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  3. 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

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

  • J Med Chem. 2024 Jun 13;67(11):9069-9090. doi: 10.1021/acs.jmedchem.4c00259.
Miljan N M Milunovic 1,  Katerina Ohui 1,  Iuliana Besleaga 1,  Tatsiana V Petrasheuskaya 2 3,  Orsolya Dömötör 2 3,  Éva A Enyedy 2 3,  Denisa Darvasiova 4,  Peter Rapta 4,  Zuzana Barbieriková 4,  Daniel Vegh 5,  Szilárd Tóth 6,  Judit Tóth 6,  Nóra Kucsma 6,  Gergely Szakács 6 7,  Ana Popović-Bijelić 8,  Ayesha Zafar 9,  Jóhannes Reynisson 10,  Anatoly D Shutalev 11,  Ruoli Bai 12,  Ernest Hamel 12,  Vladimir B Arion 1 13
Affiliations

Affiliations

  • 1 Institute of Inorganic Chemistry, University of Vienna, Vienna A-1090, Austria.
  • 2 Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, Szeged H-6720, Hungary.
  • 3 MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, Szeged H-6720, Hungary.
  • 4 Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Bratislava SK-81237, Slovakia.
  • 5 Institute of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Bratislava SK-81237, Slovakia.
  • 6 Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Hungarian Research Network, Magyar Tudósok körútja 2, Budapest H-1117, Hungary.
  • 7 Center for Cancer Research, Medical University of Vienna, Vienna A-1090, Austria.
  • 8 Faculty of Physical Chemistry, University of Belgrade, Belgrade 11158, Serbia.
  • 9 School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 10 School of Pharmacy and Bioengineering, Keele University, Newcastle-under-Lyme, Staffordshire ST5 5BG, United Kingdom.
  • 11 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russian Federation.
  • 12 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 13 Inorganic Polymers Department, "Petru Poni" Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41 A, Iasi 700487, Romania.
PMID: 38771959 DOI: 10.1021/acs.jmedchem.4c00259
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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