Synthesis, In Vitro Evaluation, Molecular Docking and DFT Studies of Some Phenyl Isothiocyanates as Anticancer Agents

Kikoleho       Richa; Rituparna       Karmaker; Naruti       Longkumer; Vishal       Das; Pulak    J.    Bhuyan; Mintu       Pal; Upasana    B.    Sinha

doi:10.2174/1871520619666190930122137

Abstract

Background: Isothiocyanates (ITCs) are small molecules that are important in synthetic organic chemistry, but their actual importance lies in their potential as anti-carcinogens. Through this piece of work, an effort was made to assess the anti-cancer activity of some simple ITCs which can be synthesized through easy greener pathways.

Methods: Cell proliferation assay was performed on ovarian cancer cells (PA-1) and non-tumorigenic ovarian epithelial cells (IOSE-364). Furthermore, qRT-PCR for transcript expression levels of Spindlin1 and caspases in ovarian cancer cells and cell cycle analysis was performed. In silico studies were incorporated to understand the mode of ligand-protein interaction, ADME/Toxicity and drug-likeliness parameters. Density functional theory studies have been also been employed on the ITCs to assess their efficiency in anticancer activity.

Results: An inexpensive, environmentally benign pathway has been developed for synthesizing a series of ITCs. Among the synthesized ITCs, NC6 showed better cytotoxic effects as compared to its counterparts. Novel findings revealed that NC6 had 5-folds lower transcript expression levels of Spindlin1 and induced caspases 3 and 7 expressions assessed by qRT-PCR in ovarian cancer cells. Furthermore, flow cytometry assay showed the cell cycle arrest at G1/S phase of cell cycle. The molecular docking studies revealed favorable binding affinities and the physiochemical parameters were predicted to be compatible with drug-likeliness.

Conclusion: The results demonstrated the possibility that small isothiocyanate molecules which can be synthesized by a simple green methodology, can pose as promising candidates for their application as anticancer agents.

Keywords: Synthesis, isothiocyanates, anticancer, in vitro, in silico, band gap energy.

« Previous Next »

Graphical Abstract

[1] 
Samundeeswari, S.; Chougala, B.; Holiyachi, M.; Shastri, L.; Kulkarni, M.; Dodamani, S.; Jalalpur, S.; Joshi, S.; Dixit, S.; Sunagar, V.; Hunnur, R. Design and synthesis of novel phenyl -1, 4-beta-carboline-hybrid molecules as potential anticancer agents. Eur. J. Med. Chem.,  2017, 128, 123-139.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.014] [PMID:  28171832] 
[2] 
Lei, X. Small molecule enabled chemical biology and drug discovery. Bioorg. Med. Chem.,  2017, 25(11), 2815-2816.
[http://dx.doi.org/10.1016/j.bmc.2017.05.025] [PMID:  28532738] 
[3] 
Swamy, P.V. Synthesis, biological evaluation and molecular docking studies of some novel cyclopropane carbohydrazide derivatives as potential anticancer agents. J. Chem. Sci.,  2016, 128, 929-939.
[http://dx.doi.org/10.1007/s12039-016-1081-5] 
[4] 
Bedane, K.G.; Singh, G.S. Reactivity and diverse synthetic applications of acyl isothiocyanates. ARKIVOC,  2015, 6, 206-245.
[5] 
Wu, X.; Zhou, Q.H.; Xu, K. Are isothiocyanates potential anti-cancer drugs? Acta Pharmacol. Sin.,  2009, 30(5), 501-512.
[http://dx.doi.org/10.1038/aps.2009.50] [PMID:  19417730] 
[6] 
Dufour, V.; Stahl, M.; Baysse, C. The antibacterial properties of isothiocyanates. Microbiology,  2015, 161(Pt 2), 229-243.
[http://dx.doi.org/10.1099/mic.0.082362-0] [PMID:  25378563] 
[7] 
Kaiser, S.J.; Mutters, N.T.; Blessing, B.; Günther, F. Natural isothiocyanates express antimicrobial activity against developing and mature biofilms of Pseudomonas aeruginosa. Fitoterapia,  2017, 119, 57-63.
[http://dx.doi.org/10.1016/j.fitote.2017.04.006] [PMID:  28390975] 
[8] 
Mukerjee, A.K.; Ashare, R. Isothiocyanates in the chemistry of heterocycles. Chem. Rev.,  1991, 91, 1-24.
[9] 
Mesheram, H.M.; Dale, S.; Yadav, J.S. A general synthesis of isothiocyanates from dithiocarbamates using claycop. Tetrahedron Lett.,  1997, 38, 8743-8744.
[http://dx.doi.org/10.1016/S0040-4039(97)10158-7] 
[10] 
Sun, N.; Li, B.; Shao, J.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. A general and facile one-pot process of isothiocyanates from amines under aqueous conditions. Beilstein J. Org. Chem.,  2012, 8, 61-70.
[http://dx.doi.org/10.3762/bjoc.8.6] [PMID:  22423272] 
[11] 
Goti, A.; Cardona, F. Hydrogen peroxide in green oxidation reactions: Recent catalytic processes. In: Green Chemical Reactions.
NATO Science for Peace and Security Series (Series C: Environmental
Security); Tundo, P.; Esposito, V., Eds.; Green Chemical Reactions, Springer; Dordrecht, 2008; pp. 191-212.
[http://dx.doi.org/10.1007/978-1-4020-8457-7_9] 
[12] 
Kashif, M.; Andersson, C.; Hassan, S.; Karlsson, H.; Senkowski, W.; Fryknäs, M.; Nygren, P.; Larsson, R.; Gustafsson, M.G. In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index. Sci. Rep.,  2015, 5, 14118.
[http://dx.doi.org/10.1038/srep14118] [PMID:  26392291] 
[13] 
Prada-Gracia, D.; Huerta-Yépez, S.; Moreno-Vargas, L.M. Application of computational methods for anticancer drug discovery, design, and optimization. Bol. Méd. Hosp. Infant. México,  2016, 73(6), 411-423.
[http://dx.doi.org/10.1016/j.bmhimx.2016.10.006] [PMID:  29421286] 
[14] 
Shaikh, S.K.J.; Kamble, R.R.; Somagond, S.M.; Devarajegowda, H.C.; Dixit, S.R.; Joshi, S.D. Tetrazolylmethyl quinolines: Design, docking studies, synthesis, anticancer and antifungal analyses. Eur. J. Med. Chem.,  2017, 128, 258-273.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.043] [PMID:  28192709] 
[15] 
Wang, J.X.; Zeng, Q.; Chen, L.; Du, J.C.; Yan, X.L.; Yuan, H.F.; Zhai, C.; Zhou, J.N.; Jia, Y.L.; Yue, W.; Pei, X.T. SPINDLIN1 promotes cancer cell proliferation through activation of WNT/TCF-4 signaling. Mol. Cancer Res.,  2012, 10(3), 326-335.
[http://dx.doi.org/10.1158/1541-7786.MCR-11-0440] [PMID:  22258766] 
[16] 
Zhao, Q.; Qin, L.; Jiang, F.; Wu, B.; Yue, W.; Xu, F.; Rong, Z.; Yuan, H.; Xie, X.; Gao, Y.; Bai, C.; Bartlam, M.; Pei, X.; Rao, Z. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J. Biol. Chem.,  2007, 282(1), 647-656.
[http://dx.doi.org/10.1074/jbc.M604029200] [PMID:  17082182] 
[17] 
Robaa, D.; Wagner, T.; Luise, C.; Carlino, L.; McMillan, J.; Flaig, R.; Schüle, R.; Jung, M.; Sippl, W. Identification and structure-activity relationship studies of small-molecule inhibitors of the methyllysine reader protein spindlin1. ChemMedChem,  2016, 11(20), 2327-2338.
[http://dx.doi.org/10.1002/cmdc.201600362] [PMID:  27634332] 
[18] 
Zhang, P.; Cong, B.; Yuan, H.; Chen, L.; Lv, Y.; Bai, C.; Nan, X.; Shi, S.; Yue, W.; Pei, X. Overexpression of Spindlin1 induces metaphase arrest and chromosomal instability. J. Cell. Physiol.,  2008, 217(2), 400-408.
[http://dx.doi.org/10.1002/jcp.21515] 
[19] 
Wang, W.; Chen, Z.; Mao, Z.; Zhang, H.; Ding, X.; Chen, S.; Zhang, X.; Xu, R.; Zhu, B. Nucleolar protein Spindlin1 recognizes H3K4 methylation and stimulates the expression of rRNA genes. EMBO Rep.,  2011, 12(11), 1160-1166.
[http://dx.doi.org/10.1038/embor.2011.184] [PMID:  21960006] 
[20] 
Sabbagh, G.; Berakdar, N. Docking studies of flavonoid compounds as inhibitors of β-ketoacyl acyl carrier protein synthase I (Kas I) of Escherichia coli. J. Mol. Graph. Model.,  2015, 61, 214-223.
[http://dx.doi.org/10.1016/j.jmgm.2015.07.005] [PMID:  26292066] 
[21] 
Singh, S.P.; Singh, N.I.; Nongalleima, K.; Doley, P.; Singh, C.B.; Sahoo, D. Molecular docking, MD simulation, DFT and ADME-toxicity study on analogs of zerumbone against IKK-β enzyme as anti-cancer agents. Netw. Model. Anal. Health Inform. Bioinform.,  2018, 7, 7.
[22] 
Singh, S.P.; Deb, C.R.; Ahmed, S.U.; Chandra, Y.S.; Konwar, B.K. Density functional theory studies on non-steroidal anti-inflammatory drugs acetic acid derivatives of cyclooxygenase inhibitor. J. Bionanosci.,  2014, 8, 328-334.
[http://dx.doi.org/10.1166/jbns.2014.1247] 
[23] 
Mousavi, M.; Ilkhani, A.R.; Sharifi, S.; Mehrzad, J.; Eghdami, A.; Monajjemi, M. DFT studies of nano anticancer on vinblastine and vincristine molecules. Int. J. Microbiol. Res. Rev.,  2013, 1(2), 032-038.
[24] 
Ghorab, M.M.; Alsaid, M.S.; El-Gaby, M.S.A.; Elaasser, M.M.; Nissan, Y.M. Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking. Chem. Cent. J.,  2017, 11(1), 32.
[http://dx.doi.org/10.1186/s13065-017-0258-4] [PMID:  29086809] 
[25] 
Wang, C. Synthesis and biological evaluation of tetrahydrobenzo[b]pyran derivatives as potential anti-ovarian cancer agents. Biomed. Res.,  2016, (Special Issue), 322-325.
[26] 
Vinoda, B.M.; Bodke, Y.D.; Vinuth, M.; Sindhe, M.A.; Venkatesh, T.; Telkar, S. One pot synthesis, antimicrobial and in silico molecular docking study of 1,3-benzoxazole-5-sulfonamide derivatives. Organic Chem. Curr. Res.,  2016, 5, 2.
[27] 
Saikia, I.; Sonowal, S.; Pal, M.; Baruah, P.K.; Das, M.R.; Tamuly, C. Biosynthesis of gold decorated reduced graphene oxide and its biological activities. Mater. Lett.,  2016, 178, 239-242.
[http://dx.doi.org/10.1016/j.matlet.2016.05.011] 
[28] 
Saikia, I.; Hazarika, M.; Yunus, S.; Pal, M.; Das, M.R.; Borah, J.C.; Tamuly, C. Green synthesis of Au-Ag-In-rGO nanocomposites and its α-glucosidase inhibition and cytotoxicity effects. Mater. Lett.,  2018, 211, 48-50.
[http://dx.doi.org/10.1016/j.matlet.2017.09.084] 
[29] 
Allou, N.B.; Yadav, A.; Pal, M.; Goswamee, R.L. Biocompatible nanocomposite of carboxymethyl cellulose and functionalized carbon-norfloxacin intercalated layered double hydroxides. Carbohydr. Polym.,  2018, 186, 282-289.
[http://dx.doi.org/10.1016/j.carbpol.2018.01.066] [PMID:  29455989] 
[30] 
Karki, N.; Tiwari, H.; Pal, M.; Chaurasia, A.; Bal, R.; Joshi, P.; Sahoo, N.G. Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study. Colloids Surf. B Biointerfaces,  2018, 169, 265-272.
[http://dx.doi.org/10.1016/j.colsurfb.2018.05.022] [PMID:  29783152] 
[31] 
Rajasekhar, K.K.; Surur, A.S.; Mekonnen, Y.T.; Padmavathamma, M.; Ranganayakulu, D.; Shankarananth, V. In silico prediction of biological activity, selected pharmacokinetic and toxicity profile of some 2,4,6-Trisubstituted pyrimidines derived from guanabenz and guanfacine. Inter. J. Innovative Pharm. Res.,  2015, 6, 468-477.
[32] 
Kong, Y.; Chen, G.; Xu, Z.; Yang, G.; Li, B.; Wu, X.; Xiao, W.; Xie, B.; Hu, L.; Sun, X.; Chang, G.; Gao, M.; Gao, L.; Dai, B.; Tao, Y.; Zhu, W.; Shi, J. Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells. Sci. Rep.,  2016, 6, 37417.
[http://dx.doi.org/10.1038/srep37417] [PMID:  27869173] 
[33] 
García, J.M.; García, V.; Peña, C.; Domínguez, G.; Silva, J.; Diaz, R.; Espinosa, P.; Citores, M.J.; Collado, M.; Bonilla, F. Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. RNA,  2008, 14(7), 1424-1432.
[http://dx.doi.org/10.1261/rna.755908] [PMID:  18456845] 
[34] 
Ross, D.D.; Joneckis, C.C.; Ordóñez, J.V.; Sisk, A.M.; Wu, R.K.; Hamburger, A.W.; Nora, R.E.; Nora, R.E. Estimation of cell survival by flow cytometric quantification of fluorescein diacetate/propidium iodide viable cell number. Cancer Res.,  1989, 49(14), 3776-3782.
[PMID:  2736519] 
[35] 
Madhuri, M.; Prasad, C.; Avupati, V.R. In silico protein-ligand docking studies on thiazolidinediones as potential anticancer agents. Int. J. Comput. Appl.,  2014, 95, 13-16.
[36] 
Sanghani, H.V.; Ganatra, S.H.; Pande, R. Molecular-docking studies of potent anticancer agent. J. Comput. Sci. Syst. Biol.,  2012, 21, 012-015.
[37] 
Pathak, D.; Chadha, N.; Silakari, O. Identification of non-resistant ROS-1 inhibitors using structure based pharmacophore analysis. J. Mol. Graph. Model.,  2016, 70, 85-93.
[http://dx.doi.org/10.1016/j.jmgm.2016.09.013] [PMID:  27693947] 
[38] 
Kamal, A.; Mallareddy, A.; Suresh, P.; Lakshma Nayak, V.; Shetti, R.V.C.R.N.C.; Sankara Rao, N.; Tamboli, J.R.; Shaik, T.B.; Vishnuvardhan, M.V.P.S.; Ramakrishna, S. Synthesis and anticancer activity of 4β-alkylamidochalcone and 4β-cinnamido linked podophyllotoxins as apoptotic inducing agents. Eur. J. Med. Chem.,  2012, 47(1), 530-545.
[http://dx.doi.org/10.1016/j.ejmech.2011.11.024] [PMID:  22136907] 
[39] 
ACD/labs, freeware version 2016.2.2, Advanced Chemistry Development, Inc., Toronto, ON, Canada 2015. Available from. www.acdlabs.com
[40] 
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model.,  2012, 52(11), 3099-3105.
[http://dx.doi.org/10.1021/ci300367a] [PMID:  23092397] 
[41] 
Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model.,  2015, 55(2), 460-473.
[http://dx.doi.org/10.1021/ci500588j] [PMID:  25558886] 
[42] 
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A., Jr; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, O.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian 09, Revision A.02-SMP; Gaussian, Inc.: Wallingford, CT, 2009. 
[43] 
Kuotsu, N.B.; Jamir, L.; Phucho, T.; Sinha, U.B. A novel one-pot synthesis of isothiocyanates and cyanamides from dithiocarbamate salts using environmentally benign reagent tetrapropylammonium tribromide. Acta Chim. Slov.,  2017, 64(4), 832-841.
[http://dx.doi.org/10.17344/acsi.2017.3342] [PMID:  29318301] 
[44] 
Saha, B.; Abu-Omar, M.M. Advances in 5-Hydroxymethylfurfural production from biomass in biphasic solvents. Green Chem.,  2014, 16, 24-38.
[http://dx.doi.org/10.1039/C3GC41324A] 
[45] 
Yuan, H.; Zhang, P.; Qin, L.; Chen, L.; Shi, S.; Lu, Y.; Yan, F.; Bai, C.; Nan, X.; Liu, D.; Li, Y.; Yue, W.; Pei, X. Overexpression of SPINDLIN1 induces cellular senescence, multinucleation and apoptosis. Gene,  2008, 410(1), 67-74.
[http://dx.doi.org/10.1016/j.gene.2007.11.019] [PMID:  18201843] 
[46] 
Egan, W.J.; Lauri, G. Prediction of intestinal permeability. Adv. Drug Deliv. Rev.,  2002, 54(3), 273-289.
[http://dx.doi.org/10.1016/S0169-409X(02)00004-2] [PMID:  11922948] 
[47] 
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol.,  2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID:  24981612] 
[48] 
Lajiness, M.S.; Vieth, M.; Erickson, J. Molecular properties that influence oral drug-like behavior. Curr. Opin. Drug Discov. Devel.,  2004, 7(4), 470-477.
[PMID:  15338956] 
[49] 
Oukil, O.; Tchouar, N.; Belaidi, S.; Salah, T.; Cinar, M. Structural investigation, drug likeness scoring and structure activity/property relationships applied on 1,2,3-thiadiazole derivatives, with kinase inhibitors activity. Rev. Roum. Chim.,  2017, 62, 81-92.
[50] 
Walters, W.P.; Murcko, M.A. Prediction of ‘drug-likeness’. Adv. Drug Deliv. Rev.,  2002, 54(3), 255-271.
[http://dx.doi.org/10.1016/S0169-409X(02)00003-0] [PMID:  11922947] 

Rights & Permissions Print Cite

Article Metrics

22

2

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1871520619666190930122137	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992

Anti-Cancer Agents in Medicinal Chemistry

Synthesis, In Vitro Evaluation, Molecular Docking and DFT Studies of Some Phenyl Isothiocyanates as Anticancer Agents

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract