Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters

Milunovic, Miljan N. M. and Ohui, Katerina and Besleaga, Iuliana and Petrasheuskaya, Tatsiana V. and Dömötör, Orsolya and Enyedy, Éva Anna and Darvasiova, Denisa and Rapta, Peter and Barbieriková, Zuzana and Vegh, Daniel and Tóth, Szilárd and Tóth, Judit and Kucsma, Nóra and Szakács, Gergely and Popović-Bijelić, Ana and Zafar, Ayesha and Reynisson, Jóhannes and Shutalev, Anatoly D. and Bai, Ruoli and Hamel, Ernest and Arion, Vladimir B. (2024) Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters. JOURNAL OF MEDICINAL CHEMISTRY, 67 (11). pp. 9069-9090. ISSN 0022-2623

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Abstract

The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H2L3–H2L6, with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3–6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y*) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

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