Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents

Author(s): Duong T. Anh, Nguyen T. Thuan, Pham-The Hai, Le-Thi-Thu Huong, Nguyen T.K. Yen, Byung W. Han, Eun J. Park, Yeo J. Choi, Jong S. Kang, Van T.M. Hue*, Sang-Bae Han*, Nguyen-Hai Nam*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101).

Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines.

Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships.

Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities.

Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

Keywords: Histone deacetylase (HDAC) inhibitors, hydroxamic acids, N-hydroxybenzamide, N-hydroxypropenamide, molecular docking, inhibitory potency.

[1]
Ruijter, A.J.M.D.; Gennip, A.H.V.; Caron, H.N.; Kemp, S.; Kuilenburg, A.B.P.V. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J., 2003, 370(3), 737-739.
[2]
Hamm, C.A.; Costa, F.F. Epigenomes as therapeutic targets. Pharmacol. Ther., 2015, 151, 72-86.
[3]
Witt, O.; Deubzer, H.E.; Milde, T.; Oehme, I. HDAC family: What are the cancer relevant targets? Cancer Lett., 2009, 277(1), 8-21.
[4]
Ververis, K.; Hiong, A.; Karagiannis, T.C.; Licciardi, P.V. Histone deacetylase inhibitors (HDACIs): Multitargeted anticancer agents. Biologics, 2013, 7, 47-60.
[5]
Valente, S.; Mai, A. Small-molecule inhibitors of histone deacetylase for the treatment of cancer and non-cancer diseases: A patent review (2011-2013). Expert Opin. Ther. Pat., 2014, 24(4), 401-415.
[6]
Jiyang, L.; Guangqiang, L.; Wenqing, X. Histone deacetylase inhibitors: an attractive strategy for cancer therapy. Curr. Med. Chem., 2013, 20(14), 1858-1886.
[7]
Qiu, T.; Zhou, L.; Zhu, W.; Wang, T.; Wang, J.; Shu, Y.; Liu, P. Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future Oncol., 2013, 9(2), 255-269.
[8]
Zwergel, C.; Valente, S.; Jacob, C.; Mai, A. Emerging approaches for histone deacetylase inhibitor drug discovery. Expert Opin. Drug Discov., 2015, 10(6), 599-613.
[9]
West, A.C.; Johnstone, R.W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest., 2014, 124(1), 30-39.
[10]
Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5(9), 769-784.
[11]
Glaser, K.B. HDAC inhibitors: Clinical update and mechanism-based potential. Biochem. Pharmacol., 2007, 74(5), 659-671.
[12]
Dallavalle, S.; Cincinelli, R.; Nannei, R.; Merlini, L.; Morini, G.; Penco, S.; Pisano, C.; Vesci, L.; Barbarino, M.; Zuco, V.; De Cesare, M.; Zunino, F. Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Eur. J. Med. Chem., 2009, 44(5), 1900-1912.
[13]
Bracker, T.U.; Sommer, A.; Fichtner, I.; Faus, H.; Haendler, B.; Hess-Stumpp, H. Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models. Int. J. Oncol., 2009, 35(4), 909-920.
[14]
Iyer, S.P.; Foss, F.F. Romidepsin for the treatment of peripheral t-cell lymphoma. Oncologist, 2015, 20(9), 1084-1091.
[15]
Guha, M. HDAC inhibitors still need a home run, despite recent approval. Nat. Rev. Drug Discov., 2015, 14(5), 365-365.
[16]
Oanh, D.T.K.; Hai, H.V.; Park, S.H.; Kim, H.J.; Han, B.W.; Kim, H-S.; Hong, J.T.; Han, S.B.; Hue, V.T.M.; Nam, N.H. Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Bioorg. Med. Chem. Lett., 2011, 21(24), 7509-7512.
[17]
Thanh, T.T.; Kim, D.T.O.; Phuong, P.T.D.; My, V.T.H.; Ho, S.P.; Woo, B.H.; Youngsoo, K.; Jin-Tae, H.; Sang-Bae, H.; Nguyen-Hai, N. New Benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents. Med. Chem., 2013, 9(8), 1051-1057.
[18]
Nam, N.H.; Huong, T.L.; Dung, D.T.M.; Dung, P.T.P.; Oanh, D.T.K.; Park, S.H.; Kim, K.; Han, B.W.; Yun, J.; Kang, J.S.; Kim, Y.; Han, S.B. Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. J. Enzyme Inhib. Med. Chem., 2014, 29(5), 611-618.
[19]
Do, T.M.D.; Phan, T.P.D.; Dao, T.K.O.; Pham, T.H.; Le, T.T.H.; Vu, D.L.; Hyunggu, H.; Byung, W.H.; Jisung, K.; Sang-Bae, H.; Nguyen-Hai, N. Novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides as histone deacetylase inhibitors and antitumor agents. Med. Chem., 2015, 11(8), 725-735.
[20]
Huong, T.T.L.; Dung, D.T.M.; Huan, N.V.; Cuong, L.V.; Hai, P.T.; Huong, L.T.T.; Kim, J.; Kim, Y.G.; Han, S.B.; Nam, N.H. Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity. Bioorg. Chem., 2017, 71, 160-169.
[21]
Hieu, D.T.; Anh, D.T.; Tuan, N.M.; Hai, P.T.; Huong, L.T.T.; Kim, J.; Kang, J.S.; Vu, T.K.; Dung, P.T.P.; Han, S.B.; Nam, N.H.; Hoa, N.D. Design, synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents. Bioorg. Chem., 2018, 76, 258-267.
[22]
Hieu, D.T.; Anh, D.T.; Hai, P.T.; Huong, L.T.T.; Park, E.J.; Choi, J.E.; Kang, J.S.; Dung, P.T.P.; Han, S.B.; Nam, N.H. Quinazoline-based hydroxamic acids: Design, synthesis, and evaluation of histone deacetylase inhibitory effects and cytotoxicity. Chem. Biodivers., 2018, 15(6), e1800027.
[23]
Dung, D.T.M.; Hai, P.T.; Anh, D.T.; Huong, L.T.T.; Yen, N.T.K.; Han, B.W.; Park, E.J.; Choi, Y.J.; Kang, J.S.; Hue, V.T.M.; Han, S.B.; Nam, N.H. Novel hydroxamic acids incorporating 1-((1H-1,2,3-Triazol-4-yl) methyl)-3-hydroxyimino-indolin-2-ones: synthesis, biological evaluation, and SAR analysis. J. Chem. Sci., 2018, 130(6), 63.
[24]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[25]
Nam, N.H.; Sardari, S.; Parang, K. Reactions of solid-supported reagents and solid supports with alcohols and phenols through their hydroxyl functional group. J. Comb. Chem., 2003, 5(5), 479-546.
[26]
Thuong, P.T.; Na, M.K.; Dang, N.H.; Hung, T.M.; Ky, P.T.; Thanh, T.V.; Nam, N.H.; Thuan, N.D.; Sok, D.E.; Bae, K.H. Antioxidant activities of Vietnamese medicinal plants. Nat. Prod. Sci., 2006, 12, 29-37.
[27]
Wu, L.; Smythe, A.M.; Stinson, S.F.; Mullendore, L.A.; Monks, A.; Scudiero, D.A.; Paull, K.D.; Koutsoukos, A.D.; Rubinstein, L.V.; Boyd, M.R.; Shoemaker, R.H. Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res., 1992, 52(11), 3029.
[28]
Trott, O.; Olson, A.J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2009, 31(2), 455-461.
[29]
Lauffer, B.E.L.; Mintzer, R.; Fong, R.; Mukund, S.; Tam, C.; Zilberleyb, I.; Flicke, B.; Ritscher, A.; Fedorowicz, G.; Vallero, R.; Ortwine, D.F.; Gunzner, J.; Modrusan, Z.; Neumann, L.; Koth, C.M.; Lupardus, P.J.; Kaminker, J.S.; Heise, C.E.; Steiner, P. Histone Deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J. Biol. Chem., 2013, 288(37), 26926-26943.
[30]
Schuttelkopf, A.W.; van-Aalten, D.M.F. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D, 2004, 60(8), 1355-1363.
[31]
Huong, T.T.L.; Van Cuong, L.; Huong, P.T.; Thao, T.P.; Huong, L.T.T.; Dung, P.T.P.; Oanh, D.T.K.; Huong, N.T.M.; Quan, H-V.; Vu, T.K.; Kim, J.; Lee, J.H.; Han, S.B.; Hai, P.T.; Nam, N.H. Exploration of some indole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Chem. Pap., 2017, 71(9), 1759-1769.
[32]
Pelzel, H.R.; Schlamp, C.L.; Nickells, R.W. Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neurosci., 2010, 11(1), 62.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 4
Year: 2019
Page: [546 - 556]
Pages: 11
DOI: 10.2174/1871520618666181114113347
Price: $58

Article Metrics

PDF: 34
HTML: 6