Citation: Xiu-Jun Wang, Ming-Li Yang, Lan-Ping Zhang, Tong Yao, Cheng Chen, Lian-Gang Mao, Yin Wang, Jie Wu. Design of novel bis-benzimidazole derivatives as DNA minor groove binding agents[J]. Chinese Chemical Letters, ;2014, 25(4): 589-592. doi: 10.1016/j.cclet.2014.01.019 shu

Design of novel bis-benzimidazole derivatives as DNA minor groove binding agents

Xiu-Jun Wang ^a,b ,
Ming-Li Yang ^b,, ,
Lan-Ping Zhang ^b ,
Tong Yao ^a,b ,
Cheng Chen ^b ,
Lian-Gang Mao ^a,b ,
Yin Wang ^b ,
Jie Wu ^c,,

1.
a The 716th Institute of CSIC, Lianyungang 222006, China;
b JARI Pharmaceutical Co.
b JARI Pharmaceutical Co., Ltd, Lianyungang 222006, China;
3.
c Department of Pharmaceutical Engineering, Wuhan Bioengineering Institute, Wuhan 430415, China

Corresponding author: Ming-Li Yang, Jie Wu,
Received Date: 5 October 2013
Available Online: 19 December 2013
Fund Project: This study was supported by Wuhan City Department of Education (No. 2009K106). (No. 2009K106)

A new series of bis-benzimidazole derivatives were designed and synthesized. In vitro cytotoxicity evaluation showed that these compounds exhibited high activity against the selected tumor cells. Among them, compound 9 owned the best potential, its IC₅₀ values being 5.95 μmol/L (mononuclear tumor cell line (U937)) and 5.58 μmol/L (cervical cancer cell (HeLa)). Fluorescence and UV-vis studies showed that compound 9 could bind into the minor groove of DNA.
- Bis-benzimidazole,
- Anti-tumor,
- DNA minor groove
1. [1]
  [1] H.H. Jardosh, C.B. Sangani, M.P. Patel, R.G. Patel, One step synthesis of pyrido[1,2-a]benzimidazole derivatives of aryloxypyrazole and their antimicrobial evaluation, Chin. Chem. Lett. 24 (2013) 123.126.
2. [2]
  [2] X.J. Wang, M.Y. Xi, J.H. Fu, et al., Synthesis, biological evaluation and SAR studies of benzimidazole derivatives as H1-antihistamine agents, Chin. Chem. Lett. 23 (2012) 707.710.
3. [3]
  [3] B.S. Reddy, S.M. Sondhi, J.W. Lown, Synthetic DNA minor groove-binding drugs, Pharmacol. Ther. 84 (1999) 1.111.
4. [4]
  [4] P.G. Baraldi, A. Bovero, F. Fruttarolo, et al., DNA minor groove binders as potential antitumor and antimicrobial agents, Med. Res. Rev. 24 (2004) 475.528.
5. [5]
  [5] J. Mann, A. Baron, Y. Opoku-Boahen, et al., A new class of symmetric bisbenzimidazole- based DNA minor groove-binding agents showing antitumor activity, J. Med. Chem. 44 (2001) 138.144.
6. [6]
  [6] S. Neidle, DNA minor-groove recognition by small molecules, Nat. Prod. Rep. 18 (2001) 291.309.
7. [7]
  [7] M. Singh, V. Tandon, Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-aryl-substituted 2-bis-1H-benzimidazoles, Eur. J. Med. Chem. 46 (2011) 659.669.
8. [8]
  [8] J. Valdez, R. Cedillo, A. Hernández-Campos, et al., Synthesis and antiparasitic activity of 1H-benzimidazole derivatives, Bioorg. Med. Chem. Lett. 12 (2002) 2221.2224.
9. [9]
  [9] A.J. Olson, D.S. Goodsell, Automated docking and the search for HⅣ protease inhibitors, SAR QSAR Environ. Res. 8 (1998) 273.285.
10. [10]
  [10] F. Dawans, C.S. Marvel, Polymers from ortho aromatic tetraamines and aromatic dianhydrides, J. Polym. Sci. A: Gen. Pap. 3 (1965) 3549.3571.
11. [11]
  [11] Analytical data for compounds 7.15:; Compound 7: yield: 54.8%, mp 211.6 213.8 8C; 1HNMR(300MHz,DMSO-d₆): d 6.84 (d, 1H, J = 8.4, Bz-7-H), 7.30 (d, 1H, J = 1.8), 7.52 (dd, 1H, J = 8.4,1.8,Bz-6-H), 12.61 (br, s, 2H), 13.56 (br, s, 2H); 13CNMR(100MHz,DMSO-d₆): d 105.6, 112.6, 115.2, 133.8, 138.1, 151.7, 168.0; ESI-HRMS: m/z 314.0288. (Calcd. for C₂₆H₂₀N₆OS₂: 314.0296). Compound 8: yield (last step): 92.6%, mp 120.3 122.2 8C; ¹H NMR (300MHz, DMSO-d₆): d 4.65 (s, 4H), 6.80.7.20 (m, 4H), 7.27 (m, 2H), 7.36 (d, 2H, J = 7.8 Hz), 7.51 (m, 2H), 7.73 (d, 2H, J = 7.8), 8.51 (m, 2H), 12.65 (br s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): d 41.2, 106.7, 114.2, 115.1, 124.5, 125.3, 134.2, 136.7, 139.4, 148.6, 149.3, 151.9, 159.6; ESI-HRMS: m/z 496.1152. (Calcd. for C₂₆H₂₀N₆OS₂: 496.1140). Compound 9: yield (last step): 88.7%, mp 118.9 122.2 8C; ¹H NMR (300MHz, DMSO-d₆): d 4.55(s, 4H), 6.85 (d, 2H, J = 8.6 Hz), 7.00 (s, 2H), 7.33 (s, 2H), 7.44 (d, 2H, J = 8.6 Hz), 7.86 (d, 2H, J = 7.7 Hz), 8.47 (d, 2H, J = 7.7 Hz), 8.54 (s, 2H), 12.59 (br s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): d 39.6, 106.7, 114.2, 115.1, 125.3, 134.2, 139.4, 146.7, 148.4, 148.6, 151.9; ESI-HRMS: m/z 496.1146. (Calcd. for C₂₆H₂₀N₆OS₂: 496.1140). Compound 10: yield (last step): 89.3%, mp 134.1 134.9 8C; ¹H NMR (300 MHz, DMSO-d₆): d 4.53 (s, 4H), 6.83 (dd, 2H, J = 8.7, 2.1 Hz), 6.98 (s, 2H), 7.43 (d, 4H, J = 8.7 Hz), 7.44 (s, 2H), 8.48 (d, 4H, J = 2.1 Hz), 12.60 (br s, 2H); ¹³C NMR (100MHz, DMSO-d₆): d 38.3, 106.7, 114.2, 115.1, 125.9, 133.4, 134.2, 134.8, 139.4, 148.6, 151.9, 152.6; ESI-HRMS: m/z 496.1149. (Calcd. for C₂₆H₂₀N₆OS₂: 496.1140). Compound 11: yield (last step): 90.7%, mp 94.9 96.1 8C; ¹H NMR (300 MHz, DMSO-d₆): d 3.79 (s, 12H), 3.88 (s, 6H), 4.64 (s, 4H), 6.80.7.20 (m, 4H), 7.07 (d, 2H, J = 5.7 Hz), 8.15 (d, 2H, J = 5.7 Hz), 12.60 (br s, 2H); ¹³C NMR (100MHz, DMSO-d₆): d 19.5, 20.6, 42.5, 57.3, 106.7, 114.2, 115.1, 118.4, 132.0, 139.4, 134.2, 143.1, 148.2, 148.6, 150.8, 151.9; ESI-HRMS: m/z 612.1981. (Calcd. for C32H32N6O3S2: 612.1977). Compound 12: yield (last step): 90.7%,mp 94.9 96.1 8C; ¹H NMR (300 MHz, DMSOd6): d 3.79 (s, 6H), 3.88 (s, 6H), 4.64 (s, 4H), 6.80.7.20 (m, 4H), 7.07 (d, 2H, J = 5.7 Hz), 7.42 (m, 2H), 8.15 (d, 2H, J = 5.7 Hz), 12.60 (br s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): d 35.1, 56.2, 56.9, 106.2, 106.8, 114.2, 115.1, 134.2, 142.7, 139.4, 142.6, 148.2, 148.6, 151.9, 157.9; ESI-HRMS: m/z 616.1567. (Calcd. for C₂₆H₂₈N₆O₅S₂: 616.1563). Compound 13: yield (last step): 87.2%, mp 123.7 126.5 8C; ¹H NMR (300MHz, DMSO-d₆): d 2.25 (s, 6H), 4.71 (s, 4H), 4.91 (dd, 4H, J = 8.7, 5.4 Hz), 6.80.7.00 (m, 4H), 7.09 (d, 2H, J = 5.4 Hz), 7.45 (s, 2H), 8.31 (d, 2H, J = 8.7 Hz), 12.60 (br s, 2H); ¹³C NMR (100MHz, DMSO-d₆): d 16.7, 39.0, 83.9, 105.8, 106.7, 112.3, 114.2, 115.1, 124.6, 134.2, 139.4, 148.9, 148.6, 151.9, 161.2, 168.7; ESI-HRMS: m/z 720.1428. (Calcd. for C32H26F6N6O3S2: 720.1412). Compound 14: yield (last step): 76.2%, mp 121.8 124.1 8C; ¹H NMR (300MHz, DMSO-d₆): d 3.96 (6H, s), 4.79 (s, 4H), 6.88 (dd, 2H, J = 8.6, 2.1 Hz), 7.04 (s, 2H), 7.47 (d, 2H, J = 8.6 Hz), 7.57 (d, 2H, J = 2.1 Hz), 8.27 (m, 2H), 12.61 (br s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): d 35.6, 56.3, 106.7, 114.2, 115.1, 122.8, 124.0, 134.2, 139.4, 143.9, 148.6, 149.2, 151.9, 156.2; ESI-HRMS: m/z 624.0560. (Calcd. for C28H22Cl2N6O3S2: 624.0572). Compound 15: yield (last step): 53.7%, mp 111.2 113.1 8C; ¹H NMR (300MHz, DMSO-d₆): d 4.54 (s, 2H), 6.80.7.30 (m, 2H), 7.43 (m, 1H), 7.46 (d, 1H, J = 8.1 Hz), 7.93 (dd, 1H, J = 8.1, 2.4 Hz), 8.47 (d, 1H, J = 2.4 Hz), 12.61 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): d 39.0, 106.7, 114.2, 115.1, 122.4, 124.1, 134.2, 139.4, 140.6, 148.2, 148.6, 151.9, 160.8; ESI-HRMS:m/z 496.1152. (Calcd. for C26H18Cl2N6OS2: 496.1140).
12. [12]
  [12] L.M. Green, J.L. Reade, C.F. Ware, Rapid colormetric assay for cell viability: application to the quantitation of cytotoxic and growth inhibitory lymphokines, J. Immunol. Methods 70 (1984) 257.268.
13. [13]
  [13] F. Barceló,M. Ortiz-Lombard.a, M. Martorell, et al., DNA binding characteristics of mithramycin and chromomycin analogues obtained by combinatorial biosynthesis, Biochemistry 49 (2010) 10543.10552.
14. [14]
  [14] K. Bielawski, A. Bielawska, T. Anchim, S. Wo.czyn丩 ski, Synthesis, DNA binding, topoisomerase inhibition and cytotoxic properties of 2-chloroethylnitrosourea derivatives of Hoechst 33258, Biol. Pharm. Bull. 28 (2005) 1004. 1009.
15. [15]
  [15] M. Shichita, R. Shimazawa, O. Nakajima, et al., Non-intercalative and sequence- selective interaction of nitropyrene/acridine-skeleton with nucleotides: application of the dextran-coupling method, Biol. Pharm. Bull. 18 (1995) 637.639.
1. [1]
  Yang Liu , Yan Liu , Kaiyin Yang , Zhiruo Zhang , Wenbo Zhang , Bingyou Yang , Hua Li , Lixia Chen . A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2. Chinese Chemical Letters, 2024, 35(8): 109264-. doi: 10.1016/j.cclet.2023.109264
2. [2]
  Xiaohong Wen , Mei Yang , Lie Li , Mingmin Huang , Wei Cui , Suping Li , Haiyan Chen , Chen Li , Qiuping Guo . Enzymatically controlled DNA tetrahedron nanoprobes for specific imaging of ATP in tumor. Chinese Chemical Letters, 2024, 35(8): 109291-. doi: 10.1016/j.cclet.2023.109291
3. [3]
  Jiangshan Xu , Weifei Zhang , Zhengwen Cai , Yong Li , Long Bai , Shaojingya Gao , Qiang Sun , Yunfeng Lin . Tetrahedron DNA nanostructure/iron-based nanomaterials for combined tumor therapy. Chinese Chemical Letters, 2024, 35(11): 109620-. doi: 10.1016/j.cclet.2024.109620
4. [4]
  Yanfei Liu , Yaqin Hu , Yifu Tan , Qiwen Chen , Zhenbao Liu . Tumor acidic microenvironment activatable DNA nanostructure for precise cancer cell targeting and inhibition. Chinese Chemical Letters, 2025, 36(1): 110289-. doi: 10.1016/j.cclet.2024.110289
5. [5]
  Chang Liu , Tao Wu , Lijiao Deng , Xuzi Li , Xin Fu , Shuzhen Liao , Wenjie Ma , Guoqiang Zou , Hai Yang . Programmed DNA walkers for biosensors. Chinese Chemical Letters, 2024, 35(9): 109307-. doi: 10.1016/j.cclet.2023.109307
6. [6]
  Yunfa Dong , Shijie Zhong , Yuhui He , Zhezhi Liu , Shengyu Zhou , Qun Li , Yashuai Pang , Haodong Xie , Yuanpeng Ji , Yuanpeng Liu , Jiecai Han , Weidong He . Modification strategies for non-aqueous, highly proton-conductive benzimidazole-based high-temperature proton exchange membranes. Chinese Chemical Letters, 2024, 35(4): 109261-. doi: 10.1016/j.cclet.2023.109261
7. [7]
  Jia-Li Xie , Tian-Jin Xie , Yu-Jie Luo , Kai Mao , Cheng-Zhi Huang , Yuan-Fang Li , Shu-Jun Zhen . Octopus-like DNA nanostructure coupled with graphene oxide enhanced fluorescence anisotropy for hepatitis B virus DNA detection. Chinese Chemical Letters, 2024, 35(6): 109137-. doi: 10.1016/j.cclet.2023.109137
8. [8]
  Haiyang Gu , Xiang Xu . Multicolor hybrid metal halides and anti-counterfeiting. Chinese Journal of Structural Chemistry, 2024, 43(9): 100352-100352. doi: 10.1016/j.cjsc.2024.100352
9. [9]
  Yanbing Shen , Yuan Yuan , Yaxin Wang , Xiaonan Ma , Wensheng Yang , Yulan Chen . Dihydroanthracene bridged bis-naphthopyrans: A multimodal chromophore with mechano- and photo-chromic properties. Chinese Chemical Letters, 2024, 35(5): 108949-. doi: 10.1016/j.cclet.2023.108949
10. [10]
  Hui-Juan Wang , Wen-Wen Xing , Zhen-Hai Yu , Yong-Xue Li , Heng-Yi Zhang , Qilin Yu , Hongjie Zhu , Yao-Yao Wang , Yu Liu . Cucurbit[7]uril confined phenothiazine bridged bis(bromophenyl pyridine) activated NIR luminescence for lysosome imaging. Chinese Chemical Letters, 2024, 35(6): 109183-. doi: 10.1016/j.cclet.2023.109183
11. [11]
  Jing Wang , Zenghui Li , Xiaoyang Liu , Bochao Su , Honghong Gong , Chao Feng , Guoping Li , Gang He , Bin Rao . Fine-tuning redox ability of arylene-bridged bis(benzimidazolium) for electrochromism and visible-light photocatalysis. Chinese Chemical Letters, 2024, 35(9): 109473-. doi: 10.1016/j.cclet.2023.109473
12. [12]
  Hao Jiang , Yuan-Yuan He , Hai-Chao Liang , Meng-Jia Shang , Han-Han Lu , Chun-Hua Liu , Yin-Shan Meng , Tao Liu , Yuan-Yuan Zhu . Tuning lanthanide luminescence from bipyridine-bis(oxazoline/thiazoline) tetradentate ligands. Chinese Journal of Structural Chemistry, 2024, 43(9): 100354-100354. doi: 10.1016/j.cjsc.2024.100354
13. [13]
  Yang Qin , Jiangtian Li , Xuehao Zhang , Kaixuan Wan , Heao Zhang , Feiyang Huang , Limei Wang , Hongxun Wang , Longjie Li , Xianjin Xiao . Toeless and reversible DNA strand displacement based on Hoogsteen-bond triplex. Chinese Chemical Letters, 2024, 35(5): 108826-. doi: 10.1016/j.cclet.2023.108826
14. [14]
  Jingwen Zhao , Jianpu Tang , Zhen Cui , Limin Liu , Dayong Yang , Chi Yao . A DNA micro-complex containing polyaptamer for exosome separation and wound healing. Chinese Chemical Letters, 2024, 35(9): 109303-. doi: 10.1016/j.cclet.2023.109303
15. [15]
  Zhongyu Wang , Lijun Wang , Huaixin Zhao . DNA-based nanosystems to generate reactive oxygen species for nanomedicine. Chinese Chemical Letters, 2024, 35(11): 109637-. doi: 10.1016/j.cclet.2024.109637
16. [16]
  Wenhao Yan , Shuaiya Xue , Xuerui Zhao , Wei Zhang , Jian Li . Hexagonal boron nitride based slippery liquid infused porous surface with anti-corrosion, anti-contaminant and anti-icing properties for protecting magnesium alloy. Chinese Chemical Letters, 2024, 35(4): 109224-. doi: 10.1016/j.cclet.2023.109224
17. [17]
  Gaofeng WANG , Shuwen SUN , Yanfei ZHAO , Lixin MENG , Bohui WEI . Structural diversity and luminescence properties of three zinc coordination polymers based on bis(4-(1H-imidazol-1-yl)phenyl)methanone. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 849-856. doi: 10.11862/CJIC.20230479
18. [18]
  Weichen WANG , Chunhua GONG , Junyong ZHANG , Yanfeng BI , Hao XU , Jingli XIE . Construction of two metal-organic frameworks by rigid bis(triazole) and carboxylate mixed-ligands and their catalytic properties for CO₂ cycloaddition reaction. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1377-1386. doi: 10.11862/CJIC.20230415
19. [19]
  Fengyun Li , Zerong Pei , Shuting Chen , Gen li , Mengyang Liu , Liqin Ding , Jingbo Liu , Feng Qiu . Multifunctional nano-herb based on tumor microenvironment for enhanced tumor therapy of gambogic acid. Chinese Chemical Letters, 2024, 35(5): 108752-. doi: 10.1016/j.cclet.2023.108752
20. [20]
  Cheng-Zhe Gao , Hao-Ran Jia , Tian-Yu Wang , Xiao-Yu Zhu , Xiaofeng Han , Fu-Gen Wu . A dual drug-loaded tumor vasculature-targeting liposome for tumor vasculature disruption and hypoxia-enhanced chemotherapy. Chinese Chemical Letters, 2025, 36(1): 109840-. doi: 10.1016/j.cclet.2024.109840

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(614)
HTML views(0)

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