摘要:
J. CHEM. SOC. DALTON TRANS. 1994 1227Co-ordination Properties of Cyclopeptides. Formation andStability of Zinc(ii) and Copper(ii) Complexes ofHistidine-containing Cyclopeptides, or Imidazole *Giuseppe Arena,a Giuseppe Impellizzeri,a Giuseppe Maccarrone,a Giuseppe Pappalardob andEnrico RizzarelliaSba Dipartimento di Scienze Chimiche, Universita di Catania, 95 125 Catania, Italy95 125 Catania, Italylstituto per lo Studio delle Sostanze Naturali di lnteresse Alimentare e Chimico Farmaceutico del CNR,In order to obtain an improved understanding of the complexing properties of cyclopeptides involved inbiological processes, the interaction of zinc( ti) with cyclo( L- histidyl-L- histidyl) was studied bypotentiometric and calorimetric techniques in aqueous solution.Comparison between the thermodynamicparameters of the complexes formed with those for analogous species formed with cyclo(glycyl-L-histidyl) allowed evidence to be obtained for the formation of chelate rings of unusual size. Thethermodynamic quantities associated with copper( ti) complex formation with cycle(-Gly-His-) weredetermined. The role of the different stereochemical requirements of copper(tt) and zinc(rt) in theformation of large chelate rings was assessed by means of previously reported data concerning thecopper(1t)-cyclo(-His-His-) complexes.Cyclopeptides have been known since the structure ofGramicidin S was discovered.' They are important for theirbiological functions such as hormones, toxins, antibiotics andregulators of ion transport. ' v 2 Cyclohistidylproline wasdiscovered in 1976,, and until now its biological properties,which include inhibition of the prolactin secretion, temperatureregulation, sleep prolongation and modification of behaviouralresponses of experimental animals, have been demon~trated,~but its role still remains largely unexplained.Certain L-histidine-containing cyclopeptides have been shown to possess anti-oxidant activity in uitro5-8 and in V , ~ V O . ~ They catalyse theoxidation of dopa (3,4-dihydroxyphenylalanine) and it hasbeen proposed that this oxidation efficiency increased in thepresence of copper(u)." Even though some studies on thecomplexing features towards transition-metal ions have beenreported,' ' only few quantitative investigations on theformation, stability and co-ordination features of metalcomplexes with histidine-con taining cyclodipeptides have beenpublished.14-' Recently, a detailed thermodynamic andspectroscopic study of the complexes of cyclo(L-histidy1-L-histidyl), cyclo(-His-His-), with copper(I1) ' was carried out inorder to obtain further information on the co-ordination abilityof copper(I1) at the imidazole moiety. Furthermore, on the basisof the speciation obtained in the above work, the superoxidedismutase-like activity of the copper(I1) complexes of cyclo-(-His-His-) was correctly determined and correlated with thestructural features of the metal complexes. ' Cyclo(L-histidy1-L-histidyl) was shown to chelate copper(n) by means of the twoimidazole residues, both at 1 : 1 and 1 : 2 metal to ligand ratios, asfound in the solid state for [Cu{cyclo(-His-His-)),(N03)2].'9The thermodynamic parameters suggested that the formation ofunusually sized chelate rings in aqueous solution was due to thefavourable geometric disposition of the two imidazole ringsstabilized by their non-covalent interactions both with thedioxopiperazine ring and with one another.'In order to ascertain whether this tendency to form largechelate rings is metal-dependent and to what extent the different(geometric and electronic) co-ordination requirements arediscriminating factors in the formation of metal complexes, wereport a detailed thermodynamic investigation of zinc(Ir)-cyclo-(-His-His-) complex formation in aqueous solution at 25 "C andI = 0.1 mol dm-, (KNO,).Potentiometric and calorimetricmeasurements were also carried out on zinc(1Itimidazole (Him)and cyclo(glycy1-L-histidyl), cyclo(-Gly-His-), under thesame experimental conditions. These systems were used asreferences to obtain thermodynamic evidence for the formationof macrochelate rings. Furthermore, for a homogeneous andcomplete picture of the complexing features of these ligands, theformation and the stability of copper(I1) complexes with cyclo-(-Gly-His-) were also investigated. These data, together withthose previously determined for the copper(IIwyclo(-His-His-)~omplex,'~ were used to compare the characteristics of thecopper(I1) complexes with those of the analogous zinc(I1) species.ExperimentalMaterials.-Copper(n) nitrate was prepared from copper(I1)basic carbonate by addition of a slight excess of HNO, and itsconcentration was determined by ethylenediamine-N,N,N',N'-tetraacetate titration with the appropriate indicator. The excessof HNO, was determined by Gran's method, and by use of theACBA computer program (see Calculations).Zinc(rr) nitratewas obtained from ZnO previously calcined at I100 "C, byadding a slight excess of HNO,. The concentration of thezinc(n) stock solution was determined in the same manner as forthe copper(@ solution.The concentrations of stock solutions of HNO, and KOHwere determined by titration with tris(hydroxymethy1)-aminomethane primary standard (Tris), and potassiumhydrogenphthalate, respectively.All solutions were preparedwith doubly distilled water. Other details were as previouslyreported.* Part of the Ph.D. thesis of G. Maccarrone.Non-SI unit employed: cal = 4.184 J.Synthesis of Cyclic D@eptides.-The compound cyclo(-His-His-) was synthesised by cyclization of L-histidine methyl esterdihydrochloride in MeOH at 37 "C.*O Cyclo(-Gly-His-) wa1228 J. CHEM. SOC. DALTON TRANS. 1994synthesized by adding triethylamine to a stirred suspension ofL-histidine methyl ester dihydrochloride in dry chloroform.Benzyloxycarbonylglycyl 4-nitrophenyl ester was then addedand the mixture stirred at room temperature overnight. Thereaction mixture was extracted with water then with ammoniaand finally with water until the washings were practicallyneutral.The organic phase was dried over anhydrous Na,SO,,concentrated in Uacuo and crystallized from ethyl acetate. TheN- benzyloxycarbon ylglycy lhistidine me thy1 ester obtained wasdissolved in absolute ethanol and hydrogenolysed over 10%palladium-on-charcoal catalyst. The N-deprotected dipeptidewas then heated under reflux in anhydrous methanol andthe desired cyclo(-Gly-His-) precipitated on cooling. Crystal-lization of the product from water-acetone gave colourlessprisms.,'Potentiometric 7'itration.s.-Computer-controlled potentio-metric titrations were performed by two distinct Metrohmdigital pH meters (model 654) equipped with model 109 glasselectrodes and model 404 saturated calomel electrodes. Thetitration cell was thermostatted at 25.0 +_ 0.1 "C, and allsolutions were kept under an atmosphere of nitrogen, which waspreviously bubbled through a solution of the same ionicstrength and temperature as the solution under study.Titrations of HNO, with KOH were performed before andafter each set of experiments to convert reading values into pH.The ionic strength was kept at 0.1 mol dmP3 (KNO,).Theexperimental details are shown in Table 1.Calorimetric Measurements.-The calorimetric data wereobtained by titration using a Tronac isoperibol apparatus(model 450) equipped with a reaction Dewar (25 cm3) at25.000 k 0.001 "C. The calorimetric apparatus was calibratedby titrating Tris or HClO, solutions with HCl or NaOH,r e ~ p e c t i v e l y . ~ ~ .~ ~ In all cases the titration data, corrected for allnon-chemical energy terms, determined in separate experiments,were refined simultaneously to obtain the final AH* values.The experimental details are shown in Table 1 .Other experimental details were as previously reported. ''Calculations.-The calculations concerning the electrodesystem, Ej and slope were performed by the ACBA computerprogram,24 which refines the parameters of acid-base titrationsusing a non-linear least-squares method minimizing thefunction U = Z( Vi,exptl - Vi,calc)2, where Vi is the volume of thetitrant added. All other potentiometric data were handled by theSUPERQUAD program.25 This program minimizes the error-square sum based on the measured electrode potentials. Forthe analysis of residuals the procedure recommended byVacca et al.26 was followed. The enthalpies of formation werecomputed by means of the DOEC least-squares program,27which minimizes the function U = Z(Qj,calc - Qj,exptl)2 whereQj is the heat of reaction at the j t h point and is related toAHe by - Q j = Z6niAH"i where 6ni and are thenumber of moles and the enthalpy of the ith species, respec-tively.Results and DiscussionThe reaction of the Him, cyclo(-L-His-L-His-) and cyclo(-Gly-~-His-) ligands with zinc(n) and copper(r1) is represented inequation (1) where L is the appropriate ligand with chargesomitted for simplicity. The stability constants are defined byequation (2). The equilibria (3H5) were considered to fit theexperimental titration curves for the above reactions.M + L F=+ [ML] (3)M + 2 L e [ML,]M + 3L [ML,] ( 5 )A simple model has been proposed for the zinc(n+yclo(-His-His-) system by Kojima,28 who took into account the [ML]and [ML,] species.Whereas that model is in accord with ourresults, the log K , value differs markedly from that determinedin the present investigation. This may be due both to the verylow concentrations employed and to the limited M : L ratiosinvestigation by Kojima 28 (Table 2).The protonation value is very close to that reported by Sigel andSaha 38 under the same experimental conditions. These authorsconcluded that only [Zn(Him)I2 + formed under theirexperimental conditions (M : L = 1 : 1). This probably explainsthe discrepancy between their value and the values obtained inthe present investigation at a larger metal : ligand ratio.Baumanand Wang 39 reported a AH value for [Zn(Him)]'+ of - 3.8kcal mol-'. The difference between this and our value (Table 2)may be due to the fact that the 'Zn" titration was terminated atlow ti value because of the precipitation of zinc imidazolate athigher ri during the enthalpic t i t r a t i ~ n ' . ~ ~ As shown in Table 2,the formation of [Zn(Him),12 ' is more entropically and lessenthalpically favoured than is that of [Zn(Hirn)l2'. This trendrecalls that found for other zinc(I1) complexes in which theoctahedral geometry present in the mono complex changes intothe tetrahedral geometry preferred by zinc(I1) in the bis complex,with a consequent increase in the metal desolvation processaccounting for the more positive AS0 and less negativeenthalpy values.40No thermodynamic data have until now been reported onmetal-complex formation with either cyclo(-Gly-His-) or cyclo-(-His-His-).The complex [Zn{cyclo(-Gly-His-)}] + is lessstable than [Zn(Him)12' due to a less favourable enthalpycontribution, while the entropy term is less unfavourable (Table2). This behaviour is similar to that found in the proton complexf ~ r m a t i o n . ' ~ , ~ ' In the latter case, it has previously beenshown 2 1 that the unprotonated cyclodipeptide exists in a foldedconformation with the imidazole residue projected towards thedioxopiperazine ring, while in its protonated species this non-covalent interaction is lost due to the arrangement of theprotonated imidazole moiety far away from this ring.Since non-covalent interactions are enthalpically favoured and entropi-cally disfavoured,2 1,41*42 the basicity decrease of the imidazolenitrogen in cyclo(-Gly-His-) compared to that of imidazoleitself can be understood. In analogy with the protonationprocess, the interaction of the metal ion with the imidazolenitrogen again involves a change of disposition of the imidazoleresidue with a consequent unfavoura ble en thalpy contributionto the complex formation.As expected, the formation of [Cu{~yclo(-Gly-His-)}]~ + isenthalpically favoured. Its stability constant is smaller than thatfound for [Cu(Him)I2' (Table 2) and, as found for theanalogous zinc(I1) complex, this is due to a less favourableenthalpy contribution which can be explained in the same way.Copper(I1) forms a bis complex with cyclo(-Gly-His-), againshowing a stability constant smaller than that of [Cu(Him)J2 + .This results from a more favourable enthalpy change and amore negative entropy contribution.This is surprising since alsoin this step the binding of cyclo(-Gly-His-) involves anunfavourable enthalpy contribution due to displacement of theimidazole residue from the dioxopiperazine ring. The reason forthis is not well understood.The stability constant for [Zn(cyclo(-His-His-)}] + is higherthan that of [Zn(~yclo(-Gly-His-)}]~ + but smaller than that of[Zn(Him),]'+ (log = 4.91); in the latter species two nitrogensare involved in the co-ordination.This raises questions as to thenumber of nitrogen atoms of cyclo(-His-His-) involved in the co-ordination to Zn". For the analogous copper(1r) species, i.e.