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Bisphosphonate chelating agents: complexation of Fe(III) and Al(III) by 1-phenyl-1-hydroxymethylene bisphosphonate and its analogues

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Bisphosphonate chelating agents: complexation of Fe(III) and Al(III) by 1-phenyl-1-hydroxymethylene bisphosphonate and its analogues
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  Bisphosphonate chelating agents: complexation of Fe(III) and Al(III)by 1-phenyl-1-hydroxymethylene bisphosphonate and its analogues Elzbieta Gumienna-Kontecka a , Roberta Sil v agni b , Radoslaw Lipinski c ,Marc Lecou v ey d , Flaminia Cesare Marincola e , Guido Crisponi b , Valeria M. Nurchi b ,Y v es Leroux d , Henryk Kozlowski a, * a Faculty of Chemistry, Uni  v ersity of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland  b Dipartimento di Chimica Inorganica ed Analitica, Uni  v ersita´ di Cagliari, Complesso di Monserrato, 09042 Monserrato Cagliari, Italy c Institute of Organic Chemistry, Technical Uni  v ersity of Wroclaw, 50-370 Wroclaw, Poland  d Laboratoire de Chimie Structurale Biomoleculaire, Uni  v ersity Paris XIII, 93017 Bobigny, France e Dipartimento di Scienze Chimiche, Uni  v ersita´ di Cagliari, Complesso di Monserrato, 09042 Monserrato Cagliari, Italy Recei v ed 31 October 2001; accepted 24 December 2001Dedicated to Professor Helmut Sigel. Abstract Bisphosphonate ligands were found to be  v ery efficient chelating agents for both Al(III) and Fe(III) ions. Potentiometric andspectroscopic data allow e v aluation of the coordination equilibria in the solutions containing 1-phenyl-1-hydroxymethylenebisphosphonate and its three analogues with Al(III) and Fe(III) ions. At pH below 4 the bis-complexes are formed, while abo v e pH4 the major species are equimolar, monomeric for Al(III) or dimeric for Fe(III) complexes. The large steric hindrance and highelectric charge are the major factors influencing the complex stoichiometry. The formation of the dimeric Fe(III) with  m -oxo or  m -hydroxo bridges were supported by measurements of the magnetic moments using E v ans’ method. The stabilities of the complexesformed are higher than those found for deferiprone, L1, used in clinics as a chelating agent. #  2002 Else v ier Science B.V. All rights reserved. Keywords:  Al(III) complexes; Fe(III) complexes; Bisphosphonates; Potentiometry; Spectrophotometry; NMR 1. Introduction Recent works on the coordination ability of bispho-sphonates ha v e shown their  v ery high efficiency in thebinding of metal ions [1    / 5]. The P   / C   / P bond system inbisphosphonates has low toxicity and high thermo-stability and it is also resistant to enzymatic degrada-tion. Moreo v er, two adjacent phosphonic functions mayaccommodate a large number of ionic radii due to theirmobility and flexibility [6    / 9]. These features as well asthe high power to bind metal ions resulted in clinical useof   v arious ligands based on bisphosphonic acid aschelating agents for calcium ions in a treatment of  v arious bone diseases [10].Among metals whose toxic effects are  v ery wellknown although not completely understood, iron isessential for life as well as toxic aluminum. Ironchelators ha v e been used in medicine from a long timeto protect patients from the consequences of irono v erload [11    / 14]. Although iron plays a basic role incontrolling the reacti v e oxygen species, when it is notstrongly bound to proteins or other ligands, it may be aneffecti v e catalyst for oxidati v e reaction, forming