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

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

1.
a Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China;
2.
b Department of Pharmacy, Wenzhou Medical University, Wenzhou 325000, China;
3.
c Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210008, China

Corresponding author: Wan-Le Hu,
Received Date: 11 December 2014
Available Online: 23 January 2015

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.
- Synthesis,
- Anti-tumor agents,
- Histone deacetylase inhibitors,
- N-Hydroxyarylamides,
- Click chemistry
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  [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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