title: Synthesis, characterization and biological evaluation of (99m)Tc/Re-tricarbonyl quinolone complexes.
abstract: New rhenium(I) tricarbonyl complexes with the quinolone antimicrobial agents oxolinic acid (Hoxo) and enrofloxacin (Herx) and containing methanol, triphenylphosphine (PPh3) or imidazole (im) as unidentate co-ligands, were synthesized and characterized. The crystal structure of complex [Re(CO)3(oxo)(PPh3)]∙0.5MeOH was determined by X-ray crystallography. The deprotonated quinolone ligands are bound bidentately to rhenium(I) ion through the pyridone oxygen and a carboxylate oxygen. The binding of the rhenium complexes to calf-thymus DNA (CT DNA) was monitored by UV spectroscopy, viscosity measurements and competitive studies with ethidium bromide; intercalation was suggested as the most possible mode and the DNA-binding constants of the complexes were calculated. The rhenium complex [Re(CO)3(erx)(im)] was assayed for its topoisomerase IIα inhibition activity and was found to be active at 100μM concentration. The interaction of the rhenium complexes with human or bovine serum albumin was investigated by fluorescence emission spectroscopy (through the tryptophan quenching) and the corresponding binding constants were determined. The tracer complex [(99m)Tc(CO)3(erx)(im)] was synthesized and identified by comparative HPLC analysis with the rhenium analog. The (99m)Tc complex was found to be stable in solution. Upon injection in healthy mice, fast tissue clearance of the (99m)Tc complex was observed, while both renal and hepatobiliary excretion took place. Preliminary studies in human K-562 erythroleukemia cells showed cellular uptake of the (99m)Tc tracer with distribution primarily in the cytoplasm and the mitochondria and less in the nucleus. These preliminary results indicate that the quinolone (99m)Tc/Re complexes show promise to be further evaluated as imaging or therapeutic agents.
authors.affiliation: Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece; Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
authors.forename: Theocharis E
authors.initials: TE
authors.lastname: Kydonaki
authors.affiliation: Department of Pharmacognosy - Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Tsoukas
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Campus Tecnológico e Nuclear, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.affiliation: Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Hatzidimitriou
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Campus Tecnológico e Nuclear, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Paulo
authors.affiliation: Department of Pharmacognosy - Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
authors.forename: Lefkothea C
authors.initials: LC
authors.lastname: Papadopoulou
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece. Electronic address: papagd@pharm.auth.gr.
authors.forename: Dionysia
authors.initials: D
authors.lastname: Papagiannopoulou
authors.affiliation: Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece. Electronic address: gepsomas@chem.auth.gr.
authors.forename: George
authors.initials: G
authors.lastname: Psomas
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D001665:Binding Sites; D002417:Cattle; D003287:Contrast Media / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D000077422:Enrofloxacin; D004996:Ethidium / Q000737:chemistry; D024841:Fluoroquinolones / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D020014:K562 Cells; D007700:Kinetics; D000432:Methanol / Q000737:chemistry; D051379:Mice; D009943:Organophosphorus Compounds / Q000737:chemistry; D010093:Oxolinic Acid / Q000737:chemistry; D011485:Protein Binding; D015363:Quinolones / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry; D013667:Technetium / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D003287:Contrast Media; D056831:Coordination Complexes; D004268:DNA-Binding Proteins; D024841:Fluoroquinolones; D007093:Imidazoles; D007364:Intercalating Agents; D009943:Organophosphorus Compounds; D015363:Quinolones; D012709:Serum Albumin; C061896:triphenylphosphine; D000077422:Enrofloxacin; D012211:Rhenium; D013667:Technetium; C029899:imidazole; D004247:DNA; C427203:calf thymus DNA; D004250:DNA Topoisomerases, Type II; D004996:Ethidium; D010093:Oxolinic Acid; D000432:Methanol
keywords: Biological activity; Imaging agents; Quinolones; Rhenium complexes; Technetium-99m