Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.

Chemistry of Natural Compounds Department Pharmaceutical and Drug Industries Research Institute National Research Center Dokki Cairo Egypt

Department of Chemistry College of Science Northern Border University Arar Saudi Arabia

Department of Pharmaceutical Sciences College of Pharmacy AlMaarefa University Diriyah Saudi Arabia

Faculty of Chemistry and Chemical Engineering University of Maribor Maribor Slovenia

Faculty of Mathematics Natural Sciences and Information Technologies University of Primorska Koper Slovenia

Institute of Environmental Protection and Sensors Maribor Slovenia

Institute of Organic Chemistry and Biochemistry Academy of Sciences Prague Czech Republic

Laboratory of Enzyme Technology Department of Biotechnology School of Applied Biology and Biotechnology Agricultural University of Athens Athens Greece

Section of Animal and Human Physiology Department of Biology National and Kapodistrian University of Athens Athens Greece

Turku Bioscience Centre University of Turku and Åbo Akademi University Turku Finland

See more in PubMed

Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45: 51–88. doi: 10.1146/annurev.pharmtox.45.120403.095857 PubMed DOI

Mazari AM, Zhang L, Ye ZW, Zhang J, Tew KD, Townsend DM. The Multifaceted Role of Glutathione S-Transferases in Health and Disease. Biomolecules. 2023;13: 688. doi: 10.3390/biom13040688 PubMed DOI PMC

Bocedi A, Noce A, Marrone G, Noce G, Cattani G, Gambardella G, et al.. Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution. Nutrients. 2019. Jul 27;11: 1741. doi: 10.3390/nu11081741 PubMed DOI PMC

Zompra A, Georgakis N, Pappa E, Thireou T, Eliopoulos E, Labrou N, et al.. Glutathione analogues as substrates or inhibitors that discriminate between allozymes of the MDR-involved human glutathione transferase P1-1. Pept Sci. 2016;106: 330–344. doi: 10.1002/bip.22844 PubMed DOI

Dirr H, Reinemer P, Huber R. X-ray crystal structures of cytosolic glutathione S-transferases. Implications for protein architecture, substrate recognition and catalytic function. Eur J Biochem/FEBS. 1994;220: 645–661. doi: 10.1111/j.1432-1033.1994.tb18666.x PubMed DOI

Mannervik B. Versatility of Glutathione Transferase Proteins. Biomolecules. 2023. Dec 6;13: 1749. doi: 10.3390/biom13121749 PubMed DOI PMC

Tew KD. Glutathione-Associated Enzymes In Anticancer Drug Resistance. Cancer Res. 2016. Jan 1;76: 7–9. doi: 10.1158/0008-5472.CAN-15-3143 PubMed DOI

Allocati N, Masulli M, Di Ilio C, Federici L. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis. 2018. Jan 24;7: 8. doi: 10.1038/s41389-017-0025-3 PubMed DOI PMC

Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, Coric V, Djukic T, Radic et al.. Glutathione transferases: Potential targets to overcome chemoresistance in solid tumors. Int J Mol Sci. 2018; 19: 3785. doi: 10.3390/ijms19123785 PubMed DOI PMC

Georgakis ND, Karagiannopoulos DA, Thireou TN, Eliopoulos EE, Labrou NE, Tsoungas PG, et al.. Concluding the trilogy: The interaction of 2, 20 -dihydroxy-benzophenones and their carbonyl N-analogues with human glutathione transferase M1-1 face to face with the P1-1 and A1-1 isoenzymes involved in MDR. Chem Biol Drug Des. 2017;90: 900–908. doi: 10.1111/cbdd.13011 PubMed DOI

Duan C, Yu M, Xu J, Li BY, Zhao Y, Kankala RK. Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges. Biomed Pharmacother. 2023;162: 114643. doi: 10.1016/j.biopha.2023.114643 PubMed DOI

Ismail A, Govindarajan S, Mannervik B. Human GST P1-1 Redesigned for Enhanced Catalytic Activity with the Anticancer Prodrug Telcyta and Improved Thermostability. Cancers (Basel). 2024. Feb 12;16: 762. doi: 10.3390/cancers16040762 PubMed DOI PMC

Cui J, Li G, Yin J, Li L, Tan Y, Wei H, et al.. GSTP1 and cancer: Expression, methylation, polymorphisms and signaling (Review). Int J Oncol. 2020;56: 867–878. doi: 10.3892/ijo.2020.4979 PubMed DOI

Lv N, Huang C, Huang H, Dong Z, Chen X, Lu C, et al.. Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications. Antioxidants (Basel). 2023. Nov 6;12: 1970. doi: 10.3390/antiox12111970 PubMed DOI PMC

Allen TC, Granville LA, Cagle PT, Haque A, Zander DS, Barrios R. Expression of glutathione S-transferase π and glutathione synthase correlates with survival in early stage non–small cell carcinomas of the lung. Hum Pathol. 2007. Feb 1;38: 220–7. doi: 10.1016/j.humpath.2006.07.006 PubMed DOI

Peklak-Scott C, Smitherman PK, Townsend AJ, Morrow CS. Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin. Mol Cancer Ther. 2008. Oct;7: 3247–55. doi: 10.1158/1535-7163.MCT-08-0250 PubMed DOI PMC

Zhang J, Grek C, Ye ZW, Manevich Y, Tew KD, Townsend DM. Pleiotropic functions of glutathione S-transferase P. Adv Cancer Res. 2014;122: 143–75. doi: 10.1016/B978-0-12-420117-0.00004-9 PubMed DOI PMC

Fan C, Yuan S, Zhang Y, Nie Y, Xiang L, Luo T, et al.. Peroxiredoxin-1 as a molecular chaperone that regulates glutathione S-transferase P1 activity and drives mutidrug resistance in ovarian cancer cells. Biochem Biophys Rep. 2024. Jan 14;37: 101639. doi: 10.1016/j.bbrep.2024.101639 PubMed DOI PMC

He J, Yu Y, He Y, He J, Ji G, Lu H. Chemotherapy induces breast cancer stem cell enrichment through repression of glutathione S-transferase Mu. Genes Dis. 2023. May 9;11: 528–531. doi: 10.1016/j.gendis.2023.04.005 PubMed DOI PMC

Okamura T, Antoun G, Keir ST, Friedman H, Bigner DD, Ali-Osman F. Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells. J Biol Chem. 2015. Dec 25;290: 30866–78. doi: 10.1074/jbc.M115.656140 PubMed DOI PMC

Axarli I, Labrou NE, Petrou C, Rassias N, Cordopatis P, Clonis YD. Sulphonamide-based bombesin prodrug analogues for glutathione transferase, useful in targeted cancer chemotherapy. Eur J Med Chem. 2009. May;44: 2009–16. doi: 10.1016/j.ejmech.2008.10.009 PubMed DOI

Sau A, Pellizzari Tregno F, Valentino F, Federici G, Caccuri AM. Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys. 2010. Aug 15;500: 116–22. doi: 10.1016/j.abb.2010.05.012 PubMed DOI

Perperopoulou FD, Tsoungas PG, Thireou TN, Rinotas VE, Douni EK, Eliopoulos EE, et al.. 2,2’-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1. Bioorg Med Chem. 2014. Aug 1;22: 3957–70. doi: 10.1016/j.bmc.2014.06.007 PubMed DOI

Laborde E. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ. 2010. Sep;17: 1373–80. doi: 10.1038/cdd.2010.80 PubMed DOI

Guneidy RA, Zaki ER, Saleh NS, Shokeer A. Inhibition of human glutathione transferase by catechin and gossypol: comparative structural analysis by kinetic properties, molecular docking and their efficacy on the viability of human MCF-7 cells. J Biochem. 2023. Dec 20;175: 69–83. doi: 10.1093/jb/mvad070 PubMed DOI

Ang WH, Pilet S, Scopelliti R, Bussy F, Juillerat-Jeanneret L, Dyson PJ. Synthesis and characterization of platinum (IV) anticancer drugs with functionalized aromatic carboxylate ligands: influence of the ligands on drug efficacies and uptake. J Med Chem. 2005. Dec 15;48: 8060–9. doi: 10.1021/jm0506468 PubMed DOI

Federici L, Lo Sterzo C, Pezzola S, Di Matteo A, Scaloni F, Federici G, et al.. Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol to human glutathione s-transferases. Cancer Res. 2009. Oct 15;69: 8025–34. doi: 10.1158/0008-5472.CAN-09-1314 PubMed DOI

De Luca A, Hartinger CG, Dyson PJ, Lo Bello M, Casini A. A new target for gold(I) compounds: glutathione-S-transferase inhibition by auranofin. J Inorg Biochem. 2013;119: 38–42. doi: 10.1016/j.jinorgbio.2012.08.006 PubMed DOI

Ganesan A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol. 2008;12: 306–17. doi: 10.1016/j.cbpa.2008.03.016 PubMed DOI

Hayeshi R, Mutingwende I, Mavengere W, Masiyanise V, Mukanganyama S. The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin. Food and chemical toxicology. 2007. Feb 1;45: 286–95. doi: 10.1016/j.fct.2006.07.027 PubMed DOI

Das M, Bickers DR, Mukhtar H. Plant phenols as in vitro inhibitors of glutathione S-transferase (s). Biochemical and biophysical research communications. 1984. Apr 30;120: 427–33. doi: 10.1016/0006-291x(84)91271-3 PubMed DOI

Özaslan MS, Demir Y, Aslan HE, Beydemir Ş, Küfrevioğlu Öİ. Evaluation of chalcones as inhibitors of glutathione S-transferase. J Biochem Mol Toxicol. 2018. May;32: e22047. doi: 10.1002/jbt.22047 PubMed DOI

Appiah-Opong R, Commandeur JN, Istyastono E, Bogaards JJ, Vermeulen NP. Inhibition of human glutathione S-transferases by curcumin and analogues. Xenobiotica. 2009. Apr 1;39: 302–11. doi: 10.1080/00498250802702316 PubMed DOI

Pantiora P, Furlan V, Matiadis D, Mavroidi B, Perperopoulou F, Papageorgiou AC, et al.. Monocarbonyl curcumin analogues as potent inhibitors against human glutathione transferase p1-1. Antioxidants. 2022. Dec 28;12: 63. doi: 10.3390/antiox12010063 PubMed DOI PMC

Kontogiorgis C, Detsi A, Hadjipavlou-Litina D. Coumarin-based drugs: a patent review (2008–present). Expert opinion on therapeutic patents. 2012. Apr 1;22: 437–54. doi: 10.1517/13543776.2012.678835 PubMed DOI

Kumar A, Kumar P, Shravya H, Pai A. Coumarins as potential anticoagulant agents. Res J Pharm Technol. 2022;15: 1659–63. doi: 10.52711/0974-360X.2022.00277 DOI

Hassan NW, Sabt A, El-Attar MAZ, Ora M, Bekhit AEA, Amagase K, et al.. Modulating leishmanial pteridine metabolism machinery via some new coumarin-1,2,3-triazoles: Design, synthesis and computational studies. Eur J Med Chem. 2023. May 5;253: 115333. doi: 10.1016/j.ejmech.2023.115333 PubMed DOI

Al-Warhi T, Sabt A, Elkaeed EB, Eldehna WM. Recent advancements of coumarin-based anticancer agents: An up-to-date review. Bioorg Chem. 2020. Oct 1;103: 104163. doi: 10.1016/j.bioorg.2020.104163 PubMed DOI

Mukanganyama S, Bezabih M, Robert M, Ngadjui BT, Kapche GF, Ngandeu F, et al.. The evaluation of novel natural products as inhibitors of human glutathione transferase P1-1. J Enzyme Inhib Med Chem. 2011. Aug 1;26: 460–7. doi: 10.3109/14756366.2010.526769 PubMed DOI

Sabt A, Abdelhafez OM, El-Haggar RS, Madkour HM, Eldehna WM, El-Khrisy EE, et al.. Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: synthesis, in vitro biological evaluation, and QSAR studies. J Enzyme Inhib Med Chem. 2018. Jan 1;33: 1095–107. doi: 10.1080/14756366.2018.1477137 PubMed DOI PMC

Konidala SK, Kotra V, Danduga RCSR, Kola PK. Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking. Bioorg Chem. 2020;104: 104207. doi: 10.1016/j.bioorg.2020.104207 PubMed DOI

Konidala SK, Kotra V, Danduga RCSR, Kola PK, Bhandare RR, Shaik AB. Design, multistep synthesis and in-vitro antimicrobial and antioxidant screening of coumarin clubbed chalcone hybrids through molecular hybridization approach. Arab J Chem. 2021;14: 103154. doi: 10.1016/j.arabjc.2021.103154 DOI

Kotra SK, Kotra V, Kola PK, Devi CBP, Anusha N, Babu BH, et al.. ZnCl2 catalyzed new coumarinyl-chalcones as cytotoxic agents. Saudi J Biol Sci. 2021;28: 386–394. doi: 10.1016/j.sjbs.2020.10.020 PubMed DOI PMC

Casini A, Scozzafava A, Mastrolorenzo A, Supuran LT. Sulfonamides and sulfonylated derivatives as anticancer agents. Curr Cancer Drug Targets. 2002;2: 55–75. doi: 10.2174/1568009023334060 PubMed DOI

Uehara T, Minoshima Y, Sagane K, Sugi NH, Mitsuhashi KO, Yamamoto N, et al.. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat Chem Biol. 2017;13: 675–680. doi: 10.1038/nchembio.2363 PubMed DOI

Reddy NS, Mallireddigari MR, Cosenza S, Gumireddy K, Bell SC, Reddy EP, et al.. Synthesis of new coumarin 3-(N-aryl) sulfonamides and their anticancer activity. Bioorg Med Chem Lett. 2004. Aug 2;14: 4093–7. doi: 10.1016/j.bmcl.2004.05.016 PubMed DOI

Ruzza P, Calderan A. Glutathione Transferase (GST)-Activated Prodrugs. Pharmaceutics. 2013. Apr 2;5: 220–31. doi: 10.3390/pharmaceutics5020220 PubMed DOI PMC

Koeplinger KA, Zhao Z, Peterson T, Leone JW, Schwende FS, Heinrikson RL, et al.. Activated sulfonamides are cleaved by glutathione-S-transferases. Drug Meta Dispos. 1999;27: 986–991. PubMed

Ertan-Bolelli T, Musdal Y, Bolelli K, Yilmaz S, Aksoy Y, Yildiz I, et al.. Synthesis and biological evaluation of 2-substituted-5-(4-nitrophenylsulfonamido) benzoxazoles as human GST P1-1 inhibitors, and description of the binding site features. ChemMedChem. 2014. May;9: 984–92. doi: 10.1002/cmdc.201400010 PubMed DOI

Musdal Y, Bolelli TE, Bolelli K, Yılmaz S, Ceyhan D, Hegazy U, et al.. Inhibition of human glutathione transferase P1-1 by novel benzazole derivatives. Turk J Biochem. 2012;37: 431–436. doi: 10.5505/tjb.2012.30301 DOI

Elkanzi NA, Hrichi H, Alolayan RA, Derafa W, Zahou FM, Bakr RB. Synthesis of chalcones derivatives and their biological activities: a review. ACS omega. 2022. Aug 2;7: 27769–86. doi: 10.1021/acsomega.2c01779 PubMed DOI PMC

Abosalim HM, Nael MA, El‐Moselhy TF. Design, synthesis and molecular docking of chalcone derivatives as potential anticancer agents. Chem Select. 2021;6: 888–95. doi: 10.1002/slct.202004088 DOI

Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CA. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem. 2007;14: 1829–52. doi: 10.2174/092986707781058805 PubMed DOI

Karthik R, Vimaladevi G, Chen SM, Elangovan A, Jeyaprabha B, Prakash P. Corrosion inhibition and adsorption behavior of 4–amino acetophenone pyridine 2-aldehyde in 1 m hydrochloric acid. Int J Electrochem Sci. 2015. Jun 1;10: 4666–81. doi: 10.1016/S1452-3981(23)06654-3 DOI

Di Paolo V, Fulci C, Rotili D, De Luca A, Tomassi S, Serra M, et al.. Characterization of water-soluble esters of nitrobenzoxadiazole-based GSTP1-1 inhibitors for cancer treatment. Biochem Pharmacol. 2020;178: 114060. doi: 10.1016/j.bcp.2020.114060 PubMed DOI

Cesareo E, Parker LJ, Pedersen JZ, Nuccetelli M, Mazzetti AP, Pastore A, et al.. Nitrosylation of human glutathione transferase P1-1 with dinitrosyl diglutathionyl iron complex in vitro and in vivo. J Biol Chem. 2005. Dec 23;280: 42172–80. doi: 10.1074/jbc.M507916200 PubMed DOI

Pouliou FM, Thireou TN, Eliopoulos EE, Tsoungas PG, Labrou NE, Clonis YD. Isoenzyme‐and Allozyme‐Specific Inhibitors: 2, 2′‐Dihydroxybenzophenones and Their Carbonyl N‐Analogues that Discriminate between Human Glutathione Transferase A1‐1 and P1‐1 Allozymes. Chem Biol Drug Des. 2015;86: 1055–1063. doi: 10.1111/cbdd.12574 PubMed DOI

Koutsoumpli GE, Dimaki VD, Thireou TN, Eliopoulos EE, Labrou NE, Varvounis GI, et al.. Synthesis and study of 2-(pyrrolesulfonylmethyl)-N-arylimines: a new class of inhibitors for human glutathione transferase A1-1. J Med Chem. 2012. Aug 9;55: 6802–13. doi: 10.1021/jm300385f PubMed DOI

Kobzar O, Shulha Y, Buldenko V, Cherenok S, Silenko O, Kalchenko V, et al.. Inhibition of glutathione S-transferases by photoactive calix[4]arene α-ketophosphonic acids. Bioorg Med Chem Lett. 2022. Dec 1;77: 129019 doi: 10.1016/j.bmcl.2022.129019 PubMed

Premetis G, Marugas P, Fanos G, Vlachakis D, Chronopoulou EG, Perperopoulou F, et al.. The Interaction of the Microtubule Targeting Anticancer Drug Colchicine with Human Glutathione Transferases. Curr Pharm Des. 2020;26: 5205–5212. doi: 10.2174/1381612826666200724154711 PubMed DOI

Alqarni MH, Foudah AI, Muharram MM, Labrou NE. The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1. Metabolites. 2021. Mar 23;11: 190. doi: 10.3390/metabo11030190 PubMed DOI PMC

Alqarni MH, Foudah AI, Muharram MM, Alam A, Labrou NE. Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1-1. Biomolecules. 2022. Sep 24;12: 1364. doi: 10.3390/biom12101364 PubMed DOI PMC

Ozalp L, Orhan B, Alparslan MM, Meletli F, Çakmakçı E, Danış Ö. Arylcoumarin and novel biscoumarin derivatives as potent inhibitors of human glutathione S-transferase. J Biomol Struct Dyn. 2023;28: 1–15. doi: 10.1080/07391102.2023.2262598 PubMed DOI

Fine J, Konc J, Samudrala R, Chopra G. CANDOCK: Chemical atomic network-based hierarchical flexible docking algorithm using generalized statistical potentials. J Chem Inf Model. 2020;60: 1509–1527. doi: 10.1021/acs.jcim.9b00686 PubMed DOI

Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res. 2015. Jul 1;43: 443–7. doi: 10.1093/nar/gkv315 PubMed DOI PMC

Patel S, Challagundla N, Rajput RA, Mishra S. Design, synthesis, characterization and anticancer activity evaluation of deoxycholic acid-chalcone conjugates. Bioorg Chem. 2022;127: 106036. doi: 10.1016/j.bioorg.2022.106036 PubMed DOI

Santos MB, Pinhanelli VC, Garcia MA, Silva G, Baek SJ, França SC, et al.. Antiproliferative and pro-apoptotic activities of 2′-and 4′-aminochalcones against tumor canine cells. Eur J Med Chem. 2017. Sep 29;138: 884–9. doi: 10.1016/j.ejmech.2017.06.049 PubMed DOI

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976. May 7;72: 248–54. doi: 10.1006/abio.1976.9999 PubMed DOI

Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. 2012;4: 17. doi: 10.1186/1758-2946-4-17 PubMed DOI PMC

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al.. Gaussian 16, Revision B.01, Gaussian, Inc., Wallingford CT, 2016.