Rare-Earth Metal Complexes of the Antibacterial Drug Oxolinic Acid: Synthesis, Characterization, DNA/Protein Binding and Cytotoxicity Studies
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molecules Article Rare-Earth Metal Complexes of the Antibacterial Drug Oxolinic Acid: Synthesis, Characterization, DNA/Protein Binding and Cytotoxicity Studies Ana-Madalina Maciuca 1, Alexandra-Cristina Munteanu 1,*, Mirela Mihaila 2, Mihaela Badea 3 , Rodica Olar 3 , George Mihai Nitulescu 4 , Cristian V. A. Munteanu 5 , Marinela Bostan 2 and Valentina Uivarosi 1,* 1 Department of General and Inorganic Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia St, 020956 Bucharest, Romania; [email protected] 2 Center of Immunology, Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Ave, 030304 Bucharest, Romania; [email protected] (M.M.); [email protected] (M.B.) 3 Department of Inorganic Chemistry, Faculty of Chemistry, University of Bucharest, 90-92 Panduri Str, 050663 Bucharest, Romania; [email protected] (M.B.); [email protected] (R.O.) 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia Str, 020956 Bucharest, Romania; [email protected] 5 Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy (IBRA), 296 Spl. Independen¸tei,060031 Bucharest, Romania; [email protected] * Correspondence: [email protected] (A.-C.M.); [email protected] (V.U.); Tel.: +4-021-318-0742 (V.U.); Fax: +4-021-318-0750 (V.U.) Academic Editors: Rodica Olar, Carlo Santini and Maura Pellei Received: 22 October 2020; Accepted: 17 November 2020; Published: 19 November 2020 Abstract: “Drug repositioning” is a current trend which proved useful in the search for new applications for existing, failed, no longer in use or abandoned drugs, particularly when addressing issues such as bacterial or cancer cells resistance to current therapeutic approaches. In this context, six new complexes of the first-generation quinolone oxolinic acid with rare-earth metal cations (Y3+, La3+, Sm3+, Eu3+, Gd3+, Tb3+) have been synthesized and characterized. The experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms; these findings are supported by DFT (density functional theory) calculations for the Sm3+ complex. The cytotoxic activity of the complexes, as well as the ligand, has been studied on MDA-MB 231 (human breast adenocarcinoma), LoVo (human colon adenocarcinoma) and HUVEC (normal human umbilical vein endothelial cells) cell lines. UV-Vis spectroscopy and competitive binding studies show that the complexes display binding affinities (Kb) towards double stranded DNA in the range of 9.33 104 10.72 105. Major and minor groove-binding most likely play a × − × significant role in the interactions of the complexes with DNA. Moreover, the complexes bind human serum albumin more avidly than apo-transferrin. Keywords: drug repositioning; quinolone; oxolinic acid; rare-earth metal ions; anticancer; DNA binding; serum proteins 1. Introduction In the context of the emergent resistance of bacteria strains and cancer cell lines to currently approved drugs, one strategy which has proved successful is that of “drug repositioning”. This refers to a process based on finding new applications for existing, failed, no longer in use or abandoned drugs [1]. The growing interest in synthesizing new metal complexes of different antibiotics is due to their new found pharmacological and toxicological properties [2,3]. Molecules 2020, 25, 5418; doi:10.3390/molecules25225418 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 25 Moleculesdrugs2020 [1]., The25, 5418 growing interest in synthesizing new metal complexes of different antibiotics is2 due of 27 to their new found pharmacological and toxicological properties [2,3]. QuinolonesQuinolones represent represent a group a group of synthetic of synthetic antibacterial antibacterial agents characterized agents characterized by a broad spectrumby a broad of activityspectrum and of good activity bioavailability and good[ 4bioavailability,5] used in the [4,5] treatment used ofin infectionsthe treatment with of various infections localizations with various [6]. Thelocalizations mechanism [6]. is The a complex mechanism one is and a complex implies one binding and implies to topoisomerase binding to topoisomerase II (DNA-gyrase) II (DNA- [7,8] andgyrase) topoisomerase [7,8] and topoisomerase IV [9,10]. This IV [9,10]. process This induces process bacteriostasis induces bacteriostasis [11], double-strand [11], double-strand breaks, chromosomebreaks, chromosome fragmentation, fragmentation, formation formation of reactive of oxygen reactive species oxygen (ROS) species [11,12 (ROS)] and eventually[11,12] and celleventually death. Mg cell2+ death.ions [13 Mg] play2+ ions a key[13] roleplay in a thekey formationrole in the offormation the quinolone-bacterial of the quinolone-bacterial DNA-enzyme DNA- complex:enzyme they complex: coordinate they twocoordinate oxygen two atoms oxygen from theatom quinolones from the molecule quinolone and mo fourlecule water and molecules four water in anmolecules octahedral in manner an octahedral [14], thus manner stabilizing [14], thus the wholestabilizing structure. the whole Quinolones structure. have Quinolones a series of have properties a series thatof makeproperties them suitablethat make for repositioningthem suitable as anti-cancerfor repositioning drugs, such as as:anti-cancer immunomodulation drugs, such [15 ],as: pro-apoptoticimmunomodulation and antiproliferative [15], pro-apoptotic properties and [ 16antipro–21] andliferative anti-metastatic properties potential [16–21] and [22,23 anti-metastatic]. potentialOxolinic [22,23]. acid (5-ethyl-5,8-dihydro-8-oxo-l,3 dioxolo[4,5-g]quinoline-7-carboxylic acid, Figure1A) is a firstOxolinic generation acid quinolone, (5-ethyl-5,8-dihydro-8-oxo-l,3 developed by Warner-Lambert, dioxolo[4,5- approvedg]quinoline-7-carboxylic by the FDA in the acid, 1970s Figure for the1A) treatment is a first of generation bacterial urinary quinolon infectionse, developed not associated by Warner-Lambert, with bacteremia approved in adults by the [24]. FDA The in spectrum the 1970s offor activity the treatment is rather narrowof bacterial and includesurinary someinfections Gram-negative not associated bacteria with [25 bacteremia–27]. Still, itin hasadults not proven[24]. The itselfspectrum to be moreof activity effective is rather or better narrow tolerated and includes than other some drugs Gram-negative such as nalidixic bacteria acid, [25–27]. ampicillin Still, it orhas trimethoprim-sulfamethoxazolenot proven itself to be more effective [24,28,29 or]. Evidencebetter tolerated shows thatthan theother effi cacydrugs of such the treatmentas nalidixic is notacid, dose-relatedampicillin [or24 ]trimethoprim-sulfamethoxazole and there have been some observations [24,28,29]. about Evidence the drug’s shows natural that tendency the efficacy to give of rise the totreatment resistant mutantsis not dose-related at a daily dose [24] ofand less there than have 2 g/ daybeen [ 30some]; these observations are aspects about that havethe drug’s limited natural the usetendency of oxolinic to give acid rise in humans. to resistant Nevertheless, mutants at it a has daily been dose approved of less than for use 2 g/day in the [30]; treatment these ofare enteric aspects infectionsthat have in limited various the animal use speciesof oxolinic such acid as poultry, in humans. pigs, Nevertheless, calves and fish it [31has] andbeen for approved the management for use in ofthe pine treatment wilt disease of enteric [32]. infections in various animal species such as poultry, pigs, calves and fish [31] and for the management of pine wilt disease [32]. FigureFigure 1. 1.(A (A) Oxolinic). Oxolinic acid; acid; (B ()B Metal). Metal coordination coordination sites sites in thein th generale general structure structure of quinolones.of quinolones. SeveralSeveral features features in in their their structures structures (see (see Figure Figure1B) 1B) render render quinolones quinolones good good candidates candidates for for metal metal binding:binding: the the carboxyl carboxyl moiety moiety in in position position 3, 3, the the carbonyl carbonyl moiety moiety in in position position 4 and4 and one one or or both both nitrogen nitrogen atomsatoms from from the the piperazinyl piperazinyl ring ring in in position position 7, 7, in in the the case case of of fluoroquinolones; fluoroquinolones; the the working working conditions conditions andand the the nature nature of of the the metal metal [33 [33–35]–35] determine determine which which of of the the moieties moieties will will be be involved involved in in complex complex formation.formation. So So far, far, a considerablea considerable number number of of quinolone-metal quinolone-metal complexes complexes have have been been synthesized synthesized and and characterizedcharacterized from from the the chemical chemical and and biological biological point poin of view;t of view; evidence evidence that thesethat these complexes complexes bind tobind calf to thymuscalf thymus DNA [ 36DNA–39] [36–39] and that and numerous that numerous complexes comp exhibitlexes antibacterial exhibit antibacterial [40–43], antitumoral [40–43], antitumoral [40,44,45], antifungal[40,44,45], [40 antifungal,45] and antiparasitic [40,45] and antiparasitic [46] properties [46] have properties led to a have growing led interestto a growing