themost disastrous (e.g. OH + ) oxygen radicals [11,12].Aluminum(III) being similar to iron(III) may enter theiron pathways. As a result it can be widely distributed inthe organism including the central ner v ous system. Onthe other hand, Al(III) being highly charged may bind toa  v ariety of functions ha v ing an oxygen donor system, * Corresponding author. Tel.:  / 48-71-3375 7251; fax:  / 48-71-33757251 E-mail address:  henrykoz@wchuwr.chem.uni.wroc.pl (H.Kozlowski).Inorganica Chimica Acta 339 (2002) 111    / 118www.else v ier.com/locate/ica0020-1693/02/$ - see front matter # 2002 Else v ier Science B.V. All rights reserved.PII: S0020-1693(02)00918-0  usually effecti v e in the coordination of both Fe(III) andAl(III) ions.The only iron chelator successfully employed inclinical practice up to 2000 is a methansulfonate saltof deferrioxamine B (Desferal TM ), a natural siderophorecontaining three hydroxamic functional groups. Its poorgastrointestinal absorption causes the drug to be ad-ministered by slow subcutaneous perfusion, resulting ina reduced compliance of the therapy. In 2000 alsodeferiprone (L1 or 1,2-dimethyl-3-hydroxy-4-pyridi-none) has been patented and is currently the first usedoral iron chelator, but its clinical properties should beconsidered only complementary to those of Desferal.The research for oral chelators is then an ob v ious aimfor bioinorganic chemists. The majority of naturalsiderophores are relati v ely large ligands with a molecu-lar weight within the 500    / 1000 Da range. This is amajor cause for their poor absorption by the gastro-intestinal tract [11,12]. Taking into account all factorsinfluencing an absorption from the gut, the molecularweight around 300 could be a reasonable one for oralchelating agents [11,12,15]. The bisphosphonates studiedin this paper are in the range of MW below 300.Howe v er, they are highly hydrophilic and their oralbioa v ailability is poor, below 7% [16]. Moreo v er the useof simple bisphosphonates with structure close topyrophosphate could be limited due to their strongaffinity to bones. This inspired us to modify bisphos-phonate moiety with a  v ariety of hydrophobic fragmentsto make potential chelators more lipophilic, especiallywhen ester deri v ati v e is administered. This problem canbe resol v ed using pro-drug approach by blockingphosphonate function with e.g. esters [17]. 2. Experimental  2.1. Reagents Studied bisphosphonates were synthesized as de-scribed earlier [18,19]. All other reagents used were atthe highest purity grade used without further purifica-tion. As potentiometric titrations for aluminum and ironsystems were made in two different laboratories (see (i)and (ii) below), technical details relati v e to the reagentsused are described separately.(i) The aluminum stock solution was prepared bydissol v ing Merck Al(NO 3 ) 3  / 9H 2 O in 1  / 10  2 moldm  3 HNO 3 . Its metal content was determined byInducti v ely Coupled Plasma analysis (ICP-AES ARL3410). The purity of the ligands and the concentrationsof the stock solutions (ca. 2 and 3  / 10  3 mol dm  3 )were e v aluated during protonation calculations. NaOHsolutions (Merck 0.1 mol dm  3 ) were standardizedagainst Merck potassium hydrogenophthalate.(ii) Iron(III) stock solution was prepared sol v ingAldrich FeCl 3  / 6H 2 O in a solution containing NaCl0.1 mol dm  3 and HCl 1.40  / 10  2 mol dm  3 , in orderto a v oid metal hydroxo-polymerization. Concentrationof Fe(III) solution was determined spectrophotometri-cally. Ligands (ca. 1  / 10  3 mol dm  3 ) were dissol v edin HCl 1  / 10  3 mol dm  3 and 0.1 mol dm  3 NaCl.  2.2. Potentiometric and spectroscopic studies (i) The potentiometric experiments for Al(III) con-taining systems were carried out at constant temperature25  8 C under argon flow using a MOLSPIN automatictitration system, with a Russel CMAW 711 microcom-bined electrode calibrated daily on the concentrationscale using HNO 3  [20]. The background electrolyte was0.1 mol dm  3 KNO 3  and the ionic product of water forthese conditions was 10  13.77 mol 2 dm  6 . Initial solu-tions of 2 cm 3 were titrated with sodium hydroxidedeli v ered by 0.25 cm 3 micrometer syringe pre v iouslycalibrated by weight titrations and titrations of standardmaterials. For the metal    / ligand systems, measurementsat fi v e or six different ratios, ranged from 1:1 to 1:10,were performed.(ii) FEM for Fe(III) were recorded with a Metrohm691 pH-meter equipped with a Metrohm combined LLglass electrode calibrated accordingly to the Gran’smethod [21]. Employed titrant was NaOH 0.1 moldm  3 , CO 2  free, checked daily using HCl according toIr v ing et al. [20]. Alkali was added with a MetrohmDosimat 991. Each titration was carried out in a sealed,water-jacketed, glass  v essel at 25 9 / 0.1  8 C under a pureargon flow. Meanwhile, UV    / Vis absorption spectrawere measured with a Varian Cary50 spectrophotometerequipped with a Fibre Optic Probe in which thescrewable tips are equi v alent to 2, 1, 0.5 and 0.2 cmquartz cells. The use of a Fibre Optic Probe allows us toobtain both potentiometric and spectrophotometricdata on the same sample at the same time, it beingpossible to dip the probe into the titration  v essel.Complex solutions in Fe(III):ligand molar ratios 1:1,1:2, 1:5 and 1:10 were titrated 12 h after their mixing.  2.3. Formation constant calculations Formation constant determinations were carried outwith the  SUPERQUAD  computer program [22]. The v alues of the hydrolysis constants corresponding to theexperimental conditions used were taken from Ref. [23]for Al(III) and Ref. [24] for Fe(III).Decomposition of UV    / Vis spectra was performedwith  SPEAKPEAK  program [25]. E v ol v ing Factor Analy-sis, indicating how many absorbing species are presentin the system and calculating the spectra relati v e to eachof the eigen v alues without any model assumption wasperformed using  SPECFIT  program [26]. E. Gumienna-Kontecka et al. / Inorganica Chimica Acta 339 (2002) 111    /  118 112   2.4. NMR measurements 1 H,  31 P and  27 Al NMR spectra were recorded at25  8 C, at 299.930, 121.419 and 78.154 MHz, respec-ti v ely, on a Varian VXR-300 spectrometer. All measure-ments were made in D 2 O in 1:2 and 1:3 molar ratios,with concentration of ligand 5  / 10  2 mol dm  3 and asexternal reference: acetonitrile for  1 H, H 3 PO 4  (40%) for 31 P and aqueous Al(NO 3 ) 3  (5  / 10  2 mol dm  3 ) for 27 Al. Measured pH* was not corrected for the isotopiceffect.  31 P NMR spectra were obtained using a spectralwidth of 25 kHz, a 90 8  pulse of 16  m s and an a v eragingo v er 100 FID. A proton decoupling was used in allcases.  27 Al NMR spectra were taken with a spectralwidth of 100 kHz, a 90 8  pulse of 22  m s and an acquisitiontime of 0.05 s; 25000 scans were collected for eachspectrum.E v ans measurements [27] were performed at 25  8 Cand 299.930 MHz in 1:2.2 and 1:5 metal to ligand molarratios. Concentration of complexes were 1.5  / 10  3 moldm  3 in a D 2 O:dioxane 10:1 ( v / v ) solution used asinternal and external reference. The differences in thedioxane peaks were measured at pH* 2, 7 and 10adjusted with 20% DCl and saturated NaOH in D 2 O Table 1Stability constants determined for the Al(III) and Fe(III) complexes at 25  8 C and  I   0.1 M KNO 3  (i) and  I   0.1 M NaCl (ii) 1-phenyl-1-hydroxy-methylene-1,1- bisphos-phonic acid[1-(diethoxyphosphinyl)-l-hydroxybenzyl]-1-phos-phonic acid1-benzyl-1-hydroxy-methylene -1,1-bisphos-phonic acid1-hydroxyethane-1,1-bisphosphonic acid log   b  log   b  log   b  log   b HL 10.80(1) 6.66(1) 11.94(2) 10.87(1)H 2 L 17.47(1)  : 7.6 18.61(2) 17.64(1)H 3 L 20.00(1)    /  21.07(2) 20.09(1)H 4 L  : 21    /  : 22  : 21AlL 18.50(7)    /  18.74(5) 19.12(3)AlH  1 L 13.75(5)    /  13.26(5) 13.93(2)AlH  2 L 3.57(5)    /  2.57(8) 2.71(3)AlH  3 L    /   11.91(2)    /    / AlH 3 L 2  43.41(7)    /  44.74(5) 44.28(3)AlHL 2    /  16.30(3)    /    / AlL 2    /  12.21(2)    /    / AlH  1 L 2    /  6.06(2)    /    / AlH  2 L 2    /   0.78(1)    /    / AlH  1a  5.41    /    /    / AlH  2   9.98    /    /    / AlH  3   15.69    /    /    / AlH  4   23.46    /    /    / Al 3 H  4    / 13.69    /    /    / Al 2 H  2   7.70    /    /    / FeH  3 L    /   5.59(7)    /    / Fe 2 L 2  46.20(13)    /  45.22(8) 48.85(5)Fe 2 H  1 L 2 42.21(9)    /  41.47(10) 44.06(5)Fe 2 H  2 L 2 33.60(8)    /  32.50(6) 34.55(5)Fe 2 H  3 L 2    /    /  22.04(12)    / FeH 3 L 2  45.31(4)    /  46.61(7) 47.52(3)FeL 2    /  18.90(7)    /    / FeH  1 L 2    /  13.38(4)    /    / FeH  2 L 2    /  6.68(7)    /    / FeH  1b    / 2.75    /    /    / FeH  2   6.99    /    /    / FeH  3   10.65    /    /    / Hydrolysis constants from ref. [23] a and ref. [24] b . E. Gumienna-Kontecka et al. / Inorganica Chimica Acta 339 (2002) 111    /  118  113  solution.  m eff   was calculated neglecting the diamagneticcontribution of the sol v ent [28]. 3. Results and discussion 3.1. Protonation constant Ligands  1 L,  3 L and  4 L are H 4 L acids but only threeprotonation constants could be accurately e v aluated.The fourth pK is well below 2 and may not be calculatedon the bases of potentiometric titration (Table 1) [1    / 5].The  2 L is a H 2 L acid with one phosphonate group di-esterified [5]. The protonation constants correspond tophosphonate functions. The alcoholic group bound toternary carbon is  v ery weakly acidic and does notdeprotonate below 13, except perhaps  1 L ( v ide infra)[1]. Deprotonations of the ligand were followed by  31 PNMR spectroscopy. The three studied bisphosphonates( 1 L,  3 L and  4 L) gi v e a single  31 P NMR signal, whichchemical shifts follow the trend of the distributioncur v es obtained from the potentiometric data (Fig. 1).It is interesting to note, howe v er, that in the case of   1 Lligand the deprotonation of the HL species into L onedoes not cause any major change in the chemical shift of the  31 P signal (Fig. 1(A)). It could suggest that the final Fig. 1. Deprotonation diagrams of   1 L (A),  3 L (B) and  2 L (C) withsuperimposed  31 P NMR chemical shifts as function of pH*.  C  L  / 5  / 10  2 mol dm  3 .Fig. 2. Species distribution profile for Al(III)    / 1 L (A) and Al(III)    / 2 L(B) systems;  C  Al  / 1.66  / 10  2 mol dm  3 ;  C  L  / 5  / 10  2 mol dm  3 . E. Gumienna-Kontecka et al. / Inorganica Chimica Acta 339 (2002) 111    /  118 114  deprotonation process could in v ol v e the hydroxyl groupas well. As the two phosphorus atoms of   2 L are notmagnetically equi v alent, we obser v e two signals whichchemical shifts also follow the respecti v e deprotonationprocesses (Fig. 1(C)). 3.2. Al(III) complexes According to the potentiometric data calculations, allthree ligands:  1 L,  3 L and  4 L form the same set of chemical species with Al(III) ions (Table 1, Fig. 2(A)). While the protonated bis-complex, AlH 3 L 2 , predomi-nates below pH 4, the equimolar complexes are themajor species formed abo v e pH 4. The formation of equimolar complexes with bisphosphonates results fromthe fact that the highly charged deprotonated ligand hasa large steric hindrance deri v ed from six oxygen atoms,while metal ion is  v ery small (ionic radius 0.5 A˚ ). All thestudied bis-phosphonates are effecti v e chelators forAl(III) ions, especially  1 L ligand for which we do notobser v e the formation of Al(OH) 4  species at mMconcentrations until pH 11 (Fig. 2(A)).NMR measurements, obtained at different experi-mental conditions (pH*, Al/L ratio), clearly support thepotentiometric speciation results discussed abo v e. Asthe Al(III) complexes are inert in the NMR scale,separate signals are obser v ed for the coordinated andmetal-free bisphosphonates. Below pH* 2 the  1 H and 31 P NMR spectra show binding of two ligands per metalion. The spectra made for 1:2 metal to ligand molarratio do not show any free ligand signal, while at 1:3ratio about 35% of free ligand is obser v ed. Abo v e pH* 3an increase of the signal intensity of free ligand is seendue to the remo v al of one bisphosphonate from themetal coordination sphere (Fig. 3). The  27 Al NMRspectrum made around pH* 1 for 1:3 molar ratioconsists of relati v ely broad single line at   / 5.389 ppmindicating the formation of the complex which in v ol v esall metal ion (Fig. 4). This line mo v es to around   / 10ppm abo v e pH* 3 and abo v e pH* 9 becomes  v ery sharp(Fig. 4). The formation of the three major complexesagrees well with potentiometric data. In the case of   1 Lfor 1:3 metal to ligand molar ratio, no NMR signal isobser v ed for Al(OH) 4  ion occurring at  / 80 ppm. Thisis also in agreement with the model obtained from thepotentiometric results.The coordination ability of   2 L, diester, with onephosphonate protected by methyl groups is completelydifferent from those described abo v e. The lowering of the negati v e charge on the ligand and exclusion of onephosphonate group from metal ion binding results information of the bis-complexes as the major species inthe whole pH range studied (Table 1, Fig. 2(B)). The ligand is much less effecti v e and the formation of theAl(OH) 4  species is obser v ed abo v e pH 9. The forma-tion of the latter ion is seen also in the  27 Al NMRspectra. 3.3. Fe(III) complexes Absorption spectra acquired during the titration weredecomposed in their single components throughout thewhole pH range in v estigated. Despite the fact that thestudied systems are not characterized by well resol v edbands with high intensity, their  v ariations gi v e informa-tion about the number of species formed. The absorp-tion spectra obser v ed show the formation of a firstcomplex already at pH below 2.5 suggesting  v ery highbinding abilities of the ligands studied (Fig. 5). In thecase of   1 L,  3 L and  4 L, the low pH species is the FeH 3 L 2 complex (Table 1, Fig. 6) in which the ligand binds most likely  v ia two phosphonate oxygens forming a six-membered chelating ring [8,9]. The deprotonation of  Fig. 3.  31 P NMR spectra for the Al(III)    / 1 L system in the 1:2 and 1:3molar ratios;  C  L  / 5  / 10  2 mol dm  3 . Species assignments refer tothe main complexes in the distribution profile in Fig. 2(A). E. Gumienna-Kontecka et al. / Inorganica Chimica Acta 339 (2002) 111    /  118  115
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