Design, Synthesis and Biological Evaluation of Novel N-hydroxyheptanamides Incorporating 6-hydroxy-2-methylquinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Cytotoxic Agents

Author(s): Nguyen V. Minh, Nguyen T. Thanh, Hoang T. Lien, Dinh T.P. Anh, Ho D. Cuong, Nguyen H. Nam, Pham T. Hai, Le Minh-Ngoc, Huong Le-Thi-Thu, Luu V. Chinh, Tran K. Vu*.

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

Volume 19 , Issue 12 , 2019

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Graphical Abstract:


Abstract:

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development worldwide, and Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer 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 vorinostat and belinostat.

Aims: This study aims at developing novel HDAC inhibitors bearing quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines.

Methods: A series of novel N-hydroxyheptanamides incorporating 6-hydroxy-2 methylquinazolin-4(3H)-ones (14a-m) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2 (liver cancer), MCF-7 (breast cancer) and SKLu-1 (lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. ADME-T predictions for selected compounds were also performed to predict some important features contributing to the absorption profile of the present hydroxamic derivatives.

Results: It was found that the N-hydroxyheptanamide 14i and 14j were the most potent, both in terms of HDAC inhibition and cytotoxicity. These compounds displayed up to 21-71-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in terms of cytotoxicity, and strong inhibition against the whole cell HDAC enzymes with IC50 values of 7.07-9.24μM. Docking experiments on HDAC2 isozyme using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.02 to -11.23 kcal/mol) compared to SAHA (-7.4 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward breast cancer cells (MCF-7) than liver (HepG2), and lung (SKLu-1) cancer cells.

Keywords: Histone deacetylase (HDAC) inhibitors, hydroxamic acids, quinazolin-4(3H)-one, molecular docking, cytotoxic agents, Nhydroxyheptanamide.

