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(Thio)substituted-1,4-benzoquinones: Synthesis, electrochemistry, DFT calculations and potential antiproliferative effect against MDAMB- 231 cells

(Thio)substituted-1,4-benzoquinones

Authors

Aysecik Kacmaz Istanbul University - Cerrahpasa, Department of Chemistry, Division of Organic Chemistry, Faculty of Engineering https://orcid.org/0000-0001-8420-6855
Elif Turker Acar Istanbul University - Cerrahpasa, Department of Chemistry, Division of Physical Chemistry, Faculty of Engineering https://orcid.org/0000-0002-0950-0584
Gulten Atun Istanbul University - Cerrahpasa, Department of Chemistry, Division of Physical Chemistry, Faculty of Engineering https://orcid.org/0000-0002-6175-8339
Zuhal Hamurcu Erciyes University, Department of Medical Biology, Faculty of Medicine https://orcid.org/0000-0002-0711-4014

DOI:

https://doi.org/10.20450/mjcce.2025.3016

Keywords:

Benzoquinones, thiols, p-chloranil, Time Dependent Density Functional Theory

Abstract

This study explores the synthesis, electrochemical properties, and computational aspects of mono-, bis-, tris-, and tetrakis(thio)-substituted 1,4-benzoquinones. The electrochemical properties of the compounds were analyzed using staircase cyclic voltammetry (CV). Ground-state energies were determined through time-dependent density functional theory (TD-DFT), utilizing the B3LYP functional and the 6-311G(d,p) basis set. Additionally, the in vitro anticancer efficacy of 2-(tert-butylthio)-3,5,6-trichloro-cyclohexa-2,5-diene-1,4-dione (compound 5) was evaluated using the triple-negative breast cancer cell line (MDA-MB-231). Notably, compound 5 demonstrated significant potency, with values of 50 µM 50 % cytotoxic concentration (IC50).

References

REFERENCES

(1) Wellington, K. W., Understanding cancer and the anticancer activities of naphthoquinones. RSC Advances 2015, 5 (26), 20309–20338. https://doi.org/10.1039/C4RA13547D

(2) Sarma, M. D.; Ghosh, R.; Patra A.; Hazra, B., Synthesis of novel aminoquinonoid analogues of diospyrin and evaluation of their inhibitory activity against murine and human cancer cells. European Journal of Medicinal Chemistry 2008, 43 (9), 1878–1888.

https://doi.org/10.1016/j.ejmech.2007.11.028

(3) Tandon, V. K.; Kumar, S; Mishra, N. N.; Shukla, P. K., Micelles catalyzed chemo- and regio-selective one pot and one step synthesis of 2,3,5,6-tetrakis(alkyl and arylsulfanyl)-1,4-benzoquinones and 2,5-diaminosubstituted-1,4-benzoquinones “In-Water” and their biological evaluation as antibacterial and antifungal agents. European Journal of Medicinal Chemistry 2012, 56, 375-386. https://doi.org/10.1016/j.ejmech.2012.07.022

(4) Tandon, V. K.; Yadav, D. B.; Singh, R. V.; Vaish, M.; Chaturvedic, A. K.; Shukla P. K., Synthesis and biological evaluation of novel 1,4-naphthoquinone derivatives as antibacterial and antiviral agents. Bioorganic & Medicinal Chemistry Letters 2005, 15 (14), 3463–3466.

https://doi.org/10.1016/j.bmcl.2005.04.075

(5) Tandon, V. K.; Maurya, H. K.; Mishra, N. N.; Shukla, P. K., Design, synthesis and biological evaluation of novel nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents. European Journal of Medicinal Chemistry 2009, 44 (8), 3130–3137.

https://doi.org/10.1016/j.ejmech.2009.03.006

(6) Benites, J.; Valderrama, J. A.; Bettega, K.; Pedrosa, R. C.; Calderon, P. B.; Verrax, J., Biological evaluation of donor acceptor aminonaphthoquinones as antitumor agents. European Journal of Medicinal Chemistry 2010, 45 (12), 6052–6057. https://doi.org/10.1016/j.ejmech.2010.10.006

(7) Brötz, E.; Herrmann, J.; Wiese, J.; Zinecker, H.; Maier, A.; Kelter, G; Imhoff, J. F.; Müller, R; Paululat, T., Synthesis and cytotoxic activity of a small naphthoquinone library: First synthesis of Juglonbutin. European Journal of Organic Chemistry 2014, 14, 5318–5338. https://doi.org/10.1002/ejoc.201402272

(8) Delarmelina, M; Daltoé, R. D,; Cerri, M. F,; Madeira, K. P.; Rangel, L. B. A,; Júnior, V. L., Romão, W.; Taranto, A. G.; Greco, S. J., Synthesis, antitumor activity and docking of 2,3-(Substituted)-1,4-Naphthoquinone derivatives containing nitrogen, oxygen and sulfur. Journal of Brazilian Chemical Society 2015, 26 (9), 1804–1816. https://dx.doi.org/10.5935/0103-5053.20150157

(9) Ranjan, K. R.; Singh, A.; Banerjee, A.; Singh, B., New homo- and hetero-bimetallic assemblies based on 2,5-bis(4-carboxyphenylamino)-3,6-dichloro-1,4-benzoquinone: synthesis, characterization, and magnetic properties. Journal of Coordination Chemistry 2011, 64 (8), 1411–1425.

https://doi.org/10.1080/00958972.2011.563382

(10) Nour El-Din, A. M.; Mourad, A.-F. E.; Hassan, A. A.; Gomaa, M. A., Reaction of amidine phenylogous with p-Benzoquinones. Bulletin of the Chemical Society of Japan 1991, 64 (6), 1966–1970. https://doi.org/10.1246/bcsj.64.1966

(11) Hameed Khan, A.; Driscoll, J. S., Potential central nervous system antitumor agents. Aziridinylbenzoquinones. Journal of Medicinal Chemistry 1976, 19 (2), 313–317.

https://doi.org/10.1021/jm00224a022

(12) Ibis, C.; Gunes, Z. O., The synthesis and spectral properties of novel thioquinone dyes. Dyes and Pigments 2008, 77 (1), 39–42. https://doi.org/10.1016/j.dyepig.2007.02.010

(13) Goksel, F. S; Bayrak, N.; Ibis, C., Synthesis of novel S,O substituted 1,4-benzoquinones. Phosphorus, Sulfur, and Silicon and the Related Elements 2014, 189 (1), 113–123.

https://doi.org/10.1080/10426507.2013.798787

(14) Abalyaeva, V. V.; Orlov, A. V.; Kiseleva, S. G.; Efimov, O. N., Karpacheva, G. P., Electrochemical synthesis and study of poly(2,5-diarylamino-3,6-dichlorobenzoquinone) and its composite with multiwalled carbon nanotubes. Russian Journal of Electrochemistry 2017, 53 (2), 210–216. https://doi.org/10.1134/S1023193517020021

(15) Batra, M. K.; Batra, C.; Ojha, K. G.; Nontraditional approaches to the synthesis of some biologically active substituted p-benzoquinones. Medicinal Chemistry Research 2008, 17 (9), 604–617. https://doi.org/10.1007/s00044-008-9101-8

(16) Bedernjak, A. F., Groundwater, P. W.; Gray, M.; James, A. L.; Orenga, S.; Perry, J. D.; Anderson, R. J., Synthesis and evaluation of halogenated nitrophenoxazinones as nitroreductase substrates for the detection of pathogenic bacteria. Tetrahedron 2013, 69 (39), 8456–8462.

https://doi.org/10.1016/j.tet.2013.07.047

(17) Batra, M.; Kriplani, P.; Batra, C.; Ojha, K. G., An efficient synthesis and biological activity of substituted p-benzoquinones. Bioorganic & Medicinal Chemistry 2006, 14 (24), 8519–8526. https://doi.org/10.1016/j.bmc.2006.08.036

(18) Tjepkema, J. J., Manufacture of organomercapto substituted Quinones. US Patent, 2,691, 661. Oct. 12, 1954.

(19) Kaçmaz, A.; Türker Acar, E.; Atun, G.; Kaya, K; Diren Sigirci, B; Bagcigil, F., Synthesis, electrochemistry, DFT calculations, antimicrobial properties and X-ray crystal structures of some NH- and/or S- substituted-1,4-quinones. Chemistry Select 2018, 3 (30), 8615–8623. https://doi.org/10.1002/slct.201801155

(20) Kacmaz, A., Hamurcu, Z., New NH-substituted 1,4-naphtho- and 1,4-benzo- quinones: Synthesis, characterization and potential antiproliferative effect against MDA-MB-231 cells. Phosphorus Sulfur and Silicon and Related Elements 2018, 193 (12), 831–839. https://doi.org/10.1080/10426507.2018.1514503

(21) Kacmaz, A., Deniz, N. G.; Aydinli, G.; Sayil, C.; Onay Ucar, E.; Mertoglu, E.; Arda, N., Synthesis and antiproliferative evaluation of some 1,4-naphthoquinone derivatives against human cervical cancer cells. Open Chemistry 2019, 17, 337–345. https://doi.org/10.1515/chem-2019-0030

(22) Yıldız, M.; Yıldırım, H.; Bayrak, N.; Çakmak, S. M.; Mataracı-Kara, E., Özbek-Çelik, B., Otsuka, M., Fujita, M.; Radwan, M. O.; Tuyun, A. F., Design, synthesis, in vitro and in silico characterization of plastoquinone analogs containing piperidine moiety as antimicrobial agents. Journal of Molecular Structure 2023, 1277, 134845. https://doi.org/10.1016/j.molstruc.2022.134845

(23) Ciftci, H.; Sever, B.; Kaya, N.; Bayrak, N.; Yıldız, M.; Yıldırım, H.; Tateishi, H.; Otsuka, M.; Fujita, M.; Tuyun, A. F.; Studies on 1,4-Quinone derivatives exhibiting anti-leukemic activity along with anti-colorectal and anti-breast cancer effects. Molecules, 2023, 28, 77. https://doi.org/10.3390/molecules28010077

(24) https://www.who.int/cancer/en/

(25) Perez-Sacau, E.; Dıaz-Penate, R. G.; Estevez-Braun A.; Ravelo, A. G.; Garcıa-Castellano, J. M.; Pardo, L.; Campillo, M., Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 Cell line. Journal of Medicinal Chemistry 2007, 50 (4), 696–706. https://doi.org/10.1021/jm060849b

(26) Suarez-Rozas, C.; Simpson, S.; Fuentes-Retamal, S.; Catalan, M.; Ferreira, J.; Theoduloz, C.; Mella, J.; Cabezas, D.; Cassels, B. K.; Yanez, C.; Castro-Castillo, V., Antiproliferative and proapoptotic activities of azaannulated naphthoquinone analogs. Toxicology in Vitro 2019, 54, 375–390.

https://doi.org/10.1016/j.tiv.2018.10.014

(27) Scherz, L. F.; Abdel-Rahman, E. A.; Ali, S. S.; Schlütera, A. D.; Abdel-Rahman, M. A., Design, synthesis and cytotoxic activity of water-soluble quinones with dibromo-p-benzoquinone cores and amino oligo(ethyleneglycol) side chains against MCF-7 breast cancer cells. Medicinal Chemistry Communations 2017, 8, 662–672. https://doi.org/10.1039/C6MD00728G

(28) A patent application has been filled with the Turkish Patent and Trademark Office for compound 5 (2-(tert-butylthio)-3,5,6-trichlorocyclohexa-2,5-diene-1,4-dione). E. Turker Acar, A. Kaçmaz, G. Atun, Z. Hamurcu. Turkish Patent and Trademark Office, Turkey, Application number: 2023/018581, Reference Number: 22150/1).

(29) Ibis, C.; Sahinler Ayla, S.; Dogan, Y.; Ozen, M., Synthesis and characterization of novel N-, S-, O-substituted p-chloranil derivatives. Synthetic Communications 2014, 44 (11), 1614–1618. https://doi.org/10.1080/00397911.2013.865059

(30) Tjepkema, J. J., The preparation of alkylthio substituted naphthoquinones-1,4 and benzoquinones-1,4. Recueil des Travaux Chimiques des Pays-Bas 1952, 71 (9), 853-856. https://doi.org/10.1002/recl.19520710903

(31) Bock, H.; Haenel. P.; Herrmann, H.-F.; Torn Dieck, H., Electron transfer and ion pairing, 7. Contact ion pairs of sulfur-containing radical anions. Zeitschrift fur Naturforschung, B: Chemical Sciences 1988, 43 (10), 1240–1246. https://doi.org/10.1515/znb-1988-1005

(32) Sheldrick, G. M., A short history of SHELX. Acta Crystallographica Section A 2008, 64, 112–122.

https://doi.org/10.1107/S0108767307043930

(33) Prince, R. C., Leslie Dutton, P.; Gunner, M. R., The aprotic electrochemistry of quinones. Biochimica et Biophysica Acta (BBA-Bioenergetics) 2022, 1863 (6), 148558. https://doi.org/10.1016/j.bbabio.2022.148558

(34) Sasaki, K.; Kashimura, T.; Ohura, M.; Ohsaki, Y.; Ohta, N., Solvent effect in the electrochemical reduction of p-quinones in several aprotic solvents. Journal of The Electrochemical Society 1990, 137 (8), 2437–2443. https://doi.org/10.1149/1.2086957

(35) Sheldrick, G. M., SHELXS-97, Program for crystal structure solution, University of Gottingen, Gottingen 1997.

(36) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H., OLEX2: A complete structure solution, refinement and analysis program. Journal of Applied Crystallography 2009, 42, 339–341. http://dx.doi.org/10.1107/S0021889808042726

(37) Gulaboski, R.; Markovski, V.; Jihe, Z., Redox chemistry of coenzyme Q- a short overview of the voltammetric features. Journal of Solid State Electrochemistry 2016, 20, 3229-3238. https://doi.org/10.1007/s10008-016-3230-7

(38) Itoh, S.; Kawakami, H.; Fukuzumi, S., Electrochemical behavior and characterization of semiquinone radical anion species of coenzyme PQQ in aprotic organic media. Journal of the American Chemical Society 1998, 120, 7271–7277. https://doi.org/10.1021/ja9813663

(39) Miranda, F. S.; Ronconi, C. M.; Sousa, M. O. B.; Silveira, G. Q.; Vargas, M. D., 6-Aminocoumarin-naphthoquinone conjugates: Design, synthesis, photophysical and electrochemical properties and DFT calculations. Journal of the Brazilian Chemical Society 2014, 25, 133–142.

http://dx.doi.org/10.5935/0103-5053.20130279

(40) Malkin, V. G.; Malkina, O. L.; Eriksson, L. A.; Salahub, D. R., In modern density functional theory. A tool for chemistry, Seminario, J. M., Politzer P, (Eds.). Elsevier, Amsterdam, 1995.

(41) Frisch, M. J. et al., Gaussian, Inc., Wallingford CT, to be found under

http://gaussian.com/ g09citation/ 2009

(42) Becke, A. D., Density‐functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics 1993, 98, 5648–5652. https://doi.org/10.1063/1.464913

(43) Lee, C.; Yang, W.; Parr, R.G., Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Physical Review B 1988, 37, 785–789. https://doi.org/10.1103/PhysRevB.37.785

(44) Liao, M. S.; Lu, Y.; Parker, V. D.; Scheiner, S., DFT calculations and spectral measurements of charge

transfer complexes formed by aromatic amines and nitrogen heterocycles with tetracyanoethylene and chloranil. The Journal of Physical Chemistry A 2003, 107 (42), 8939–8948. https://doi.org/10.1021/jp034985t

(45) Balraj, C.; Satheshkumar, A.; Ganesh, K.; Elango, K. P., Charge transfer complexes of quinones in aqueous medium: Spectroscopic and theoretical studies on interaction of cimetidine with novel substituted 1,4-benzoquinones and its application in colorimetric sensing of anions. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2013, 114, 256–266. https://doi.org/10.1016/j.saa.2013.05.031

(46) Guediri, A.; Bouguettoucha, A; Chebli, D.; Chafai, N., Amrane, A., Molecular dynamic simulation and DFT computational studies on the adsorption performances of methylene blue in aqueous solutions by orange peel modified phosphoric acid. Journal of Molecular Structure 2020, 1202, 127290.

https://doi.org/10.1016/j.molstruc.2019.127290

(47) Fukui, K., The role frontier orbitals in chemical reactions. Angewandte. Chemie International. Edition in English 1982, 21, 801–876. https://doi.org/10.1002/anie.198208013

(48) Nikfar, Z.; Shariatinia, Z., The RGD tripeptide anticancer drug carrier: DFT computations and molecular dynamics simulations. Journal of Molecular Liquids 2019, 281, 565–583. https://doi.org/10.1016/j.molliq.2019.02.114

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2025-05-28

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2025-06-29 (2)
2025-05-28 (1)

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Kacmaz, A., Turker Acar, E., Atun, G., & Hamurcu, Z. (2025). (Thio)substituted-1,4-benzoquinones: Synthesis, electrochemistry, DFT calculations and potential antiproliferative effect against MDAMB- 231 cells : (Thio)substituted-1,4-benzoquinones. Macedonian Journal of Chemistry and Chemical Engineering, 44(1). https://doi.org/10.20450/mjcce.2025.3016

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Vol. 44 No. 1 (2025)

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Organic Chemistry

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(Thio)substituted-1,4-benzoquinones: Synthesis, electrochemistry, DFT calculations and potential antiproliferative effect against MDAMB- 231 cells