 秦上尚, 冯翠宁, 李佩佩, 张茜, 龙跃, 有机化学, 2016, 36, 406.) |
| [17] | Zhang, M.; Liu, B.; Lei, Q.; Yan, J.; Zhao, Z.; Long, Y. Chin. J. Org. Chem. 2019, 39, 1064 (in Chinese). |
| [17] | ( 张明千, 刘斌凯, 雷强, 颜景东, 赵中玉, 龙跃, 有机化学, 2019, 39, 1064.) |
| [18] | Chen, Y.; Zhang, M.; Li, Z.; Luo, D.; Li, L.; Yu, T.; Long, Y. Chin. J. Org. Chem. 2019, 39, 3283 (in Chinese). |
| [18] | ( 陈彦君, 张明千, 李子秋, 罗德福, 李龙辉, 俞婷婷, 龙跃, 有机化学, 2019, 39, 3283.) |
| [19] | Chen, Z. X.; Riggs, A. D. J. Biol. Chem. 2011, 286, 18347. |
| [20] | Jin, J.; Gong, J.; Yin, T.; Lu, Y.; Xia, J.; Xie, Y.; Di, Y.; He, L.; Guo, J. Eur. J. Pharm. 2011, 654, 17. |
| [21] | Xiao, Q. W.; Lu, Y. F.; Chen, X. P. Ind. J. Pharm. Sci. 2020, 82, 361. |
| [22] | Chen, M.; Su, D.; Xu, H.; Ai, Z.; Wang, R.; Chai, X.; Luo, W.; Yang, M.; Liu, Y.; Song, Y. Chin. Arch. Traditional Chin. Med. 2022, 40, 191 (in Chinese). |
| [22] | ( 陈梦莹, 苏丹, 徐焕华, 艾志福, 王瑞英, 柴晓燕, 罗湾湾, 杨明, 刘亚丽, 宋永贵, 中华中医药学刊, 2022, 40, 191.) |
| [23] | Teramoto, S. Int. J. Chronic Obstruct. Pulm. Dis. 2022, 17, 1453. |
| [24] | Al Jamal, M.; Al Bathish, M.; Gazy, A. Pharmacia 2023, 70, 299. |
| [25] | Losada-Barreiro, S.; Paiva-Martins, F.; Bravo-Diaz, C. Antioxidants 2023, 12, 828. |
| [26] | Qiao, Y.; Xia, S.; Ma, P. Chem. Eng. Data 2008, 53, 280. |
| [27] | Kolar, G. F. Z. Naturforsch.,B: Anorg. Chem., Org. Chem.,Biochem., Biophys., Biol. 1972, 27, 1183. |
| [28] | Voronin, V. G.; Pleshkova, A. P.; Ermakov, A. I.; Petrova, I. D.; Karaseva, N. F.; Zelenova, V. P. Zh. Org. Khim. 1979, 15, 63. |
| [29] | Liu, J.; Zhang, B.; Sun, J.; Chen, Y. Chin. J. Pharm. 1984, 9, 20 (in Chinese). |
| [29] | ( 刘纪云, 张葆珣, 孙家莉, 陈奕, 中国医药工业杂志, 1984, 9, 20.) |
| [30] | Wilman, D. E. V.; Cox, P. J.; Goddard, P. M.; Hart, L. I.; Merai, K.; Newell, D. R. J. Med. Chem. 1984, 27, 870. |
| [31] | Freimanis, J.; Markava, E.; Matisova, G.; Gerca, L.; Muzikante, I.; Rutkis, M.; Silinsh, E. Langmuir 1994, 10, 3311. |
| [32] | Wilman, D. E. V.; Goddard, P. M.; Heales, B. E. J. Med. Chem. 1991, 2, 101. |
| [33] | Dunn, W. J. 3rd.; Greenberg, M. J. J. Pharm. Sci. 1977, 66, 1416. |
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