[1]
Nam, N.H.; Parang, K. Current targets for anticancer drug discovery. Curr. Drug Targets, 2003, 4(2), 159-179.
[http://dx.doi.org/10.2174/1389450033346966] [PMID: 12558068]
[2]
Marks, P.; Rifkind, R.A.; Richon, V.M.; Breslow, R.; Miller, T.; Kelly, W.K. Histone deacetylases and cancer: Causes and therapies. Nat. Rev. Cancer, 2001, 1(3), 194-202.
[http://dx.doi.org/10.1038/35106079] [PMID: 11902574]
[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.
[http://dx.doi.org/10.1016/j.canlet.2008.08.016] [PMID: 18824292]
[4]
Delcuve,, G.P.; Khan,, D.H.; Davie,, J.R. Roles of histone deacetylases in epigenetic regulation: Emerging paradigms from studies with inhibitors. Clin. Epigenetics., 2012, 4(1), 5.
[5]
de Ruijter, A.J.M.; van Gennip, A.H.; Caron, H.N.; Kemp, S.; van Kuilenburg, A.B. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J., 2003, 370(Pt 3), 737-749.
[http://dx.doi.org/10.1042/bj20021321] [PMID: 12429021]
[6]
Li, G.; Jiang, H.; Chang, M.; Xie, H.; Hu, L. HDAC6 α-tubulin deacetylase: a potential therapeutic target in neurodegenerative diseases. J. Neurol. Sci., 2011, 304(1-2), 1-8.
[http://dx.doi.org/10.1016/j.jns.2011.02.017] [PMID: 21377170]
[7]
Ropero, S.; Esteller, M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol., 2007, 1(1), 19-25.
[http://dx.doi.org/10.1016/j.molonc.2007.01.001] [PMID: 19383284]
[8]
Ververis, K.; Hiong, A.; Karagiannis, T.C.; Licciardi, P.V. Histone deacetylase inhibitors (HDACIs): Multitargeted anticancer agents. Biologics, 2013, 7, 47-60.
[PMID: 23459471]
[9]
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.
[http://dx.doi.org/10.2217/fon.12.173] [PMID: 23414475]
[10]
West, A.C.; Johnstone, R.W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest., 2014, 124(1), 30-39.
[http://dx.doi.org/10.1172/JCI69738] [PMID: 24382387]
[11]
Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5(9), 769-784.
[http://dx.doi.org/10.1038/nrd2133] [PMID: 16955068]
[12]
Marks, P.A.; Dokmanovic, M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin. Investig. Drugs, 2005, 14(12), 1497-1511.
[http://dx.doi.org/10.1517/13543784.14.12.1497] [PMID: 16307490]
[13]
Johnstone, R.W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov., 2002, 1(4), 287-299.
[http://dx.doi.org/10.1038/nrd772] [PMID: 12120280]
[14]
Glaser, K.B. HDAC inhibitors: Clinical update and mechanism-based potential. Biochem. Pharmacol., 2007, 74(5), 659-671.
[http://dx.doi.org/10.1016/j.bcp.2007.04.007] [PMID: 17498667]
[15]
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.
[http://dx.doi.org/10.1016/j.ejmech.2008.11.005] [PMID: 19084294]
[16]
Mercurio, C.; Minucci, S.; Pelicci, P.G. Histone deacetylases and epigenetic therapies of hematological malignancies. Pharmacol. Res., 2010, 62(1), 18-34.
[http://dx.doi.org/10.1016/j.phrs.2010.02.010] [PMID: 20219679]
[17]
Stimson, L.; Wood, V.; Khan, O.; Fotheringham, S.; La Thangue, N.B. HDAC inhibitor-based therapies and haematological malignancy. Ann. Oncol., 2009, 20(8), 1293-1302.
[http://dx.doi.org/10.1093/annonc/mdn792] [PMID: 19515748]
[18]
Ma, N.; Luo, Y.; Wang, Y.; Liao, C.; Ye, W.C.; Jiang, S. Selective histone deacetylase inhibitors with anticancer activity. Curr. Top. Med. Chem., 2016, 16(4), 415-426.
[http://dx.doi.org/10.2174/1568026615666150813145629] [PMID: 26268343]
[19]
Arrowsmith, C.H.; Bountra, C.; Fish, P.V.; Lee, K.; Schapira, M. Epigenetic protein families: A new frontier for drug discovery. Nat. Rev. Drug Discov., 2012, 11(5), 384-400.
[http://dx.doi.org/10.1038/nrd3674] [PMID: 22498752]
[20]
Huong, T.T.L.; Dung, D.T.M.; Dung, P.T.P.; Huong, P.T.; Vu, T.K.; Hahn, H.; Han, B.W.; Kim, J.; Pyo, M.; Han, S.B.; Nam, N.H. Novel 2-oxoindoline-based hydroxamic acids: synthesis, cytotoxicity, and inhibition of histone deacetylation. Tetrahedron Lett., 2015, 56, 6425-6429.
[http://dx.doi.org/10.1016/j.tetlet.2015.09.147]
[21]
Ha, V.T.; Kien, V.T.; Binh, H.; Tien, V.D.; My, N.T.T.; Nam, N.H.; Baltas, M.; Hahn, H.; Han, B.W.; Thao, T.; Vu, T.K. Design, synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton. Bioorg. Chem., 2016, 66, 63-71.
[http://dx.doi.org/10.1016/j.bioorg.2016.03.008] [PMID: 27018835]
[22]
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.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.007] [PMID: 29223029]
[23]
