Citation: Tao You, Ke Chen, Fei-Hai Wang, Pi-Hong Li, Li-Yi Li, Zhi-Hao Wu, Kong-Hai Ni, Zhi-Qiang Zheng. Design, synthesis, and biological evaluation of N-hydroxycinnamamide/salicylic acid hybrids as histone deacetylase inhibitors[J]. Chinese Chemical Letters, ;2014, 25(3): 474-478. doi: 10.1016/j.cclet.2013.11.039 shu

Design, synthesis, and biological evaluation of N-hydroxycinnamamide/salicylic acid hybrids as histone deacetylase inhibitors

Tao You ^a ,
Ke Chen ^b ,
Fei-Hai Wang ^a ,
Pi-Hong Li ^a ,
Li-Yi Li ^a ,
Zhi-Hao Wu ^a ,
Kong-Hai Ni ^a ,
Zhi-Qiang Zheng ^a,,

1.
a Department of General Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China;
2.
b School of Clinical Medicine, Wenzhou Medical University, Wenzhou 325035, China

Corresponding author: Zhi-Qiang Zheng,
Received Date: 28 August 2013
Available Online: 7 November 2013

Novel histone deacetylase (HDAC) inhibitors 9a-1 were designed and synthesized by coupling the carboxyl group of salicylic acid (SA) with N-hydroxycinnamamides through various alkylol amines, and their in vitro biological activities were evaluated. The N-hydroxycinnamamide/SA hybrids 9b-f and 9h showed good to moderate anti-tumor activities. Notably, compound 9e had a greater potency, comparable to vorinostat (SAHA), in human colon carcinoma cells, which was probably, or at least partially, attributable to the positive effects of the chain length noted in alkylol amines. Furthermore, the HDAC inhibitory activities of 9e against Hela cell nuclear were also similar to that of vorinostat (SAHA), while the tested compounds 9c-f did not exhibit any isoform selectivity in the inhibition of HDACs. In addition, compound 9e could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. Our findings suggest that the N-hydroxycinnamamide/SA hybrids may hold significant promise as therapeutic agents for the intervention of human cancers.
- Synthesis,
- Anti-tumor agents,
- Histone deacetylase inhibitors,
- N-Hydroxycinnamamides,
- Salicylic acid
1. [1]
  [1] T.K. Kelly, D.D. de Carvalho, P.A. Jones, Epigenetic modifications as therapeutic targets, Nat. Biotechnol. 28 (2010) 1069-1078.
2. [2]
  [2] L.P. Blair, Q. Yan, Epigenetic mechanisms in commonly occurring cancers, DNA Cell Biol. 31 (2012) S49-S61.
3. [3]
  [3] H. Lehrmann, L.L. Pritchard, A. Harel-Bellan, et al., Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation, Adv. Cancer. Res. 86 (2002) 41-65.
4. [4]
  [4] O. Witt, H.E. Deubzer, T. Milde, I. Oehme, HDAC family: what are the cancer relevant targets, Cancer Lett. 277 (2009) 8-21.
5. [5]
  [5] A.A. Lane, B.A. Chabner, Histone deacetylase inhibitors in cancer therapy, J. Clin. Oncol. 27 (2009) 5459-5468.
6. [6]
  [6] B.E. Gryder, Q.H. Sodji, A.K. Oyelere, Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed, Future Med. Chem. 4 (2012) 505-524.
7. [7]
  [7] P.A. Marks, The clinical development of histone deacetylase inhibitors as targeted anticancer drugs, Expert Opin. Invest. Drugs 19 (2010) 1049-1066.
8. [8]
  [8] H.S. Wang, B.W. Dymock, New patented histone deacetylase inhibitors, Expert Opin. Ther. Pat. 19 (2009) 1727-1757.
9. [9]
  [9] M. Paris, M. Porcelloni, M. Binaschi, D. Fattori, Histone deacetylase inhibitors: from bench to clinic, J. Med. Chem. 51 (2008) 1505-1529.
10. [10]
  [10] P.A. Marks, Discovery and development of SAHA as an anticancer agent, Oncogene 26 (2007) 1351-1356.
11. [11]
  [11] C. Campas-Moya, Romidepsin for the treatment of cutaneous T-cell lymphoma, Drugs Today 45 (2009) 787-795.
12. [12]
  [12] P.A. Cassier, A. Lefranc, E.Y. Amela, et al., A phase Ⅱ trial of panobinostat in patients with advanced pretreated soft tissue sarcoma: a study from the French Sarcoma Group, Br. J. Cancer 19 (2013) 909-914.
13. [13]
  [13] J.A. Plumb, P.W. Finn, R.J. Williams, et al., Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101, Mol. Cancer Ther. 2 (2003) 721-728.
14. [14]
  [14] A.R. Razak, S.J. Hotte, L.L. Siu, et al., Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours, Br. J. Cancer 104 (2011) 756-762.
15. [15]
  [15] C. Doñas, M. Fritz, V. Manríquez, et al., Trichostatin A promotes the generation and suppressive functions of regulatory T cells, Clin. Dev. Immunol. (2013) 679-804.
16. [16]
  [16] K. Rao-Bindal, N.V. Koshkina, J. Stewart, et al., The histone deacetylase inhibitor, MS-275 (entinostat), downregulates c-FLIP, sensitizes osteosarcoma cells to FasL, and induces the regression of osteosarcoma lung metastases, Curr. Cancer Drug Targets 13 (2013) 411-422.
17. [17]
  [17] Y. Boumber, A. Younes, G. Garcia-Manero, Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor, Expert Opin. Investig. Drugs 20 (2011) 823-829.
18. [18]
  [18] T.A. Miller, D.J. Witter, S. Belvedere, Histone deacetylase inhibitors, J. Med. Chem. 46 (2003) 5097-5116.
19. [19]
  [19] Z.H. Zhao, M.H. Moghadasian, Chemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: a review, Food Chem. 109 (2008) 691-702.
20. [20]
  [20] M.D. Lu, X. Zhou, Y.J. Yu, et al., Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents, Chin. Chem. Lett. 24 (2013) 415-418.
21. [21]
  [21] A. Ghasemzadeh, H.Z. Jaafar, E. Karimi, Involvement of salicylic acid on antioxidant and anticancer properties, anthocyanin production and chalcone synthase activity in ginger (Zingiber officinale Roscoe) varieties, Int. J. Mol. Sci. 13 (2012) 14828-14844.
22. [22]
  [22] J. Sonnemann, I. Hü ls, M. Sigler, et al., Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells, Oncol. Rep. 20 (2008) 219-224.
23. [23]
  [23] The data of selected compounds. 9b: Yield 46%, mp 111-114 ℃; MS (ESI): m/z 387[M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 8.96 (s, 1H), 7.66-7.78 (m, 2H), 7.42 (d, 1H, J = 16.2 Hz), 6.78-7.12 (m, 5H), 6.38 (d, 1H, J = 16.2 Hz), 4.12 (t, 2H, J = 4.5 Hz), 3.83 (s, 3H), 3.62 (t, 2H, J = 4.5 Hz), 1.96-2.21 (m, 2H); Anal. Calcd. for C₂₀H₂₂N₂O₆: C, 62.17; H, 5.74; N, 7.25; Found: C, 62.28; H, 5.56; N, 7.13. 9c: Yield 52%, mp 102-104 ℃; MS (ESI): m/z 401 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 8.89 (s, 1H), 7.65-7.77 (m, 2H), 7.40 (d, 1H, J = 16.2 Hz), 6.73-7.15 (m, 5H), 6.35 (d, 1H, J = 16.2 Hz), 4.10 (t, 2H, J = 4.5 Hz), 3.80 (s, 3H), 3.59 (t, 2H, J = 4.5 Hz), 1.75-1.98 (m, 4H); Anal. Calcd. for C21H24N2O6: C, 62.99; H, 6.04; N, 7.00; Found: C, 62.85; H, 4.96; N, 7.13. 9d: Yield 38%, mp 119-122 ℃; MS (ESI): m/z 387 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 7.68-7.79 (m, 2H), 7.45 (d, 1H, J = 16.2 Hz), 6.79-7.21 (m, 5H), 6.39 (d, 1H, J = 16.2 Hz), 4.15 (t, 2H, J = 4.5 Hz), 3.84 (s, 3H), 3.65 (t, 2H, J = 4.5 Hz), 3.06 (s, 3H); Anal. Calcd. for C₂₀H₂₂N₂O₆: C, 62.17; H, 5.74; N, 7.25; Found: C, 62.03; H, 5.86; N, 7.17. 9e: Yield 47%, mp 108-111 ℃; MS (ESI): m/z 401 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 7.65-7.78 (m, 2H), 7.43 (d, 1H, J = 16.2 Hz), 6.76-7.19 (m, 5H), 6.37 (d, 1H, J = 16.2 Hz), 4.13 (t, 2H, J = 4.5 Hz), 3.81 (s, 3H), 3.64 (t, 2H, J = 4.5 Hz), 3.03 (s, 3H), 1.98-2.23 (m, 2H); Anal. Calcd. for C21H24N2O6: C, 62.99; H, 6.04; N, 7.00; Found: C, 63.07; H, 6.26; N, 7.16. 9f: Yield 55%, mp 103-106 ℃; MS (ESI): m/z 415[M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.47 (s, 1H), 7.63-7.77 (m, 2H), 7.40 (d, 1H, J = 16.2 Hz), 6.73-7.17 (m, 5H), 6.34 (d, 1H, J = 16.2 Hz), 4.10 (t, 2H, J = 4.5 Hz), 3.79 (s, 3H), 3.61 (t, 2H, J = 4.5 Hz), 3.02 (s, 3H), 1.78-2.02 (m, 4H); Anal. Calcd. for C₂₂H₂₆N₂O₆: C, 63.76; H, 6.32; N, 6.76; Found: C, 63.57; H, 6.56; N, 7.59. 9h: Yield 57%, mp 95-98 ℃; MS (ESI): m/z 415 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 7.59-7.75 (m, 2H), 7.38 (d, 1H, J = 16.2 Hz), 6.70-7.16 (m, 5H), 6.32 (d, 1H, J = 16.2 Hz), 4.07 (t, 2H, J = 4.5 Hz), 3.80 (s, 3H), 3.57 (t, 2H, J = 4.5 Hz), 3.00 (s, 3H), 1.95-2.22 (m, 2H); Anal. Calcd. for C₂₂H₂₆N₂O₆: C, 63.76; H, 6.32; N, 6.76; Found: C, 63.53; H, 6.48; N, 7.62.
1. [1]
  Yulong Shi , Fenbei Chen , Mengyuan Wu , Xin Zhang , Runze Meng , Kun Wang , Yan Wang , Yuheng Mei , Qionglu Duan , Yinghong Li , Rongmei Gao , Yuhuan Li , Hongbin Deng , Jiandong Jiang , Yanxiang Wang , Danqing Song . Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1. Chinese Chemical Letters, 2024, 35(5): 108792-. doi: 10.1016/j.cclet.2023.108792
2. [2]
  Huiju Cao , Lei Shi . sp¹-Hybridized linear and cyclic carbon chain. Chinese Chemical Letters, 2025, 36(4): 110466-. doi: 10.1016/j.cclet.2024.110466
3. [3]
  Mianling Yang , Meehyein Kim , Peng Zhan . Modular miniaturized synthesis and in situ biological evaluation facilitate rapid discovery of potent MraY inhibitors as antibacterial agents. Chinese Chemical Letters, 2025, 36(2): 110455-. doi: 10.1016/j.cclet.2024.110455
4. [4]
  Fengmiao Yu , Yang Sheng , Chanyue Li , Bao Li . The Three Lives of Aspirin. University Chemistry, 2024, 39(9): 115-121. doi: 10.12461/PKU.DXHX202402033
5. [5]
  Jiaming Xu , Yu Xiang , Weisheng Lin , Zhiwei Miao . Research Progress in the Synthesis of Cyclic Organic Compounds Using Bimetallic Relay Catalytic Strategies. University Chemistry, 2024, 39(3): 239-257. doi: 10.3866/PKU.DXHX202309093
6. [6]
  Wenyi Mei , Lijuan Xie , Xiaodong Zhang , Cunjian Shi , Fengzhi Wang , Qiqi Fu , Zhenjiang Zhao , Honglin Li , Yufang Xu , Zhuo Chen . Design, synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells. Chinese Chemical Letters, 2024, 35(5): 108825-. doi: 10.1016/j.cclet.2023.108825
7. [7]
  Yulin Mao , Jingyu Ma , Jiecheng Ji , Yuliang Wang , Wanhua Wu , Cheng Yang . Crown aldoxime ethers: Their synthesis, structure, acid-catalyzed/photo-induced isomerization and adjustable guest binding. Chinese Chemical Letters, 2024, 35(11): 109927-. doi: 10.1016/j.cclet.2024.109927
8. [8]
  Guoping Yang , Zhoufu Lin , Xize Zhang , Jiawei Cao , Xuejiao Chen , Yufeng Liu , Xiaoling Lin , Ke Li . Assembly of Y(Ⅲ)-containing antimonotungstates induced by malic acid with catalytic activity for the synthesis of imidazoles. Chinese Chemical Letters, 2024, 35(12): 110274-. doi: 10.1016/j.cclet.2024.110274
9. [9]
