Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

Author(s): Tran Khac Vu*, Nguyen Thi Thanh, Nguyen Van Minh, Nguyen Huong Linh, Nguyen Thi Phương Thao, Trương Thuc Bao Nguyen, Doan Thi Hien, Luu Van Chinh, Ta Hong Duc, Lai Duc Anh and Pham-The Hai

Volume 17, Issue 7, 2021

Published on: 20 April, 2020

Page: [732 - 749] Pages: 18

DOI: 10.2174/1573406416666200420081540

Price: $65

Abstract

Background: The target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. 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 conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines.

Methods: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin- 4(3H)-ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structureactivity relationships.

Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 μM, and HDAC inhibition with IC50 value of 6.36 μM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2.

Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

Keywords: Anticancer agents, histone deacetylase (HDAC) inhibitors, hydroxamic acids, quinazolin-4(3H)-one, conjugated, molecular docking.

Graphical Abstract
[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOC AN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Mellinghoff, I.K.; Sawyers, C.L. The emergence of resistance to targeted cancer therapeutics. Pharmacogenomics, 2002, 3(5), 603-623.
[http://dx.doi.org/10.1517/14622416.3.5.603] [PMID: 12223047]
[3]
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]
[4]
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]
[5]
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]
[6]
Choi, J.H.; Kwon, H.J.; Yoon, B.I.; Kim, J.H.; Han, S.U.; Joo, H.J.; Kim, D.Y. Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn. J. Cancer Res., 2001, 92(12), 1300-1304.
[http://dx.doi.org/10.1111/j.1349-7006.2001.tb02153.x] [PMID: 11749695]
[7]
Halkidou, K.; Gaughan, L.; Cook, S.; Leung, H.Y.; Neal, D.E.; Robson, C.N. Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate, 2004, 59(2), 177-189.
[http://dx.doi.org/10.1002/pros.20022] [PMID: 15042618]
[8]
Zhang, Z.; Yamashita, H.; Toyama, T.; Sugiura, H.; Omoto, Y.; Ando, Y.; Mita, K.; Hamaguchi, M.; Hayashi, S.; Iwase, H. HDAC6 expression is correlated with better survival in breast cancer. Clin. Cancer Res., 2004, 10(20), 6962-6968.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0455] [PMID: 15501975]
[9]
Zhu, P.; Martin, E.; Mengwasser, J.; Schlag, P.; Janssen, K-P.; Göttlicher, M. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell, 2004, 5(5), 455-463.
[http://dx.doi.org/10.1016/S1535-6108(04)00114-X] [PMID: 15144953]
[10]
Wilson, A.J.; Byun, D-S.; Popova, N.; Murray, L.B.; L’Italien, K.; Sowa, Y.; Arango, D.; Velcich, A.; Augenlicht, L.H.; Mariadason, J.M. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J. Biol. Chem., 2006, 281(19), 13548-13558.
[http://dx.doi.org/10.1074/jbc.M510023200] [PMID: 16533812]
[11]
Ververis, K.; Hiong, A.; Karagiannis, T.C.; Licciardi, P.V. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. Biologics, 2013, 7, 47-60.
[PMID: 23459471]
[12]
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]
[13]
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]
[14]
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]
[15]
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]
[16]
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]
[17]
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]
[18]
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]
[19]
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]
[20]
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]
[21]
Khan, O.; La Thangue, N.B. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol., 2012, 90(1), 85-94.
[http://dx.doi.org/10.1038/icb.2011.100] [PMID: 22124371]
[22]
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]
[23]
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]
[24]
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(46), 6425-6429.
[http://dx.doi.org/10.1016/j.tetlet.2015.09.147]
[25]
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]
[26]
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]
[27]
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]
[28]
Kamal, A.; Tamboli, J.R.; Ramaiah, M.J.; Adil, S.F.; Pushpavalli, S.N.C.V.L.; 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]
[29]
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.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01342] [PMID: 26443078]
[30]
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]
[31]
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]
[32]
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 microc ulture tetrazolium assay. Cancer Res., 1988, 48, 4827-4833.
[PMID: 3409223]
[33]
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]
[34]
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]
[35]
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]
[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]
Neves, M.A.; Totrov, M.; Abagyan, R. Docking and scoring with ICM: the benchmarking results and strategies for improvement. J. Comput. Aided Mol. Des., 2012, 26(6), 675-686.
[http://dx.doi.org/10.1007/s10822-012-9547-0] [PMID: 22569591]
[38]
An, J.; Totrov, M.; Abagyan, R. Pocketome via comprehensive identification and classification of ligand binding envelopes. Mol. Cell. Proteomics, 2005, 4(6), 752-761.
[http://dx.doi.org/10.1074/mcp.M400159-MCP200] [PMID: 15757999]
[39]
Arthur, D.E.; Uzairu, A. Molecular docking studies on the interaction of NCI anticancer analogues with human Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit. J. King Saud Univ. Sci., 2019, 31, 1151-1166.
[http://dx.doi.org/10.1016/j.jksus.2019.01.011]
[40]
Molecular Operating Environment (MOE)Chemical Computing Group ULC. 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7 2009, 10.
[41]
Huong, T.T.; Dung, D.T.; Huan, N.V.; Cuong, L.V.; Hai, P.T.; Huong, L.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.
[http://dx.doi.org/10.1016/j.bioorg.2017.02.002] [PMID: 28196602]
[42]
Wu, R.; Lu, Z.; Cao, Z.; Zhang, Y. Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel. J. Am. Chem. Soc., 2011, 133(16), 6110-6113.
[http://dx.doi.org/10.1021/ja111104p] [PMID: 21456530]
[43]
Molecular Operating Environment (MOE). Version 2009.10, Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite # 910, Montreal, QC, Canada, 2016., 2016. http://www.chemcomp.com available at:
[44]
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Modeling Environment; Accelrys Inc.: San Diego, CA, USA, 2016.
[45]
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.
[46]
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]
[47]
Ververis, K.; Karagiannis, T.C. An atlas of histone deacetylase expression in breast cancer: fluorescence methodology for comparative semi-quantitative analysis. Am. J. Transl. Res., 2012, 4(1), 24-43.
[PMID: 22347520]
[48]
Lombardi, P.M.; Cole, K.E.; Dowling, D.P.; Christianson, D.W. Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Curr. Opin. Struct. Biol., 2011, 21(6), 735-743.
[http://dx.doi.org/10.1016/j.sbi.2011.08.004] [PMID: 21872466]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy