Spectroscopic and In Silico DNA Binding Studies on the Interaction of Some New N-Substituted Rhodanines with Calf-thymus DNA: In Vitro Anticancer Activities

Author(s): Imran Ali* , Mohammad N. Lone , Zeid A. Alothman , Ahmad Y. Badjah , Abdullah G. Alanazi .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Background: In this era of science, cancer is a black dot on the face of humankind. Consequently, the search of promising anticancer agents continues.

Aims: Here we designed and synthesized new N-substituted rhodanines (RD1-7), evaluated their multispectroscopic interaction with calf thymus DNA, in silico and anticancer studies against MDA-MB-231cancer cell line.

Methods: By MTT assay rhodanine RD1 was found to be the most potent with IC50 value of 72.61 μM. In addition, DNA binding studies (UV-vis and fluorescence) revealed strong binding affinity of RD1-7 with DNA (Kb in the range of 1.5-7.4 × 105 M-1). Moreover, molecular docking study, experimental DNA binding and anticancer studies are all well agreed to each other.

Results: It was observed that H-bonding and hydrophobic attractions were responsible for stability of DNAcompound adducts. Besides, the reported rhodanines (RD1-7) were found as minor groove binders of DNA. Concisely, RD1-7 indicated promising pharmacological properties and hence, shows auspicious future for the development of novel anticancer agents.

Conclusion: The reported rhodanines showed excellent anticancer properties. Therefore, the described rhodanines may be used as potential anticancer agents in the future.

Keywords: Anticancer activity, Ct-DNA binding studies, molecular docking, rhodanines, Calf-thymus DNA, N-substituted rhodanines.

Ali, I.; Lone, M.N.; Othman, Z.A.; Alwarthan, A. Heterocyclic scaffolds: Centrality in anticancer drug development. Curr. Drug Target, 2015, 16, 711-734.
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Glutamic acid and its derivatives: Candidates for rational design of anticancer drugs. Fut Med. Chem., 2013, 5, 961-978.
Ali, I.; Haque, A.; Saleem, K.; Hsieh, M.F. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: Synthesis, pharmacological and simulation studies. Bioorg. Med. Chem., 2013, 21, 3808-3820.
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Platinum compounds: A hope for future cancer chemotherapy. Anti-Cancer. Agents Med. Chem., 2013, 13, 296-306.
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Thalidomide: A banned drug resurged into future anticancer drug. Curr. Drug Ther., 2012, 7, 13-23.
Basheer, A.A. Chemical chiral pollution: Impact on the society and science and need of the regulations in the 21st century. Chirality, 2018, 30(4), 402-406.
Ali, I.; Naim, L.; Ghanem, A.; Aboul-Enein, H.Y. Chiral separations of piperidine-2, 6-dione analogues on Chiralpak IA and Chiralpak IB columns by using HPLC. Talanta, 2006, 69, 1013-1017.
Aboul-Enein, H.Y.; Ali, I. Comparative study of the enantiomeric resolution of chiral antifungal drugs econazole, miconazole and sulconazole by HPLC on various cellulose chiral columns in normal phase mode. J. Pharm. Biomed. Analysis., 2002, 27, 441-446.
Ali, I.; Aboul‐Enein, H.Y. Enantioseparation of some clinically used drugs by HPLC using cellulose Tris (3, 5‐dichlorophenylcarbamate) chiral stationary phase. Biomed. Chromatograph., 2003, 17, 113-117.
Ali, I.; AlOthman, Z.A.; Alwarthan, A.; Asim, M.; Khan, T.A. Removal of arsenic species from water by batch and column operations on bagasse fly ash. Environ. Sci. Poll. Res., 2004, 21, 3218-3229.
Aboul-Enein, H.Y.; Ali, I. HPLC enantiomeric resolution of nebivolol on normal and reversed amylose based chiral phases. Die Pharm., 2001, 56, 214-216.
Ali, I.; Gupta, V.K.; Khan, T.A.; Asim, M. Removal of arsenate from aqueous solution by electro-coagulation method using Al-Fe electrodes. Int. J. Electrochem. Sci., 2012, 7, 1898-1907.
Gupta, V.K.; Ali, I. Environmental water: advances in treatment, remediation and recycling; Elsevier: The Netherlands, 2012.
Ali, I.; Jain, C.K. Advances in arsenic speciation techniques. Int. J. Environ. Analytical. Chem., 2004, 84, 947-964.
Ali, I. Rahis-ud-din; Saleem, K.; Aboul-Enein, H.Y.; Rather, A. Social aspects of cancer genesis. Cancer Ther., 2011, 8, 6-14.
Ali, I. Nano anti-cancer drugs: Pros and cons and future perspectives. Curr. Cancer Drug Targets, 2011, 11, 131-134.
Ali, I.; Saleem, K. Rahis-ud-din; Haque, A.; El-Azzouny, A. Natural products: Human friendly anti-cancer medications. Egypt. Pharm. J., 2010, 9, 133-179.
Ali, I.; Wani, W.A.; Saleem, K.; Wesselinova, D. Syntheses, DNA binding and anticancer profiles of L-glutamic acid ligand and its copper (II) and ruthenium (III) complexes. Med. Chem., 2013, 9, 11-21.
Ali, I.; Saleem, K.; Wesselinova, D.; Haque, A. Synthesis, DNA binding, hemolytic, and anti-cancer assays of curcumin I-based ligands and their ruthenium (III) complexes. Med. Chem. Res., 2013, 22, 1386-1398.
Ali, I.; Wani, W.A.; Saleem, K.; Hseih, M.F. Design and synthesis of thalidomide based dithiocarbamate Cu(II), Ni(II) and Ru(III) complexes as anticancer agents. Polyhedron, 2013, 56, 134-143.
Ali, I.; Wani, W.A.; Saleem, K.; Hseih, M.F. Anticancer metallodrugs of glutamic acid sulphonamides: in silico, DNA binding, hemolysis and anticancer studies. RSC Adv, 2014, 4, 29629-29641.
Ali, I.; Lone, M.N.; Suhail, M.; Mukhtar, S.D. Advanced in nanocarriers for anticancer drug delivery. Curr. Med. Chem., 2016, 23, 2159-2187.
Ali, I.; Lone, M.N.; Alothman, Z.A.; Alwarthan, A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings: DNA binding, molecular docking, and anticancer studies. J. Mol. Liquids., 2017, 234, 391-402.
Dehghani, M.H.; Sanaei, D.; Ali, I. Removal of chromium(VI) from aqueous solution using treated waste newspaper as a low-cost adsorbent: Kinetic modeling and isotherm studies. J. Mol. Liquids., 2016, 215, 671-679.
Gupta, V.K.; Ali, I. Adsorbents for water treatment: Low cost alternatives to carbonEncyclopaedia of surface and colloid science, (edited by Arthur Hubbard); Marcel Dekker, New York, USA, 2002, 1, pp. 136-166.
American Cancer Society Breast Cancer Facts & Figures 2017- 2018. Atlanta: American Cancer Society, Inc. , 2017.
Brown, F.C.; Bradsher, C.K.; Morgan, E.C. Tetenbaum, M.; Wilder Jr, P. Some 3-substituted rhodanines. J. Am. Chem. Soc., 1956, 78(2), 384-388.
Moorthy, B.; Ravi, S.; Srivastava, M.; Chiruvella, K.; Hemlal, H.; Joy, O.; Raghavan, S. Novel rhodanine derivatives induce growth inhibition followed by apoptosis. Bioorg. Med. Chem. Lett., 2010, 20, 6297-6301.
Nitsche, C.; Klein, C.D. Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines. Tetrahed Lett., 2012, 53(39), 5197-5201.
Kumar, B.P.; Baig, N.R.; Sudhir, S.; Kar, K.; Kiranmai, M.; Pankaj, M.; Joghee, N.M. Discovery of novel glitazones incorporated with phenylalanine and tyrosine: Synthesis, antidiabetic activity and structure–activity relationships. Bioorg. Chem., 2012, 45, 12-28.
Kamila, S.; Ankati, H.; Harry, E.; Biehl, E.R. A facile synthesis of novel 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-ones using microwave heating. Tetrahed Lett., 2012, 53(17), 2195-2198.
Frankov, I.A.; Kirillov, M.V.; Sokolova, T.N.; Skupskaya, R.V.; Kharitonovich, A.N.; Chizhevskaya, I.I. Synthesis and pharmacoloical properties of 3-carboxyalkylrhodanines containing alkylating moieties. Pharm. Chem. J., 1985, 19(8), 544-547.
Ramkumar, K.; Yarovenko, V.N.; Nikitina, A.S.; Zavarzin, I.V.; Krayushkin, M.M.; Kovalenko, L.V.; Neamati, N. Design, synthesis and structure-activity studies of rhodanine derivatives as HIV-1 integrase inhibitors. Molecules, 2010, 15(6), 3958-3992.
Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hosseinpour, R. A simple and effective approach to the synthesis of rhodanine derivatives via three-component reactions in water. Tetrahed Lett., 2009, 50(14), 1533-1535.
Talele, T.T.; Arora, P.; Kulkarni, S.S.; Patel, M.R.; Singh, S.; Chudayeu, M.; Kaushik-Basu, N. Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase. Bioorg. Med. Chem., 2010, 18(13), 4630-4638.
Powers, J.P.; Piper, D.E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J.M.; Tonn, G.R. SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem., 2006, 49(3), 1034-1046.
Mendgen, T.; Steuer, C.; Klein, C.D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry. J. Med. Chem., 2012, 55(2), 743-753.
Terashima, H.; Hama, K.A.Z.U.A.K.I.; Yamamoto, R.Y.U.Z.O.; Tsuboshima, M.A.S.A.M.I.; Kikkawa, R.Y.U.I.C.H.I.; Hatanaka, I.K.U.O.; Shigeta, Y.U.K.I.O. Effects of a new aldose reductase inhibitor on various tissues in vitro. J. Pharmacol. Exp. Ther., 1984, 229(1), 226-230.
Ramirez, M.A.; Borja, N.L. Epalrestat: An aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy, 2008, 28(5), 646-655.
Steele, J.W.; Faulds, D.; Goa, K.L. Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus. Drugs Aging, 1993, 3(6), 532-555.
Alizadeh, A.; Zohreh, N. A novel multicomponent method for the synthesis of 2-thioxo-1, 3-thiazolidin-4-ones. Synlett, 2009, 2009(13), 2146-2148.
Jacobine, A.M.; Posner, G.H. Three-component, one-flask synthesis of rhodanines (thiazolidinones). J. Org. Chem., 2011, 76(19), 8121-8125.
Ravi, S.; Chiruvella, K.K.; Rajesh, K.; Prabhu, V.; Raghavan, S.C. 5-Isopropylidene-3-ethyl rhodanine induce growth inhibition followed by apoptosis in leukemia cells. Eur. J. Med. Chem., 2010, 45(7), 2748-2752.
Bernardo, P.; Sivaraman, T.; Wan, K.; Xu, J.; Krishnamoorthy, J.; Song, C.; Tian, L.; Chin, J.; Lim, D.; Mok, H.; Yu, V.; Tong, J.; Chai, C. Structural insights into the design of small molecule inhibitors that selectively antagonize Mcl-1. J. Med. Chem., 2010, 53, 2314-2318.
Bernardo, P.H.; Xu, J.; Wan, K.F.; Sivaraman, T.; Krishnamurthy, J.; Mok, H.Y.K.; Yu, V.C.; Chai, C.L.L. Rhodanine-based Pan-Bcl-2 inhibitors and Mcl-1-specific inhibitors as anti-cancer compounds. WO Patent 2010024783 2009.
Benesi, H.A.; Hildebrand, J.H.J. Spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons. J. Am. Chem. Soc., 1949, 71, 2703-2707.
Wolfe, A.; Shimer, G.H., Jr; Meehan, T. Polycyclic aromatic hydrocarbons physically intercalate into duplex regions of denatured DNA. Biochemistry, 1987, 26, 6392.
