Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Rhodanine Derivatives as Anticancer Agents: QSAR and Molecular Docking Studies

Author(s): Maja Molnar, Melita Lončarić, Teuta Opačak-Bernardi, Ljubica Glavaš-Obrovac and Vesna Rastija*

Volume 23, Issue 7, 2023

Published on: 15 November, 2022

Page: [839 - 846] Pages: 8

DOI: 10.2174/1871520623666221027094856

Price: $65

Abstract

Background: Rhodanine derivatives have a proven wide range of biological activities.

Objective: The aim of this study was to evaluate the cytotoxic effect of a series of rhodanine derivatives and investigate the quantitative structure-activity relationships, as well as binding modes to tyrosine kinase.

Methods: Cytotoxic effect on cell proliferation (CaCo-2, HeLa, MDCK-1, Hut-78, K562) in vitro was evaluated by the MTT viability assay. QSAR analysis was performed with Dragon descriptors using QSARINS software. Molecular docking was performed on the tyrosin kinase (c-Src) (PDB ID: 3G6H) using iGEMDOCK.

Results: Compounds with the best inhibiting activity toward all cell lines were the ones possessing only one group in the C2 of the phenyl ring. QSAR study on the cytotoxic activity against Human T cell lymphoma achieved the model that satisfies the fitting and internal cross-validation criteria (R2 = 0.75; Q2 LOO = 0.64). Descriptors included in the model (MATS2e, MATs7e, RDF060p) revealed the importance of the presence of atoms with higher polarizability in the outer region of molecules. The findings of the molecular docking study performed on the c-Src are in accordance with the results of the QSAR study. The key interactions with binding site residues were achieved through oxygen atoms from phenoxy and rhodanine groups and rhodanine sulphur atoms.

Conclusion: Rhodanine derivatives could be developed as novel tyrosine kinase inhibitors in the treatment of leukemia.

Keywords: Rhodamine, cytotoxicity, T cell lymphoma, QSAR, molecular docking, tyrosine kinase, c-Src.

Graphical Abstract
[1]
Krithika, U.; Prabitha, P.; Mandal, S.P.; Yuvaraj, S.; Priya, D.; Wadhwani, A.D.; Prashantha, K.B.R. Development of novel rhodanine analogs as anticancer agents: design, synthesis, evaluation and CoMSIA study. Med. Chem., 2021, 17(3), 216-229.
[http://dx.doi.org/10.2174/1573406416666200610191002] [PMID: 32520692]
[2]
Sawaguchi, Y.; Yamazaki, R.; Nishiyama, Y.; Sasai, T.; Mae, M.; Abe, A.; Yaegashi, T.; Nishiyama, H.; Matsuzaki, T. Rational design of a potent Pan-Pim kinases inhibitor with a rhodanine–benzoimidazole structure. Anticancer Res., 2017, 37(8), 4051-4057.
[http://dx.doi.org/10.21873/anticanres.11790] [PMID: 28739687]
[3]
Cutshall, N.S.; O’Day, C.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg. Med. Chem. Lett., 2005, 15(14), 3374-3379.
[http://dx.doi.org/10.1016/j.bmcl.2005.05.034] [PMID: 15961311]
[4]
Mandal, S.P.; Mithuna, M.; Garg, A.; Sahetya, S.S.; Nagendra, S.R.; Sripad, H.S.; Manjunath, M.M.; Sitaram, S.; Soni, M.; Baig, R.N.; Kumar, S.V.; Kumar, B.R.P. Novel rhodanines with anticancer activity: Design, synthesis and CoMSIA study. RSC Advances, 2016, 6(63), 58641-58653.
[http://dx.doi.org/10.1039/C6RA08785J]
[5]
Krátký, M.; Vinšová, J. Stolaříková, J. Antimicrobial activity of rhodanine-3-acetic acid derivatives. Bioorg. Med. Chem., 2017, 25(6), 1839-1845.
[http://dx.doi.org/10.1016/j.bmc.2017.01.045] [PMID: 28196707]
[6]
Song, M.X.; Deng, X.Q.; Wei, Z.Y.; Zheng, C.J.; Wu, Y.; An, C.S.; Piao, H.R. Synthesis and antibacterial evaluation of (s,z)-4-methyl-2-(4-oxo-5-((5-substituted phenylfuran-2-yl) methylene)-2-thioxothiazolidin-3-yl)pentanoic acids. Iran. J. Pharm. Res., 2015, 14(1), 89-96.
[PMID: 25561915]
[7]
Tejchman, W.; Korona-Glowniak, I.; Malm, A.; Zylewski, M.; Suder, P. Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids. Med. Chem. Res., 2017, 26(6), 1316-1324.
[http://dx.doi.org/10.1007/s00044-017-1852-7] [PMID: 28515623]
[8]
AbdelKhalek, A.; Ashby, C.R., Jr; Patel, B.A.; Talele, T.T.; Seleem, M.N. In vitro antibacterial activity of rhodanine derivatives against pathogenic clinical isolates. PLoS One, 2016, 11(10), e0164227.
[http://dx.doi.org/10.1371/journal.pone.0164227] [PMID: 27711156]
[9]
Tintori, C.; Iovenitti, G.; Ceresola, E.R.; Ferrarese, R.; Zamperini, C.; Brai, A.; Poli, G.; Dreassi, E.; Cagno, V.; Lembo, D.; Canducci, F.; Botta, M. Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides. PLoS One, 2018, 13(6), e0198478.
[http://dx.doi.org/10.1371/journal.pone.0198478] [PMID: 29870553]
[10]
Ramkumar, K.; Yarovenko, V.N.; Nikitina, A.S.; Zavarzin, I.V.; Krayushkin, M.M.; Kovalenko, L.V.; Esqueda, A.; Odde, S.; Neamati, N. Design, synthesis and structure-activity studies of rhodanine derivatives as HIV-1 integrase inhibitors. Molecules, 2010, 15(6), 3958-3992.
[http://dx.doi.org/10.3390/molecules15063958] [PMID: 20657419]
[11]
El-Miligy, M.M.M.; Hazzaa, A.A.; El-Messmary, H.; Nassra, R.A.; El-Hawash, S.A.M. New hybrid molecules combining benzothiophene or benzofuran with rhodanine as dual COX-1/2 and 5-LOX inhibitors: Synthesis, biological evaluation and docking study. Bioorg. Chem., 2017, 72, 102-115.
[http://dx.doi.org/10.1016/j.bioorg.2017.03.012] [PMID: 28390993]
[12]
Tomašić T.; Peterlin Mašič L. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Expert Opin. Drug Discov., 2012, 7(7), 549-560.
[http://dx.doi.org/10.1517/17460441.2012.688743] [PMID: 22607309]
[13]
Boureghda, C.; Boulcina, R.; Dorcet, V.; Berrée, F.; Carboni, B.; Debache, A. Facile synthesis of 5-arylidene rhodanine derivatives using Na2SO3 as an eco-friendly catalyst. Access to 2-mercapto-3-aryl-acrylic acids and a benzoxaborole derivative. Tetrahedron Lett., 2021, 62, 152690.
[http://dx.doi.org/10.1016/j.tetlet.2020.152690]
[14]
Suresh; Sandhu, J.S. Ultrasound-assisted synthesis of 2,4-thiazolidinedione and rhodanine derivatives catalyzed by task-specific ionic liquid: [TMG][Lac]. Org. Med. Chem. Lett., 2013, 3(1), 2.
[http://dx.doi.org/10.1186/2191-2858-3-2] [PMID: 23458122]
[15]
Alizadeh, A.; Khodaei, M.M.; Eshghi, A. A solvent-free protocol for the green synthesis of arylalkylidene rhodanines in a task-specific ionic liquid. Can. J. Chem., 2010, 88(6), 514-518.
[http://dx.doi.org/10.1139/V10-011]
[16]
