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Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and in Vitro Research on Their Cytotoxic Activity

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Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and in Vitro Research on Their Cytotoxic Activity pharmaceuticals Article Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity Henryk Mastalarz 1,*, Agnieszka Mastalarz 2, Joanna Wietrzyk 3 , Magdalena Milczarek 3 , Andrzej Kochel 2 and Andrzej Regiec 1 1 Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, 211A Borowska Street, 50-556 Wrocław, Poland; [email protected] 2 Faculty of Chemistry, The University of Wrocław, 14F Joliot-Curie Street, 50-383 Wrocław, Poland; [email protected] (A.M.); [email protected] (A.K.) 3 Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl Street, 53-114 Wrocław, Poland; [email protected] (J.W.); [email protected] (M.M.) * Correspondence: [email protected]; Tel.: +48-717840347; Fax: +48-717840341 Received: 6 October 2020; Accepted: 25 November 2020; Published: 28 November 2020 Abstract: A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with K2PtCl4 and characterized by elemental analysis, ESI MS spectrometry, 1H NMR, 195Pt NMR, IR and far IR spectroscopy. Thermal isomerization of cis-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 1 to trans-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 2 has been presented, and the structure of the compound 2 has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method. The trans complex 2 showed better antiproliferative activity than cisplatin for all the tested cancer cell lines. Additionally, trans-dichloridobis(1-methyl-5-nitropyrazole)platinum(II) 4 has featured a lower IC50 value than reference cisplatin against MCF-7 cell line. To gain additional information that may facilitate the explanation of the mode of action of tested compounds cellular platinum uptake, stability in L-glutathione solution, influence on cell cycle progression of HL-60 cells and ability to apoptosis induction were determined for compounds 1 and 2. Keywords: nitropyrazoles-Pt(II)complexes; synthesis; structural analysis; LogP; cellular platinum uptake; antiproliferative activity; normoxia-hypoxia; L-glutathione (GSH); cell cycle; X-ray crystallography 1. Introduction Since the discovery of cisplatin cytostatic properties, platinum complexes have been widely used in modern medicine for the treatment of various solid tumors. Three of these compounds, namely cisplatin, oxaliplatin and carboplatin, are in clinical use as anti-cancer drugs. Four others, namely heptaplatin, nedaplatin, miriplatin and lobaplatin, have gained limited approval for their oncological purposes (Figure1). In addition, a number of other platinum derivatives are currently under clinical trials. Despite being used medically for over 30 years, their detailed mechanism of antitumor action remains ambiguous, partly because these compounds display numerous intracellular targets. The anticancer activity of cisplatin is believed to arise from its interaction with DNA. Several cellular pathways are activated in response to this interaction, including recognition by repair enzymes, translation synthesis by polymerases, and induction of apoptosis. All these processes are suspected to Pharmaceuticals 2020, 13, 433; doi:10.3390/ph13120433 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 23 Pharmaceuticals 2020, 13, 433 2 of 21 DNA. Several cellular pathways are activated in response to this interaction, including recognition by repair enzymes, translation synthesis by polymerases, and induction of apoptosis. All these beprocesses responsible are suspected for developing to be cisplatinresponsible resistance for developi of tumorng cisplatin cells, which resistance is the important of tumor factorcells, which limiting is thethe eimportantffectiveness factor of cisplatin limiting in the medication effectiveness in the of treatment cisplatin ofin cancermedication disease. in the Additionally, treatment platinumof cancer baseddisease. anticancer Additionally, drugs areplatinum characterized based anticancer by a narrow drugs therapeutic are characterized index that results by a narrow from their therapeutic systemic toxicityindex that which results is tightly from their connected systemic with toxicity their lackwhich of tumoris tightly selectivity. connected To with improve their thelack e ffiofcacy tumor of platinum-containingselectivity. To improve chemotherapeutic the efficacy of agents,platinum-c thereontaining is still interest chemotherapeutic in the design andagents, synthesis there ofis thisstill classinterest of compoundsin the design with and diminished synthesis systemicof this clas toxicitys of compounds and maximized with activitydiminished in tumors systemic employing toxicity site-specificand maximized activation activity [1 ].in tumors employing site-specific activation [1]. Cisplatin Carboplatin Oxaliplatin Nedaplatin Lobaplatin Miriplatin Heptaplatin Figure 1. Clinically approved platinum drugs that areare presentlypresently usedused inin anticanceranticancer therapies.therapies. ItIt isis wellwell knownknown thatthat tumortumor hypoxiahypoxia providesprovides aa crucialcrucial didifferencefference betweenbetween cancercancer cellscells andand normalnormal cells,cells, oofferingffering aa reductivereductive environmentenvironment forfor biobio reduciblereducible prodrugprodrug activation.activation. Tumor hypoxiahypoxia hashas beenbeen shownshown inin manymany studiesstudies toto bebe responsibleresponsible forfor treatmenttreatment resistanceresistance andand poorpoor prognosisprognosis inin variousvarious cancercancer types.types. Considering these these facts, anaerobic reduction may be a promising routeroute toto achieveachieve targetingtargeting andand selectivityselectivity inin anticanceranticancer drugdrug design.design. In our investigationinvestigation to obtainobtain andand testtest biologicallybiologically novelnovel compoundscompounds withwith potentiallypotentially increasedincreased therapeutictherapeutic eeffectivenessffectiveness andand diminisheddiminished systemicsystemic sideside eeffectsffects ofof cancercancer chemotherapy,chemotherapy, aa seriesseries ofof platinum(II)platinum(II) complexescomplexes withwith nitropyrazolenitropyrazole ligandsligands werewere designed designed as potentialas potential anticancer anticancer prodrugs prodrugs containing containing a nitro groupa nitro as agroup moiety as susceptible a moiety tosusceptible bioreductive to activation.bioreductive Several activation. attempts Several to utilize attempts the process to utilize of nitro the group process reduction of nitro as a triggergroup mechanismreduction as for a trigger the site-specific mechanism activation for the ofsite-specifi potentialc anticanceractivation of prodrugs potential in anticancer hypoxic tumor prodrugs tissues in havehypoxic been tumor made tissues with promising have been eff ectsmade [2 ,3with]. In prom 1984,ising the synthesis effects [2,3]. and biologicalIn 1984, the activity synthesis of similar and nitroheterocyclicbiological activity complexes of similar with nitroheterocyclic Au(III), Pd(II), complexes Rh(III), Pt(IV) with and Au(III), Pt(II) wasPd(II), patented Rh(III), and Pt(IV) claimed and toPt(II) be cytotoxic,was patented but and no details claimed of to a structurebe cytotoxic, (cis butor transno detailsgeometry), of a structure biological (cis activity, or trans separation,geometry), purification,biological activity, spectroscopic separation, and physical purification, properties sp ofectroscopic Pt(II) derivatives and physical were given properties there [4]. of Pt(II) derivativesEarly classical were given structure-activity there [4]. relationships for platinum coordination compounds established that onlyEarly those classical with cis geometrystructure-activity possess the relation ability toships inhibit for cell platinum growth. For coordination example, cisplatin compounds exhibits antitumorestablished activity, that only whereas those itswithtrans cisisomer geometry was possess proven tothe be ability inactive to [ 5inhibit]. Additionally, cell growth. the For vast example, majority ofcisplatin cisplatin exhibits analogues antitumor with remarkable activity, cytostaticwhereas propertiesits trans isomer contain was at least proven one N–H to be group, inactive which [5]. is claimedAdditionally, as a hydrogen-bond the vast majority donor of cisplatin in the approach analogues of thewith biological remarkable target, cytostatice.g., a DNApropertiesmolecule contain [6]. Thus,at least typical one platinumN–H group, anticancer which complexesis claimed have as a the hydrogen-bond general formula donorcis-[Pt(NHR in the1 Rapproach2)2X2], in whichof the Rbiological1 and R2 target,are organic e.g., a moieties DNA molecule and X is[6]. a leavingThus, typical group, platinum usually aanticancer monovalent complexes and biologically have the acceptablegeneral formula ion such cis-[Pt(NHR as chlorido,1R2)2X2 nitrato], in which or carboxylato R1 and R2 are ligands organic [7]. moieties Although and theseX is a findings leaving cangroup, still usually be useful a monovalent in the development and biologically of new acceptable platinum ion complexes such as chlorido, with anticancernitrato or carboxylato
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