Kljun Jakob, Pavlič Renata, Hafner Eva, Lipec Tanja, Moreno-Da Silva Sara, Tič Primož, Turel Iztok, Büdefeld Tomaž, Stojan Jure, Rižner Tea Lanišnik
Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Front Pharmacol. 2022 Aug 11;13:920379. doi: 10.3389/fphar.2022.920379. eCollection 2022.
In this study, we present the synthesis, kinetic studies of inhibitory activity toward aldo-keto reductase 1C (AKR1C) enzymes, and anticancer potential toward chemoresistant ovarian cancer of 10 organoruthenium compounds bearing diketonate (-) and hydroxyquinolinate (-) chelating ligands with the general formula [(η--cymene)Ru(chel)(X)] where chel represents the chelating ligand and X the chlorido or pta ligand. Our studies show that these compounds are potent inhibitors of the AKR enzymes with an uncommon inhibitory mechanism, where two inhibitor molecules bind to the enzyme in a first fast and reversible step and a second slower and irreversible step. The binding potency of each step is dependent on the chemical structure of the monodentate ligands in the metalloinhibitors with the chlorido complexes generally acting as reversible inhibitors and pta complexes as irreversible inhibitors. Our study also shows that compounds - have a moderate yet better anti-proliferative and anti-migration action on the chemoresistant ovarian cancer cell line COV362 compared to carboplatin and similar effects to cisplatin.
在本研究中，我们介绍了10种带有二酮酸酯（-）和羟基喹啉酸酯（-）螯合配体的有机钌化合物的合成、对醛糖酮还原酶1C（AKR1C）酶抑制活性的动力学研究以及对耐化疗卵巢癌的抗癌潜力，其通式为[(η-对异丙基苯)Ru(螯合剂)(X)]，其中螯合剂代表螯合配体，X代表氯或pta配体。我们的研究表明，这些化合物是AKR酶的有效抑制剂，具有罕见的抑制机制，即两个抑制剂分子在第一步快速且可逆的过程以及第二步较慢且不可逆的过程中与酶结合。每个步骤的结合效力取决于金属抑制剂中单齿配体的化学结构，氯配合物通常作为可逆抑制剂，pta配合物作为不可逆抑制剂。我们的研究还表明，与卡铂相比，化合物 - 对耐化疗卵巢癌细胞系COV362具有适度但更好的抗增殖和抗迁移作用，且与顺铂效果相似。
