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

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

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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

    • 通讯作者: Ming-Li Yang,
    Jie Wu,
  • 基金项目:

    This study was supported by Wuhan City Department of Education (No. 2009K106). (No. 2009K106)

摘要: 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.

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    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).[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).

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  • 发布日期:  2014-01-14
  • 收稿日期:  2013-10-05
  • 网络出版日期:  2013-12-19
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