TY - JOUR
T1 - 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
AU - Milunovic, Miljan N.M.
AU - Ohui, Katerina
AU - Besleaga, Iuliana
AU - Petrasheuskaya, Tatsiana V.
AU - Dömötör, Orsolya
AU - Enyedy, Éva A.
AU - Darvasiova, Denisa
AU - Rapta, Peter
AU - Barbieriková, Zuzana
AU - Vegh, Daniel
AU - Tóth, Szilárd
AU - Tóth, Judit
AU - Kucsma, Nóra
AU - Szakács, Gergely
AU - Popović-Bijelić, Ana
AU - Zafar, Ayesha
AU - Reynisson, Jóhannes
AU - Shutalev, Anatoly D.
AU - Bai, Ruoli
AU - Hamel, Ernest
AU - Arion, Vladimir B.
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
Accession Number
WOS:001228927100001
PubMed ID
38771959
PY - 2024/6/13
Y1 - 2024/6/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85193984554&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c00259
DO - 10.1021/acs.jmedchem.4c00259
M3 - Article
AN - SCOPUS:85193984554
SN - 0022-2623
VL - 67
SP - 9069
EP - 9090
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -
