Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents

Author(s): Margarita E. Neganova, Sergey G. Klochkov, Yulia R. Aleksandrova, Vasily N. Osipov, Dmitry V. Avdeev, Sergey A. Pukhov, Alexandr V. Gromyko and Gjumrakch Aliev*

Volume 21, Issue 5, 2021

Published on: 27 May, 2020

Page: [597 - 610] Pages: 14

DOI: 10.2174/1871520620666200527132420

Price: $65

Abstract

Aims: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds.

Background: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics.

Objective: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated.

Methods: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity.

Results: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines.

Conclusion: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Keywords: Anti-cancer agents, hydroxamic acids, cytotoxicity profile, potential antioxidant properties, mitochondria, histone deacetylases, glycolysis.

Graphical Abstract
[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Torre, L.A.; Siegel, R.L.; Jemal, A. Lung Cancer Statistics. Adv. Exp. Med. Biol., 2016, 893, 1-19.
[http://dx.doi.org/10.1007/978-3-319-24223-1_1] [PMID: 26667336]
[3]
Pontiki, E.; Hadjipavlou-Litina, D. Histone Deacetylase Inhibitors (HDACIs). Structure--activity relationships: History and new QSAR perspectives. Med. Res. Rev., 2012, 32(1), 1-165.
[http://dx.doi.org/10.1002/med.20200] [PMID: 20162725]
[4]
Mishchenko, D.V.; Neganova, M.E.; Klimanova, E.N.; Sashenkova, T.E.; Klochkov, S.G.; Shevtsova, E.F.; Vystorop, I.V.; Tarasov, V.V.; Chubarev, V.N.; Samsonova, A.N.; Ashraf, G.M.; Barreto, G.; Yarla, N.S.; Aliev, G. Chemosensitizing activity of histone deacetylases inhibitory cyclic hydroxamic acids for combination chemotherapy of lymphatic leukemia. Curr. Cancer Drug Targets, 2018, 18(4), 365-371.
[http://dx.doi.org/10.2174/1568009617666170623104030] [PMID: 28669342]
[5]
Thurn, K.T.; Thomas, S.; Moore, A.; Munster, P.N. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol., 2011, 7(2), 263-283.
[http://dx.doi.org/10.2217/fon.11.2] [PMID: 21345145]
[6]
Mut-Salud, N.; Álvarez, P.J.; Garrido, J.M.; Carrasco, E.; Aránega, A.; Rodríguez-Serrano, F. Antioxidant intake and antitumor therapy: Toward nutritional recommendations for optimal results. Oxid. Med. Cell. Longev., 2016, 20166719534
[http://dx.doi.org/10.1155/2016/6719534] [PMID: 26682013]
[7]
Gogvadze, V.; Orrenius, S.; Zhivotovsky, B. Mitochondria in cancer cells: What is so special about them? Trends Cell Biol., 2008, 18(4), 165-173.
[http://dx.doi.org/10.1016/j.tcb.2008.01.006] [PMID: 18296052]
[8]
Kroesen, M.; Gielen, P.; Brok, I.C.; Armandari, I.; Hoogerbrugge, P.M.; Adema, G.J. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget, 2014, 5(16), 6558-6572.
[http://dx.doi.org/10.18632/oncotarget.2289] [PMID: 25115382]
[9]
Mankoff, D.A.; Eary, J.F.; Link, J.M.; Muzi, M.; Rajendran, J.G.; Spence, A.M.; Krohn, K.A. Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clin. Cancer Res., 2007, 13(12), 3460-3469.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0074] [PMID: 17575208]
[10]
Präbst, K.; Engelhardt, H.; Ringgeler, S.; Hübner, H. Basic colorimetric proliferation assays: MTT, WST, and resazurin. Methods Mol. Biol., 2017, 1601, 1-17.
[http://dx.doi.org/10.1007/978-1-4939-6960-9_1] [PMID: 28470513]
[11]
Rose, A.; Funk, D.; Neiger, R. Comparison of refractometry and biuret assay for measurement of total protein concentration in canine abdominal and pleural fluid specimens. J. Am. Vet. Med. Assoc., 2016, 248(7), 789-794.
[http://dx.doi.org/10.2460/javma.248.7.789] [PMID: 27003020]
[12]
Neganova, M.E.; Klochkov, S.G.; Petrova, L.N.; Shevtsova, E.F.; Afanasieva, S.V.; Chudinova, E.S.; Fisenko, V.P.; Bachurin, S.O.; Barreto, G.E.; Aliev, G. Securinine derivatives as potential anti-amyloid therapeutic approach. CNS Neurol. Disord. Drug Targets, 2017, 16(3), 351-355.
[http://dx.doi.org/10.2174/1871527315666161107090525] [PMID: 27823572]
[13]
Milackova, I.; Kovacikova, L.; Veverka, M.; Gallovic, J.; Stefek, M. Screening for antiradical efficiency of 21 semi-synthetic derivatives of quercetin in a DPPH assay. Interdiscip. Toxicol., 2013, 6(1), 13-17.
[http://dx.doi.org/10.2478/intox-2013-0003] [PMID: 24170974]
[14]
Gülçin, I.; Mshvildadze, V.; Gepdiremen, A.; Elias, R. Screening of antiradical and antioxidant activity of monodesmosides and crude extract from Leontice smirnowii tuber. Phytomedicine, 2006, 13(5), 343-351.
[http://dx.doi.org/10.1016/j.phymed.2005.03.009] [PMID: 16635742]
[15]
Graham, J.M. Isolation of mitochondria from tissues and cells by differential centrifugation. Curr. Protoc. Cell Biol., 2001, 3, Unit 3.3.,
[16]
Akerman, K.E.; Wikström, M.K. Safranine as a probe of the mitochondrial membrane potential. FEBS Lett., 1976, 68(2), 191-197.
[http://dx.doi.org/10.1016/0014-5793(76)80434-6] [PMID: 976474]
[17]
Zhang, J.; Zhang, Q. Using Seahorse machine to measure OCR and ECAR in cancer cells. Methods Mol. Biol., 2019, 1928, 353-363.
[http://dx.doi.org/10.1007/978-1-4939-9027-6_18] [PMID: 30725464]
[18]
Endicott, M.M.; Alden, B.W.; Sherrill, M.L. Quinazoline derivatives; the synthesis of 4-(3′-diethylaminopropoxy)-6-chloroquinazoline (SN 12,254). J. Am. Chem. Soc., 1946, 68, 1303.
[http://dx.doi.org/10.1021/ja01211a057] [PMID: 20990988]
[19]
Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis, 2nd ed; Springer: NewYork, 1984, p. 116.
[20]
Jadach, T.; Eckstein, Z.; Lipczynska-Kochany, E. A facile method of benzimidazo-2-ones synthesis by modified Lossen rearrangement. J. Chem. Eng. Data, 1983, 28, 279-281.
[http://dx.doi.org/10.1021/je00032a042]
[21]
Revathy, K.; Lalitha, A. p-TSA-catalyzed synthesis of spiroquinazolinones. J. Iran Chem. Soc., 2015, 12, 2045-2049.
[http://dx.doi.org/10.1007/s13738-015-0680-2]
[22]
Bennett, L.L.; Rojas, S.; Seefeldt, T. Role of antioxidants in the prevention of cancer. J. Exp. Clin. Med., 2012, 4(4), 215-222.
[http://dx.doi.org/10.1016/j.jecm.2012.06.001]
[23]
Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol., 2007, 39(1), 44-84.
[http://dx.doi.org/10.1016/j.biocel.2006.07.001] [PMID: 16978905]
[24]
Hu, M.L. Dietary polyphenols as antioxidants and anticancer agents: more questions than answers. Chang Gung Med. J., 2011, 34(5), 449-460.
[PMID: 22035889]
[25]
Baur, J.A.; Sinclair, D.A. Therapeutic potential of resveratrol: The in vivo evidence. Nat. Rev. Drug Discov., 2006, 5(6), 493-506.
[http://dx.doi.org/10.1038/nrd2060] [PMID: 16732220]
[26]
Lu, M.; Yuan, B.; Zeng, M.; Chen, J. Antioxidant capacity and major phenolic compounds of spices commonly consumed in China. Food Res. Int., 2011, 44(2), 530-536.
[http://dx.doi.org/10.1016/j.foodres.2010.10.055]
[27]
Bonner, M.Y.; Arbiser, J.L. The antioxidant paradox: What are antioxidants and how should they be used in a therapeutic context for cancer. Future Med. Chem., 2014, 6(12), 1413-1422.
[http://dx.doi.org/10.4155/fmc.14.86] [PMID: 25329197]
[28]
Athar, M.; Back, J.H.; Tang, X.; Kim, K.H.; Kopelovich, L.; Bickers, D.R.; Kim, A.L. Resveratrol: A review of preclinical studies for human cancer prevention. Toxicol. Appl. Pharmacol., 2007, 224(3), 274-283.
[http://dx.doi.org/10.1016/j.taap.2006.12.025] [PMID: 17306316]
[29]
Vaz-da-Silva, M.; Loureiro, A.I.; Falcao, A.; Nunes, T.; Rocha, J.F.; Fernandes-Lopes, C.; Soares, E.; Wright, L.; Almeida, L.; Soares-da-Silva, P. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int. J. Clin. Pharmacol. Ther., 2008, 46(11), 564-570.
[http://dx.doi.org/10.5414/CPP46564] [PMID: 19000554]
[30]
Arbiser, J.L.; Bips, M.; Seidler, A.; Bonner, M.Y.; Kovach, C. Combination therapy of imiquimod and gentian violet for cutaneous melanoma metastases. J. Am. Acad. Dermatol., 2012, 67(2), e81-e83.
[http://dx.doi.org/10.1016/j.jaad.2011.10.028] [PMID: 22794825]
[31]
Liang, G.; Tang, A.; Lin, X.; Li, L.; Zhang, S.; Huang, Z.; Tang, H.; Li, Q.Q. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int. J. Oncol., 2010, 37(1), 111-123.
[PMID: 20514403]
[32]
Qiao, J.; Gu, C.; Shang, W.; Du, J.; Yin, W.; Zhu, M.; Wang, W.; Han, M.; Lu, W. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem. Toxicol., 2011, 49(6), 1410-1415.
[http://dx.doi.org/10.1016/j.fct.2011.03.033] [PMID: 21440026]
[33]
Sahin, K.; Tuzcu, M.; Gencoglu, H.; Dogukan, A.; Timurkan, M.; Sahin, N.; Aslan, A.; Kucuk, O. Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci., 2010, 87(7-8), 240-245.
[http://dx.doi.org/10.1016/j.lfs.2010.06.014] [PMID: 20619277]
[34]
Zamzami, N.; Kroemer, G. The mitochondrion in apoptosis: How Pandora’s box opens. Nat. Rev. Mol. Cell Biol., 2001, 2(1), 67-71.
[http://dx.doi.org/10.1038/35048073] [PMID: 11413468]
[35]
Michelakis, E.D.; Webster, L.; Mackey, J.R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer, 2008, 99(7), 989-994.
[http://dx.doi.org/10.1038/sj.bjc.6604554] [PMID: 18766181]
[36]
Saha, S.; Ghosh, M.; Dutta, S.K. Role of metabolic modulator Bet-CA in altering mitochondrial hyperpolarization to suppress cancer associated angiogenesis and metastasis. Sci. Rep., 2016, 6, 23552.
[http://dx.doi.org/10.1038/srep23552] [PMID: 27003027]
[37]
Galluzzi, L.; Morselli, E.; Kepp, O.; Vitale, I.; Rigoni, A.; Vacchelli, E.; Michaud, M.; Zischka, H.; Castedo, M.; Kroemer, G. Mitochondrial gateways to cancer. Mol. Aspects Med., 2010, 31(1), 1-20.
[http://dx.doi.org/10.1016/j.mam.2009.08.002] [PMID: 19698742]
[38]
Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov., 2010, 9(6), 447-464.
[http://dx.doi.org/10.1038/nrd3137] [PMID: 20467424]
[39]
Weinberg, S.E.; Chandel, N.S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol., 2015, 11(1), 9-15.
[http://dx.doi.org/10.1038/nchembio.1712] [PMID: 25517383]
[40]
Brahimi-Horn, M.C.; Chiche, J.; Pouysségur, J. Hypoxia signalling controls metabolic demand. Curr. Opin. Cell Biol., 2007, 19(2), 223-229.
[http://dx.doi.org/10.1016/j.ceb.2007.02.003] [PMID: 17303407]
[41]
Schwartz, L.; Supuran, C.T.; Alfarouk, K.O. The Warburg Effect and the hallmarks of cancer. Anticancer. Agents Med. Chem., 2017, 17(2), 164-170.
[http://dx.doi.org/10.2174/1871520616666161031143301] [PMID: 27804847]
[42]
Gatenby, R.A.; Gillies, R.J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer, 2004, 4(11), 891-899.
[http://dx.doi.org/10.1038/nrc1478] [PMID: 15516961]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy