Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1

Panagiota Pantiora; Veronika Furlan; Dimitris Matiadis; Barbara Mavroidi; Fereniki Perperopoulou; Anastassios C Papageorgiou; Marina Sagnou; Urban Bren; Maria Pelecanou; Nikolaos E Labrou

doi:10.3390/antiox12010063

Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1

Antioxidants (Basel). 2022 Dec 28;12(1):63. doi: 10.3390/antiox12010063.

Authors

Affiliations

¹ Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855 Athens, Greece.
² Institute of Biosciences & Applications, NCSR "Demokritos", 15310 Athens, Greece.
³ Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia.
⁴ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20521 Turku, Finland.
⁵ Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia.
⁶ Institute of Environmental Protection and Sensors, Beloruska Ulica 7, SI-2000 Maribor, Slovenia.

Abstract

The isoenzyme of human glutathione transferase P1-1 (hGSTP1-1) is involved in multi-drug resistance (MDR) mechanisms in numerous cancer cell lines. In the present study, the inhibition potency of two curcuminoids and eleven monocarbonyl curcumin analogues against hGSTP1-1 was investigated. Demethoxycurcumin (Curcumin II) and three of the monocarbonyl curcumin analogues exhibited the highest inhibitory activity towards hGSTP1-1 with IC₅₀ values ranging between 5.45 ± 1.08 and 37.72 ± 1.02 μM. Kinetic inhibition studies of the most potent inhibitors demonstrated that they function as non-competitive/mixed-type inhibitors. These compounds were also evaluated for their toxicity against the prostate cancer cells DU-145. Interestingly, the strongest hGSTP1-1 inhibitor, (DM96), exhibited the highest cytotoxicity with an IC₅₀ of 8.60 ± 1.07 μΜ, while the IC₅₀ values of the rest of the compounds ranged between 44.59-48.52 μΜ. Structural analysis employing molecular docking, molecular dynamics (MD) simulations, and binding-free-energy calculations was performed to study the four most potent curcumin analogues as hGSTP1-1 inhibitors. According to the obtained computational results, DM96 exhibited the lowest binding free energy, which is in agreement with the experimental data. All studied curcumin analogues were found to form hydrophobic interactions with the residue Gln52, as well as hydrogen bonds with the nearby residues Gln65 and Asn67. Additional hydrophobic interactions with the residues Phe9 and Val36 as well as π-π stacking interaction with Phe9 contributed to the superior inhibitory activity of DM96. The van der Waals component through shape complementarity was found to play the most important role in DM96-inhibitory activity. Overall, our results revealed that the monocarbonyl curcumin derivative DM96 acts as a strong hGSTP1-1 inhibitor, exerts high prostate cancer cell cytotoxicity, and may, therefore, be exploited for the suppression and chemosensitization of cancer cells. This study provides new insights into the development of safe and effective GST-targeted cancer chemosensitizers.

Keywords: curcumin analogues; curcuminoids; enzyme inhibition; glutathione transferase; human glutathione transferase P1-1 (hGSTP1-1); multi-drug resistance.

Grants and funding

J1-2471; P2-0046/Slovenian Research Agency