Yadav, M.R.; Naik, P.P.; Gandhi, H.P.; Chauhan, B.S.; Giridhar, R. Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism. Bioorg. Med. Chem. Lett., 2013, 23(13), 3959-3966.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.054] [PMID: 23683590]
[24]
Venkatesh, R.; Ramaiah, M.J.; Gaikwad, H.K.; Janardhan, S.; Bantu, R.; Nagarapu, L.; Sastry, G.N.; Ganesh, A.R.; Bhadra, M. Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells. Eur. J. Med. Chem., 2015, 94, 87-101.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.057] [PMID: 25757092]
[25]
a)Kamal, A.; Tamboli, J.R.; Ramaiah, M.J.; Adil, S.F.; Pushpavalli, S.N.; Ganesh, R.; Sarma, P.; Bhadra, U.; Pal-Bhadra, M. Quinazolino linked 4β-amidopodophyllotoxin conjugates regulate angiogenic pathway and control breast cancer cell proliferation. Bioorg. Med. Chem., 2013, 21(21), 6414-6426.
[http://dx.doi.org/10.1016/j.bmc.2013.08.051] [PMID: 24055291]
b)Yang, Z.; Wang, T.; Wang, F.; Niu, T.; Liu, Z.; Chen, X.; Long, C.; Tang, M.; Cao, D.; Wang, X.; Xiang, W.; Yi, Y.; Ma, L.; You, J.; Chen, L. Discovery of selective histone deacetylase 6 inhibitors using the quinazoline as the cap for the treatment of cancer. J. Med. Chem., 2016, 59(4), 1455-1470.
[26]
Finnin, M.S.; Donigian, J.R.; Cohen, A.; Richon, V.M.; Rifkind, R.A.; Marks, P.A.; Breslow, R.; Pavletich, N.P. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature, 1999, 401(6749), 188-193.
[http://dx.doi.org/10.1038/43710] [PMID: 10490031]
[27]
Cai, X.; Zhai, H.X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C.J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem., 2010, 53(5), 2000-2009.
[http://dx.doi.org/10.1021/jm901453q] [PMID: 20143778]
[28]
Theodorou, V.; Skobridis, K.; Tzakos, A.G.; Ragoussis, V. A simple method for the alkaline hydrolysis of esters. Tetrahedron Lett., 2007, 48, 8230-8233.
[http://dx.doi.org/10.1016/j.tetlet.2007.09.074]
[29]
Yeom, C.E.; Shin, Y.J.; Kim, B.M. Acetyl chloride-mediated mild and chemoselective attachment and removal of tetrahydropyranyl (THP) group. Bull. Korean Chem. Soc., 2007, 1, 103-107.
[30]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[31]
Scudiero, D.A.; Shoemaker, R.H.; Paull, K.D.; Monks, A.; Tierney, S.; Nofziger, T.H.; Currens, M.J.; Seniff, D.; Boyd, M. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 1988, 48, 4827-4833.
[PMID: 3409223]
[32]
Kardono, L.B.S.; Angerhofer, C.K.; Tsauri, S.; Padmawinata, K.; Pezzuto, J.M.; Kinghorn, A.D. Cytotoxic and antimalarial constituents of the roots of Eurycoma longifolia. J. Nat. Prod., 1991, 54(5), 1360-1367.
[http://dx.doi.org/10.1021/np50077a020] [PMID: 1800638]
[33]
Alley, M.C.; Scudiero, D.A.; Monks, A.; Hursey, M.L.; Czerwinski, M.L.; Fine, D.L.; Abbott, B.J.; Mayo, J.G.; Shoemaker, R.H.; Boyd, M.R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res., 1988, 48, 589-601.
[PMID: 3335022]
[34]
Shoemaker, R.H.; Scudiero, D.A.; Melillo, G.; Currens, M.J.; Monks, A.P.; Rabow, A.A.; Covell, D.G.; Sausville, E.A. Application of high-throughput, molecular-targeted screening to anticancer drug discovery. Curr. Top. Med. Chem., 2002, 2(3), 229-246.
[http://dx.doi.org/10.2174/1568026023394317] [PMID: 11944818]
[35]
Paglia, D.E.; Valentine, W.N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med., 1967, 70(1), 158-169.
[PMID: 6066618]
[36]
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.
[http://dx.doi.org/10.1074/jbc.M113.490706] [PMID: 23897821]
[37]
Hai, P.T.; Huong, L.T.T. Integrating structure and ligand-based approaches for modelling the histone deacetylase inhibition activity of hydroxamic acid derivatives. Asian J. Pharm. Clin. Res., 2018, 2, 198-206.
[38]
Molecular Operating Environment (MOE), 2009.10; Chemical Computing Group Inc.: 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada , 2016.
[39]
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
[http://dx.doi.org/10.1002/cbdv.201800027] [PMID: 29667768]
[40]
Dassault Systèmes, B.I.O.V.I.A. Discovery studio modeling environment, 3.5.0; Accelrys Inc.: San Diego, CA, USA, 2016.
[41]
Glozak, M.A.; Seto, E. Histone deacetylases and cancer. Oncogene, 2007, 26(37), 5420-5432.
[http://dx.doi.org/10.1038/sj.onc.1210610] [PMID: 17694083]


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VOLUME: 19
ISSUE: 12
Year: 2019
Page: [1543 - 1557]
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DOI: 10.2174/1871520619666190702142654
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