Nitsche, C.; Klein, C.D. Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines. Tetrahedron Lett., 2012, 53(39), 5197-5201.
[http://dx.doi.org/10.1016/j.tetlet.2012.07.002]
[17]
Kamila, S.; Ankati, H.; Biehl, E.R. An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors. Tetrahedron Lett., 2011, 52(34), 4375-4377.
[http://dx.doi.org/10.1016/j.tetlet.2011.05.114] [PMID: 21804651]
[18]
Angajala, G.; Aruna, V.; Pavan, P.; Reddy, P.G. Ultrasound promoted montmorillonite K-10 catalyzed synthesis, characterization, molecular modelling, SAR and hypoglycemic studies of new rhodanine bejeweled acridine analogues. J. Mol. Struct., 2021, 1242, 130828.
[http://dx.doi.org/10.1016/j.molstruc.2021.130828]
[19]
Azizi, N.; Hasani, M.; Khajeh, M.; Edrisi, M. A straightforward and sustainable one-pot, four-component synthesis of rhodanine derivatives. Tetrahedron Lett., 2015, 56(10), 1189-1192.
[http://dx.doi.org/10.1016/j.tetlet.2015.01.102]
[20]
Molnar, M.; Brahmbhatt, H.; Rastija, V. Pavić V.; Komar, M.; Karnaš, M.; Babić J. Environmentally friendly approach to knoevenagel condensation of rhodanine in choline chloride:Urea deep eutectic solvent and QSAR studies on their antioxidant activity. Molecules, 2018, 23(8), 1897.
[http://dx.doi.org/10.3390/molecules23081897] [PMID: 30060629]
[21]
Alonso, D.A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I.M.; Ramón, D.J. Deep eutectic solvents: The organic reaction medium of the century. Eur. J. Org. Chem., 2016, 2016(4), 612-632.
[http://dx.doi.org/10.1002/ejoc.201501197]
[22]
Dai, Y.; van Spronsen, J.; Witkamp, G.J.; Verpoorte, R.; Choi, Y.H. Natural deep eutectic solvents as new potential media for green technology. Anal. Chim. Acta, 2013, 766, 61-68.
[http://dx.doi.org/10.1016/j.aca.2012.12.019] [PMID: 23427801]
[23]
Florindo, C.; Oliveira, F.S.; Rebelo, L.P.N.; Fernandes, A.M.; Marrucho, I.M. Insights into the synthesis and properties of deep eutectic solvents based on cholinium chloride and carboxylic acids. ACS Sustain. Chem.& Eng., 2014, 2(10), 2416-2425.
[http://dx.doi.org/10.1021/sc500439w]
[24]
Francisco, M.; van den Bruinhorst, A.; Kroon, M.C. Low-transition-temperature mixtures (LTTMs): a new generation of designer solvents. Angew. Chem. Int. Ed., 2013, 52(11), 3074-3085.
[http://dx.doi.org/10.1002/anie.201207548] [PMID: 23401138]
[25]
Hansen, B.B.; Spittle, S.; Chen, B.; Poe, D.; Zhang, Y.; Klein, J.M.; Horton, A.; Adhikari, L.; Zelovich, T.; Doherty, B.W.; Gurkan, B.; Maginn, E.J.; Ragauskas, A.; Dadmun, M.; Zawodzinski, T.A.; Baker, G.A.; Tuckerman, M.E.; Savinell, R.F.; Sangoro, J.R. Deep eutectic solvents: A review of fundamentals and applications. Chem. Rev., 2021, 121(3), 1232-1285.
[http://dx.doi.org/10.1021/acs.chemrev.0c00385] [PMID: 33315380]
[26]
Paul, M.K.; Mukhopadhyay, A.K. Tyrosine kinase – Role and significance in Cancer. Int. J. Med. Sci., 2004, 1(2), 101-115.
[http://dx.doi.org/10.7150/ijms.1.101] [PMID: 15912202]
[27]
Amanchy, R.; Zhong, J.; Molina, H.; Chaerkady, R.; Iwahori, A.; Kalume, D.E.; Grønborg, M.; Joore, J.; Cope, L.; Pandey, A. Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays. J. Proteome Res., 2008, 7(9), 3900-3910.
[http://dx.doi.org/10.1021/pr800198w] [PMID: 18698806]
[28]
Li, S. Src kinase signaling in leukaemia. Int. J. Biochem. Cell Biol., 2007, 39(7-8), 1483-1488.
[http://dx.doi.org/10.1016/j.biocel.2007.01.027] [PMID: 17350876]
[29]
Dos Santos, C.; McDonald, T.; Ho, Y.W.; Liu, H.; Lin, A.; Forman, S.J.; Kuo, Y.H.; Bhatia, R. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood, 2013, 122(11), 1900-1913.
[http://dx.doi.org/10.1182/blood-2012-11-466425] [PMID: 23896410]
[30]
Irino, S.; Tanaka, T.; Kubota, Y. Alteration of p60c-src expression in human leukemia-lymphoma cells correlated with induced differentiation. Jpn. J. Med., 1988, 27(2), 135-141.
[http://dx.doi.org/10.2169/internalmedicine1962.27.135] [PMID: 2458497]
[31]
Roskoski, R., Jr Src protein–tyrosine kinase structure and regulation. Biochem. Biophys. Res. Commun., 2004, 324(4), 1155-1164.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.171] [PMID: 15504335]
[32]
Seeliger, M.A.; Ranjitkar, P.; Kasap, C.; Shan, Y.; Shaw, D.E.; Shah, N.P.; Kuriyan, J.; Maly, D.J. Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res., 2009, 69(6), 2384-2392.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3953] [PMID: 19276351]
[33]
Molnar, M. Lončarić M. Green synthesis of 2-thioxothiazolidin-4-one derivatives in deep eutectic solvents via Knoevenagel condensation. Lett. Org. Chem., 2022, 19(10), 890-901. E-pub Ahead of Print]
[http://dx.doi.org/10.2174/1570178619666220112121638]
[34]
van Meerloo, J.; Kaspers, G.J.L.; Cloos, J. Cell sensitivity assays: the MTT assay. Methods Mol. Biol., 2011, 731, 237-245.
[http://dx.doi.org/10.1007/978-1-61779-080-5_20] [PMID: 21516412]
[35]
Hocquet, A.; Langgård, M. An evaluation of the MM+ force field. J. Mol. Model., 1998, 4(3), 94-112.
[http://dx.doi.org/10.1007/s008940050128]
[36]
Stewart, J.J.P. Optimization of parameters for semiempirical methods IV: extension of MNDO, AM1, and PM3 to more main group elements. J. Mol. Model., 2004, 10(2), 155-164.
[http://dx.doi.org/10.1007/s00894-004-0183-z] [PMID: 14997367]
[37]
Gramatica, P.; Chirico, N.; Papa, E.; Cassani, S.; Kovarich, S. QSARINS: A new software for the development, analysis, and validation of QSAR MLR models. J. Comput. Chem., 2013, 34(24), 2121-2132.
[http://dx.doi.org/10.1002/jcc.23361]
[38]
Gramatica, P. Principles of QSAR models validation: internal and external. QSAR Comb. Sci., 2007, 26(5), 694-701.
[http://dx.doi.org/10.1002/qsar.200610151]
[39]
Eriksson, L.; Jaworska, J.; Worth, A.P.; Cronin, M.T.D.; McDowell, R.M.; Gramatica, P. Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ. Health Perspect., 2003, 111(10), 1361-1375.
[http://dx.doi.org/10.1289/ehp.5758] [PMID: 12896860]
[40]
Hsu, K.C.; Chen, Y.F.; Lin, S.R.; Yang, J.M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics, 2011, 12(S1)(Suppl. 1), S33.
[http://dx.doi.org/10.1186/1471-2105-12-S1-S33] [PMID: 21342564]
[41]
Moreau, G.; Broto, P. Autocorrelation of a topological structure: A new molecular descriptor. Nouv. J. Chim., 1980, 4, 359-360.
[42]
Hemmer, M.C.; Steinhauer, V.; Gasteiger, J. Deriving the 3D structure of organic molecules from their infrared spectra. Vib. Spectrosc., 1999, 19(1), 151-164.
[http://dx.doi.org/10.1016/S0924-2031(99)00014-4]
[43]
Basuroy, S.; Sheth, P.; Kuppuswamy, D.; Balasubramanian, S.; Ray, R.M.; Rao, R.K. Expression of kinase-inactive c-Src delays oxidative stress-induced disassembly and accelerates calcium-mediated reassembly of tight junctions in the Caco-2 cell monolayer. J. Biol. Chem., 2003, 278(14), 11916-11924.
[http://dx.doi.org/10.1074/jbc.M211710200] [PMID: 12547828]
[44]
Bazzoni, G.; Dejana, E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev., 2004, 84(3), 869-901.
[http://dx.doi.org/10.1152/physrev.00035.2003] [PMID: 15269339]
[45]
Meyer, T.N. Hunt, J.; Schwesinger, C.; Denker, B.M. Gα 12 regulates epithelial cell junctions through Src tyrosine kinases. Am. J. Physiol. Cell Physiol., 2003, 285(5), C1281-C1293.
[http://dx.doi.org/10.1152/ajpcell.00548.2002] [PMID: 12890651]
[46]
Baty, R.S. Protective effect of Bosutinib with caspase inhibitors on human K562 cells. Saudi J. Biol. Sci., 2022, 29(4), 2323-2328.
[http://dx.doi.org/10.1016/j.sjbs.2021.11.068] [PMID: 35531147]
[47]
Ivanova, E.; Tatarskiy, V.; Yastrebova, M.; Khamidullina, A.; Shunaev, A.; Kalinina, A.; Zeifman, A.; Novikov, F.; Dutikova, Y.; Chilov, G.; Shtil, A. PF 114, a novel selective inhibitor of BCR ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int. J. Oncol., 2019, 55(1), 289-297.
[http://dx.doi.org/10.3892/ijo.2019.4801] [PMID: 31115499]
[48]
Vijayan, R.S.K.; He, P.; Modi, V.; Duong-Ly, K.C.; Ma, H.; Peterson, J.R.; Dunbrack, R.L., Jr; Levy, R.M. Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. J. Med. Chem., 2015, 58(1), 466-479.
[http://dx.doi.org/10.1021/jm501603h] [PMID: 25478866]
[49]
Rastija, V. Jukić M.; Opačak-Bernardi, T.; Krstulović L.; Stolić I.; Glavaš-Obrovac, L.; Bajić M. Investigation of the structural and physicochemical requirements ofquinoline-arylamidine hybrids for the growth inhibition of K562 and Rajileukemia cells. Turk. J. Chem., 2019, 43(1), 251-265.
[http://dx.doi.org/10.3906/kim-1807-61]
[50]
Cui, Z.; Chen, S.; Wang, Y.; Gao, C.; Chen, Y.; Tan, C.; Jiang, Y. Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment. Eur. J. Med. Chem., 2017, 136, 372-381.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.006] [PMID: 28525838]

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