Nayab, P.S.; Pulaganti, M.; Chitta, S.K. Rahisuddin. Multi-spectroscopic and molecular docking studies on the interaction of new phthalimides with calf-thymus DNA: In vitro free radical scavenging activities. Spectroscop. Lett., 2016, 49(2), 108-117.
Martin, A.; Clynes, M. Comparison of 5 microplate colorimetric assays for in vitro cytotoxicity testing and cell proliferation assays. Cytotechnology, 1993, 11, 49-58.
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
Protein Data Bank. Available online at: . http://www.rcsb.org/pdb
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1998, 19(14), 1639-1662.
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng. Design Selection., 1995, 8(2), 127-134.
Kennard, O. DNA-drug interactions. Pure Appl. Chem., 1993, 65, 1213-1222.
Barton, J.K.; Danishefsky, A.; Goldberg, J. Tris(phenanthroline) ruthenium(II): Stereoselectivity in binding to DNA. J. Am. Chem. Soc., 1984, 106, 2172.
Sun, H.; Xiang, J.; Liu, Y.; Li, L.; Li, Q.; Xu, G.; Tang, Y. A stabilizing and denaturing dual-effect for natural polyamines interacting with G-quadruplexes depending on concentration. Biochimie, 2011, 93(8), 1351-1356.
Jaumot, J.; Gargallo, R. Experimental methods for studying the interactions between G-quadruplex structures and ligands. Curr. Pharmaceut. Des., 2012, 18(14), 1900-1916.
Wei, C.; Wang, J.; Zhang, M. Spectroscopic study on the binding of porphyrins to (G4T4G4)4 parallel G-quadruplex. Biophys. Chem., 2010, 148(1-3), 51-55.
Bhadra, K.; Kumar, G.S. Interaction of berberine, palmatine, coralyne, and sanguinarine to quadruplex DNA: A comparative spectroscopic and calorimetric study. Biochim. Biophys. Acta, 2011, 1810(4), 485-496.
(a)Liu, J.G.; Zhang, Q.L.; Shi, X.F.; Ji, L.N. Interaction of [Ru (dmp) 2 (dppz)] 2+ and [Ru (dmb) 2 (dppz)] 2+ with DNA: Effects of the ancillary ligands on the DNA-binding behaviors. Inorg. Chem., 2001, 40, 5045-5050.
(b)Pyle, A.M.; Rehmann, J.P.; Meshoyrer, R.; Kumar, C.V.; Turro, N.J.; Barton, J.K.J. Mixed-ligand complexes of ruthenium (II): Factors governing binding to DNA. Am. Chem. Soc, 1989, 111(8), 3051.
Sirajuddin, M.; Ali, S.; Haider, A.; Shah, N.A.; Shah, A.; Khan, M.R. Synthesis, characterization, biological screenings and interaction with calf thymus DNA as well as electrochemical studies of adducts formed by azomethine [2-((3,5-dimethylphenylimino)methyl) phenol] and organotin(IV) chlorides. Polyhedron, 2012, 40(1), 19-31.
Sirajuddin, M.; Ali, S.; Shah, N.A.; Khan, M.R.; Tahir, M.N. Synthesis, characterization, biological screenings and interaction with calf thymus DNA of a novel azomethine 3-((3,5-dimethylphenylimino) methyl)benzene-1,2-diol. Spectrochim. Acta A, 2012, 94, 134-142.
Ali, I.; Lone, M.N.; Alothman, Z.A.; Alwarthan, A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings: DNA binding, molecular docking, and anticancer studies. J. Mol. Liquids., 2017, 234, 391-402.
Saleem, K.; Wani, W.A.; Haque, A.; Lone, M.N.; Hsieh, M.F.; Jairajpuri, M.A.; Ali, I. Synthesis, DNA binding, hemolysis assays and anticancer studies of copper (II), nickel (II) and iron (III) complexes of a pyrazoline-based ligand. Fut Med. Chem., 2013, 5(2), 135-146.
Ali, I.; Lone, M.N.; Hsieh, M.F. N-Substituted (substituted-5-benzylidine) thiazolidine-2, 4-diones: Crystal structure, In Silico, DNA binding and anticancer studies. Biointerf. Res. Appl. Chem., 2016, 6(4), 1356-1379.
Shahabadi, N.; Kashanian, S.; Purfoulad, M. DNA interaction studies of a platinum(II) complex, PtCl(2)(NN) (NN=4,7-dimethyl-1,10-phenanthroline), using different instrumental methods. SpectrochimicaActa. Part A Mol. Biomol. Spectroscop., 2009, 72(4), 757-761.
Indumathy, R.; Kanthimathi, M.; Weyhermuller, T.; Nair, B.U. Cobalt complexes of terpyridine ligands: crystal structure and nuclease activity. Polyhedron, 2008, 27, 3443-3450.
Arjmand, F.; Jamsheera, A. DNA binding studies of new valine derived chiral complexes of tin(IV) and zirconium(IV). Spectrochim. Acta A, 2011, 78(1), 45-51.
Allardyce, C.S.; Dyson, P.J.; Ellis, D.J.; Heath, S.L. [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo- [] decane): A water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells. Chem. Commu., 2001, 1396-1397.
Martínez, R.; García, L.C. The search of DNA-intercalators as antitumoral drugs:what it worked and what did not work. Curr. Med. Chem., 2005, 12, 127-151.
Shui, X.; Peek, M.E.; Lipscomb, L.A.; Gao, Q.; Ogata, C.; Roques, B.P.; Garbay-Jaureguiberry, C.; Wilkinson, A.P.; Williams, L.D. Effects of cationic charge on three-dimensional structures of intercalative complexes structure of a bisintercalated DNA complex solved by MAD phasing. Curr. Med. Chem., 2000, 7, 59-71.
(a)Waring, M.J.; Bailly, C. The purine 2-amino group as a critical recognition element for binding of small molecules to DNA. Gene, 1994, 149, 69-79.
(b)Rehn, C.; Pindur, U. Molecular modeling of intercalation complexes of antitumor active 9-aminoacridine and a [d,e]-anellated isoquinoline derivative with base paired deoxytetranucleotides. Monatsh. Chem., 1996, 127, 645-658.
Baginski, M.; Fogolari, F.; Briggs, J.M. Electrostatic and non-electrostatic contributions to the binding free energies of anthracycline antibiotics to DNA. J. Mol. Biol., 1997, 274, 253.
Pasternack, R.F.; Gibbs, E.J.; Villafrancas, J.J. Interactions of porphyrins with nucleic acids. Biochemistry, 1983, 22, 5409-5417.
Zhao, P.; Xu, L.; Huang, J.; Liu, J.; Yu, H.; Zheng, K.; Ji, L. Experimental and DFT studies on DNA binding and photocleavage of two cationic porphyrins: Effects of the introduction of a carboxyphenyl into pyridinium porphyrin. SpectrochimicaActa, Part A Mol. Biomol. Spectroscop., 2008, 71, 1216-1223.
Pratviel, G.; Bernadou, J.; Meunier, B. DNA and RNA cleavage by metal complexes. Adv. Inorg. Chem., 1998, 45, 251-312.
Arjmand, F.; Parveen, S.; Afzal, M.; Toupet, L.; Hadda, T.B. Molecular drug design, synthesis and crystal structure determination of Cu II–Sn IV heterobimetallic core: DNA binding and cleavage studies. Eur. J. Med. Chem., 2012, 49, 141-150.
Haq, I. Thermodynamics of drug-DNA interactions. Arch. Biochem. Biophys., 2002, 403, 1-15.
Anbu, S.; Kandaswamy, M.; Suthakaran, P.; Murugan, V.; Varghese, B. Structural, magnetic, electrochemical, catalytic, DNA binding and cleavage studies of new macrocyclic binuclear copper(II) complexes. J. Inorg. Biochem., 2009, 103, 401-410.
Lakowicz, J.R.; Weber, G. Quenching of fluorescence by oxygen. Probe for structural fluctuations in macromolecules. Biochemistry, 1973, 12, 4161-4170.

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Year: 2019
Page: [425 - 433]
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DOI: 10.2174/1871520618666181002131125
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