  Dongdong YANG , Jianhua XUE , Yuanyu YANG , Meixia WU , Yujia BAI , Zongxuan WANG , Qi MA . Design and synthesis of two coordination polymers for the rapid detection of ciprofloxacin based on triphenylpolycarboxylic acid ligands. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2466-2474. doi: 10.11862/CJIC.20240266
10. [10]
  Jiajun Lu , Zhehui Liao , Tongxiang Cao , Shifa Zhu . Synergistic Brønsted/Lewis acid catalyzed atroposelective synthesis of aryl-β-naphthol. Chinese Chemical Letters, 2025, 36(1): 109842-. doi: 10.1016/j.cclet.2024.109842
11. [11]
  Jimin HOU , Mengyang LI , Chunhua GONG , Shaozhuang ZHANG , Caihong ZHAN , Hao XU , Jingli XIE . Synthesis, structures, and properties of metal-organic frameworks based on bipyridyl ligands and isophthalic acid. Chinese Journal of Inorganic Chemistry, 2025, 41(3): 549-560. doi: 10.11862/CJIC.20240348
12. [12]
  Shengkai Li , Yuqin Zou , Chen Chen , Shuangyin Wang , Zhao-Qing Liu . Defect engineered electrocatalysts for C–N coupling reactions toward urea synthesis. Chinese Chemical Letters, 2024, 35(8): 109147-. doi: 10.1016/j.cclet.2023.109147
13. [13]
  Kaimin WANG , Xiong GU , Na DENG , Hongmei YU , Yanqin YE , Yulu MA . Synthesis, structure, fluorescence properties, and Hirshfeld surface analysis of three Zn(Ⅱ)/Cu(Ⅱ) complexes based on 5-(dimethylamino) isophthalic acid. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1397-1408. doi: 10.11862/CJIC.20240009
14. [14]
  Jing LIANG , Qian WANG , Junfeng BAI . Synthesis and structures of cdq-topological quaternary and (4, 4, 8)-c topological quinary Zn-MOFs with both oxalic acid and triazole ligands. Chinese Journal of Inorganic Chemistry, 2024, 40(11): 2186-2192. doi: 10.11862/CJIC.20240177
15. [15]
  Yuexiang Liu , Xiangqiao Yang , Tong Lin , Guantian Yang , Xiaoyong Xu , Bubing Zeng , Zhong Li , Weiping Zhu , Xuhong Qian . Efficient continuous synthesis of 2-[3-(trifluoromethyl)phenyl]malonic acid, a key intermediate of Triflumezopyrim, coupling with esterification-condensation-hydrolysis. Chinese Chemical Letters, 2025, 36(1): 109747-. doi: 10.1016/j.cclet.2024.109747
16. [16]
  Hangwen Zheng , Ziqian Wang , HuiJie Zhang , Jing Lei , Rihui Li , Jian Yang , Haiyan Wang . Synthesis and applications of B, N co-doped carbons for zinc-based energy storage devices. Chinese Chemical Letters, 2025, 36(3): 110245-. doi: 10.1016/j.cclet.2024.110245
17. [17]
  Xinyu Hou , Xuelian Yu , Meng Liu , Hengxing Peng , Lijuan Wu , Libing Liao , Guocheng Lv . Ultrafast synthesis of Mo₂N with highly dispersed Ru for efficient alkaline hydrogen evolution. Chinese Chemical Letters, 2025, 36(4): 109845-. doi: 10.1016/j.cclet.2024.109845
18. [18]
  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
19. [19]
  Ao Sun , Zipeng Li , Shuchun Li , Xiangbao Meng , Zhongtang Li , Zhongjun Li . Stereoselective synthesis of α-3-deoxy-D-manno-oct-2-ulosonic acid (α-Kdo) derivatives using a C3-p-tolylthio-substituted Kdo fluoride donor. Chinese Chemical Letters, 2025, 36(3): 109972-. doi: 10.1016/j.cclet.2024.109972
20. [20]
  Jin Wang , Xiaoyan Pan , Junyu Zhang , Qingqing Zhang , Yanchen Li , Weiwei Guo , Jie Zhang . Active molecule-based theranostic agents for tumor vasculature normalization and antitumor efficacy. Chinese Chemical Letters, 2024, 35(8): 109187-. doi: 10.1016/j.cclet.2023.109187

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(588)
HTML views(1)

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