title: New Iminodiacetate-Thiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity.
abstract: As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate-thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV-vis;1H and13C NMR), electrospray ionization mass spectrometry, and X-ray diffraction. The antiproliferative effects were examined in several human cancer and one noncancerous cell lines. Several of the compounds showed high cytotoxicity and marked selectivity for cancer cells. On the basis of this, and on molecular docking calculations one lead dicopper(II) complex and one thiosemicarbazone were chosen for in vitro analysis as potential R2 inhibitors. Their interaction with R2 and effect on the Fe(III)2-Y· cofactor were characterized by microscale thermophoresis, and two spectroscopic techniques, namely, electron paramagnetic resonance and UV-vis spectroscopy. Our findings suggest that several of the synthesized proligands and copper(II) complexes are effective antiproliferative agents in several cancer cell lines, targeting RNR, which deserve further investigation as potential anticancer drugs.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Währinger Strasse 42, 1090 Vienna, Austria.|Inorganic Polymers Department, Petru Poni Institute of Macromolecular Chemistry, Romanian Academy , Aleea G. Ghica Voda 41A, 700487 Iasi, Romania.
authors.forename: Mirela F
authors.initials: MF
authors.lastname: Zaltariov
authors.affiliation: Section for Biochemistry and Molecular Biology, Department of Biosciences, University of Oslo , P.O. Box 1066, Blindern, NO-0316 Oslo, Norway.
authors.forename: Marta
authors.initials: M
authors.lastname: Hammerstad
authors.affiliation: School of Chemical Sciences, University of Auckland , Auckland, New Zealand.
authors.forename: Homayon J
authors.initials: HJ
authors.lastname: Arabshahi
authors.affiliation: Institute for Oncology and Radiology of Serbia , Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Jovanović
authors.affiliation: Institute of Inorganic Chemistry-Functional Materials, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Richter
authors.affiliation: Inorganic Polymers Department, Petru Poni Institute of Macromolecular Chemistry, Romanian Academy , Aleea G. Ghica Voda 41A, 700487 Iasi, Romania.
authors.forename: Maria
authors.initials: M
authors.lastname: Cazacu
authors.affiliation: Inorganic Polymers Department, Petru Poni Institute of Macromolecular Chemistry, Romanian Academy , Aleea G. Ghica Voda 41A, 700487 Iasi, Romania.
authors.forename: Sergiu
authors.initials: S
authors.lastname: Shova
authors.affiliation: Inorganic Polymers Department, Petru Poni Institute of Macromolecular Chemistry, Romanian Academy , Aleea G. Ghica Voda 41A, 700487 Iasi, Romania.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Balan
authors.affiliation: Department of Chemistry, University of Oslo , P.O. Box 1033, Blindern, NO-0315 Oslo, Norway.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Andersen
authors.affiliation: Institute for Oncology and Radiology of Serbia , Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
authors.affiliation: School of Chemical Sciences, University of Auckland , Auckland, New Zealand.
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.affiliation: Section for Biochemistry and Molecular Biology, Department of Biosciences, University of Oslo , P.O. Box 1066, Blindern, NO-0316 Oslo, Norway.
authors.forename: K Kristoffer
authors.initials: KK
authors.lastname: Andersson
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Währinger Strasse 42, 1090 Vienna, Austria.
authors.forename: Vladimir B
authors.identifier: http://orcid.org/0000-0002-1895-6460
authors.initials: VB
authors.lastname: Arion
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007098:Imino Acids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007098:Imino Acids; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D003300:Copper; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit; C008109:iminodiacetic acid