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Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

Mao Cai ,  Jie Hu ,  Ji-Lai Tian ,  Huang Yan ,  Chen-Guo Zheng ,  Wan-Le Hu

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Citation:  Mao Cai, Jie Hu, Ji-Lai Tian, Huang Yan, Chen-Guo Zheng, Wan-Le Hu. Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities[J]. Chinese Chemical Letters, 2015, 26(6): 675-680. doi: 10.1016/j.cclet.2015.03.015 shu

Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

    • 通讯作者: Wan-Le Hu,
摘要: Novel hybrid molecules 8a-8o were designed and synthesized by connecting indole ring with N-hydroxyarylamide through alkyl substituted triazole, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed promising anticancer activities, particularly for 8n, which had a significant HDACs inhibitory and antiproliferative activities comparable to or slightly stronger than SAHA against human carcinoma cells. Furthermore, compound 8n exhibited much better selectivity for HDAC1 over HDAC6 and HDAC8 than SAHA. In addition, compound 8n also could dose-dependently induce cancer cell cycling arrest at G0/G1 phase and promote the expression of the acetylation for histone H3 and tubulin in vitro. Therefore, our novel findings may provide a new framework for the design of new selective HDAC inhibitor for the treatment of cancer.

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    28. [28] The data of selected compounds: 8c: Yield: 86%, mp 116-119℃; ESI-MSm/z: 390[M+H]+. 1H NMR (300 MHz, DMSO-d6):δ5.31 (s, 2H), 5.43 (s, 2H), 6.55 (d, 1H, J = 15.9 Hz), 6.96-6.99 (m, 2H), 7.08-7.11 (m, 2H), 7.15 (d, 1H, J = 2.4 Hz), 7.35 (m, 1H), 7.57 (d, 1H, J = 7.8 Hz), 7.63-7.68 (m, 3H), 7.79 (s, 1H), 8.96 (s, 1H), 10.41 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.5, 71.2, 107.4, 111.8, 115.6, 118.2, 118.5, 119.3, 120.7, 122.7, 123.1, 127.1, 130.5, 136.0, 139.2, 146.3, 155.1, 164.6. ESIHRMS (m/z): [M+H]+ calcd. for C21H20N5O3: 390.1566; found: 390.1558. 8d: Yield: 83%, mp 123-125℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.81 (s, 3H), 5.29 (s, 2H), 5.50 (s, 2H), 6.53 (d, 1H, J = 15.9 Hz), 6.94-6.97 (m, 3H), 7.08-7.10 (m, 2H), 7.15-7.21 (m, 3H), 7.33 (d, 1H, J = 7.8 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 15.9 Hz), 7.77 (s, 1H), 8.91 (s, 1H), 10.35 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.0, 56.3, 71.5, 107.7, 110.7, 111.6, 114.4, 118.3, 118.9, 119.5, 121.0, 122.9, 123.3, 127.6, 136.3, 138.9, 146.2, 146.5, 154.8, 164.7. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1665. 8i: Yield: 89%, mp 105-108℃; ESI-MS m/z: 434 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ2.61 (t, 2H, J = 6.6 Hz), 3.37 (t, 2H, J = 6.6 Hz), 3.83 (s, 3H), 5.33 (s, 2H), 6.56 (d, 1H, J = 15.9 Hz), 6.92-6.98 (m, 3H), 7.09-7.12 (m, 2H), 7.17-7.22 (m, 3H), 7.35 (d, 1H, J = 7.8 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 15.9 Hz), 7.80 (s, 1H), 8.95 (s, 1H), 10.39 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ28.1, 50.3, 56.5, 71.3, 106.9, 110.5, 111.3, 114.5, 117.8, 118.5, 119.2, 120.7, 122.5, 123.1, 127.3, 136.3, 138.9, 146.2, 146.7, 155.1, 164.9. ESI-HRMS (m/z):[M+H]+ calcd. for C23H24N5O4: 434.1828; found: 434.1842. 8m: Yield: 82%, mp 121-124℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.80 (s, 3H), 5.30 (s, 2H), 5.46 (s, 2H), 6.52 (d, 1H, J = 15.9 Hz), 6.76 (m, 1H), 6.96 (d, 2H, J = 8.4 Hz), 7.11-7.15 (m, 2H), 7.22 (d, 1H, J = 7.8 Hz), 7.61-7.66 (m, 3H), 7.75 (s, 1H), 8.87 (s, 1H), 10.25 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.1, 56.8, 71.5, 102.1, 111.9, 112.2, 115.5, 118.4, 122.6, 123.3, 128.3, 129.1, 130.1, 138.9, 146.2, 146.6, 155.3, 165.1. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1681. 8n: Yield: 85%, mp 110-112℃; ESI-MS m/z: 450 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.83 (s, 6H), 5.35 (s, 2H), 5.53 (s, 2H), 6.57 (d, 1H, J = 15.9 Hz), 6.79 (m, 1H), 6.95-7.00 (m, 3H), 7.12-7.23 (m, 5H), 7.65 (d, 1H, J = 15.9 Hz), 7.81 (s, 1H), 8.97 (s, 1H), 10.41 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.3, 56.8, 71.6, 101.9, 110.3, 111.1, 112.1, 112.7, 118.5, 122.5, 123.2, 128.9, 129.3, 130.4, 138.7, 146.2, 146.4, 146.8, 154.7, 164.7. ESI-HRMS (m/z): [M+H]+ calcd. for C23H24N5O5: 450.1777; found: 450.1786. 8o: Yield: 83%, mp 118-120℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.79 (s, 3H), 5.32 (s, 2H), 5.45 (s, 2H), 6.50 (d, 1H, J = 15.9 Hz), 6.88-6.93 (m, 2H), 7.09-7.17 (m, 4H), 7.24 (d, 1H, J = 7.8 Hz), 7.53 (m, 1H), 7.62 (d, 1H, J = 15.9 Hz), 7.73 (s, 1H), 8.82 (s, 1H), 10.33 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.8, 71.5, 102.0, 112.0, 112.4, 114.7, 118.5, 122.7, 123.1, 128.0, 128.5, 130.2, 137.6, 146.2, 146.4, 155.3, 164.9. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1659.[28] The data of selected compounds: 8c: Yield: 86%, mp 116-119℃; ESI-MSm/z: 390[M+H]+. 1H NMR (300 MHz, DMSO-d6):δ5.31 (s, 2H), 5.43 (s, 2H), 6.55 (d, 1H, J = 15.9 Hz), 6.96-6.99 (m, 2H), 7.08-7.11 (m, 2H), 7.15 (d, 1H, J = 2.4 Hz), 7.35 (m, 1H), 7.57 (d, 1H, J = 7.8 Hz), 7.63-7.68 (m, 3H), 7.79 (s, 1H), 8.96 (s, 1H), 10.41 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.5, 71.2, 107.4, 111.8, 115.6, 118.2, 118.5, 119.3, 120.7, 122.7, 123.1, 127.1, 130.5, 136.0, 139.2, 146.3, 155.1, 164.6. ESIHRMS (m/z): [M+H]+ calcd. for C21H20N5O3: 390.1566; found: 390.1558. 8d: Yield: 83%, mp 123-125℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.81 (s, 3H), 5.29 (s, 2H), 5.50 (s, 2H), 6.53 (d, 1H, J = 15.9 Hz), 6.94-6.97 (m, 3H), 7.08-7.10 (m, 2H), 7.15-7.21 (m, 3H), 7.33 (d, 1H, J = 7.8 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 15.9 Hz), 7.77 (s, 1H), 8.91 (s, 1H), 10.35 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.0, 56.3, 71.5, 107.7, 110.7, 111.6, 114.4, 118.3, 118.9, 119.5, 121.0, 122.9, 123.3, 127.6, 136.3, 138.9, 146.2, 146.5, 154.8, 164.7. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1665. 8i: Yield: 89%, mp 105-108℃; ESI-MS m/z: 434 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ2.61 (t, 2H, J = 6.6 Hz), 3.37 (t, 2H, J = 6.6 Hz), 3.83 (s, 3H), 5.33 (s, 2H), 6.56 (d, 1H, J = 15.9 Hz), 6.92-6.98 (m, 3H), 7.09-7.12 (m, 2H), 7.17-7.22 (m, 3H), 7.35 (d, 1H, J = 7.8 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 15.9 Hz), 7.80 (s, 1H), 8.95 (s, 1H), 10.39 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ28.1, 50.3, 56.5, 71.3, 106.9, 110.5, 111.3, 114.5, 117.8, 118.5, 119.2, 120.7, 122.5, 123.1, 127.3, 136.3, 138.9, 146.2, 146.7, 155.1, 164.9. ESI-HRMS (m/z):[M+H]+ calcd. for C23H24N5O4: 434.1828; found: 434.1842. 8m: Yield: 82%, mp 121-124℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.80 (s, 3H), 5.30 (s, 2H), 5.46 (s, 2H), 6.52 (d, 1H, J = 15.9 Hz), 6.76 (m, 1H), 6.96 (d, 2H, J = 8.4 Hz), 7.11-7.15 (m, 2H), 7.22 (d, 1H, J = 7.8 Hz), 7.61-7.66 (m, 3H), 7.75 (s, 1H), 8.87 (s, 1H), 10.25 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.1, 56.8, 71.5, 102.1, 111.9, 112.2, 115.5, 118.4, 122.6, 123.3, 128.3, 129.1, 130.1, 138.9, 146.2, 146.6, 155.3, 165.1. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1681. 8n: Yield: 85%, mp 110-112℃; ESI-MS m/z: 450 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.83 (s, 6H), 5.35 (s, 2H), 5.53 (s, 2H), 6.57 (d, 1H, J = 15.9 Hz), 6.79 (m, 1H), 6.95-7.00 (m, 3H), 7.12-7.23 (m, 5H), 7.65 (d, 1H, J = 15.9 Hz), 7.81 (s, 1H), 8.97 (s, 1H), 10.41 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.3, 56.8, 71.6, 101.9, 110.3, 111.1, 112.1, 112.7, 118.5, 122.5, 123.2, 128.9, 129.3, 130.4, 138.7, 146.2, 146.4, 146.8, 154.7, 164.7. ESI-HRMS (m/z): [M+H]+ calcd. for C23H24N5O5: 450.1777; found: 450.1786. 8o: Yield: 83%, mp 118-120℃; ESI-MS m/z: 420 [M+H]+. 1H NMR (300 MHz, DMSO-d6):δ3.79 (s, 3H), 5.32 (s, 2H), 5.45 (s, 2H), 6.50 (d, 1H, J = 15.9 Hz), 6.88-6.93 (m, 2H), 7.09-7.17 (m, 4H), 7.24 (d, 1H, J = 7.8 Hz), 7.53 (m, 1H), 7.62 (d, 1H, J = 15.9 Hz), 7.73 (s, 1H), 8.82 (s, 1H), 10.33 (s, 1H). 13C NMR (75 MHz, DMSO-d6):δ52.8, 71.5, 102.0, 112.0, 112.4, 114.7, 118.5, 122.7, 123.1, 128.0, 128.5, 130.2, 137.6, 146.2, 146.4, 155.3, 164.9. ESI-HRMS (m/z): [M+H]+ calcd. for C22H22N5O4: 420.1672; found: 420.1659.

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  • 发布日期:  2015-03-27
  • 收稿日期:  2014-12-11
  • 网络出版日期:  2015-01-23
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