[Cu{ cycle(-His-His))] * + , we have previously demonstrated byThe zinc(rI)-Him system has been extensivelJ. CHEM. SOC. DALTON TRANS. 1994 1229Table IConcentration range, clmol dm-3Summary of experimental parameters for potentiometric and calorimetric measurements at 25 "C and I = 0.1 mol dm-, KNO,CyClO(-Gly-c u 2 + Zn2 + Him His-)Potentiometry0.0035-0.00600.00634.00900.00504 .0080 0.0 1 604.0 1 990.04704 .OO 5 5 0.00514.00960.0050-0.0070Calorimetry0.00804.00990.0047-0.00500.0037-O .0040cyclo(-His-His-) Titrant ConcentrationKOH 0.10014.10 170.0998-O.10170.09984.10170.00514.0091 0.09994.10 1 5Him- 0.401 5,0.2399H,im+His-&H +His-tH'cyclo(-Gly- 0.2001, 0.0700cyclo(-Gly- 0.2001,0.07000.0058-0.066 Zn2+ 0.2032PHrange3.1-6.03.5-6.93.1-6.22.7-7.24.0-5.62.04.22.64.24.5No.of No.oftitrations points28486 33 I4 2039 3848 2844 1064 906 263Table 2 Thermodynamic parameters for the interactions of Him, cyclo(-Gly-His-) and cyclo(-His-His-) with Zn2+ at 25 "C and I = 0.1 mol dm-3(KNO,) *ReactionA S " 1-AG"/ -AH"/ cal K - 'kcal mol-' kcal mol-' mol- Ref.log KZn2+ + Him e [Zn(Him)I2+ 2.28(6) 3.1 l(8) 4.7(1)[Zn(Him)]' + + Him [Zn(Him),l2' 2.63(6) 3.59(9) 1.6(5)[Zn(Him),12+ + Him F=+ [Zn(Him),]'+ 2.26(6) 3.08(9) 3.7(9)Zn2 + + cyclo(-Gly-His-) T [Zn{cy~lo(-Gly-His-)}]~ + 1.71(1) 2.34(1) 2.4(2)Zn2 + + cyclo(-His-His-) [Zn{cyclo(-Hi~-His-)}]~ + 2.55(3) 3.48(4) 4.9(2)[Zn{cy~lo(-His-His-)}]~+ + cyclo(-His-His-) [Zn{~yclo(-His-His-)},]~ + 2.87(2) 3.91(3) 6.0(3)* Uncertainties given in parentheses as 30.3.82.9- -- -- 5.3(5) This work6.0(2) This work-4.0(3) This work-0.2(9) This work-4.7(8)- 7.3(9)2828__._ -Table 3 Thermodynamic parameters for the interactions of Him, cyclo(-Gly-His-) and cycle(-His-His-) with Cu' + at 25 "C and I = 0.1 mol dm-,(KNO3) *A S " J-AG"/ - A H " I cal K 'Reaction log KCu2+ + Him e [Cu(Him)I2+[Cu(Him)]" + Him e [Cu(Him),]'+[Cu(Hirn),]" + Him F= [Cu(Him),]"[Cu(Hirn),l2+ + Him e [Cu(Him),]'+[Cu { cyclo( -GI y -His-)}]' + + cyclo(-Gly-His-) e [Cu{cyclo(-Gly-His-)} 2] ' +4.323.292.701.902.675.99Cu2 + + cyclo(-Gly-His-) [Cu{~yclo(-Gly-His-)}]~ + 3.35Cu2+ + cyclo(-His-His-) e [Cu{cy~lo(-His-His-))]~ +[Cu{cy~lo(-His-His-)}]~ + + cyclo(-His-His-) [Cu{cyclo(-His-His-)}2]2 + 4.55* Uncertainties given in parentheses as 30.kcal mol-' kcal5.90 6.944.48 6.53.68 6.72.64 3.54.57(1) 5.05(3.65(2) 7.13(8.17 9.886.21 7.1101-' mol-' Ref.- 3.5 17- 6.4 17- 10.3 17- 2.8 171 - 1.60( 1 ) This work1 1 1.67( 1 ) This work- 5.7 17- 2.9 17means of ESR measurements that both cyclo(-His-His-)nitrogens are co-ordinated, thus leading to the formation of amacrochelate, as found in the solid state." The comparison ofthe A H + values associated with the formation of [Zn{cyclo-(-His-His-))l2 + and of [Zn{cy~lo(-Gly-His-)}]~ + shows this tobe very likely the case also for Zn".The AH" value for theformer is higher than that for the latter, where only one nitrogenis co-ordinated; the negative entropy contribution is alsoconsistent with the formation of a macrochelate. In contrastwith our conclusion, on the basis of NMR results, it has beenpreviously suggested that cyclo(-His-His-) acts as a mono-dentate ligand 43 in [Zn{cycl~(-His-His-)}]~+. Given theexothermicity of the reaction, as indicated by the present results,we are inclined t o believe that the experimental conditionsemployed for the NMR experiments (50 "C) may have causedthe detachment of a histidine nitrogen.The complex [Zn{~yclo(-His-His-)),]~ + is more stable than[Zn{cycl~(-His-His-)}]~ + due to the more favourable enthalpychange.This behaviour is different from that found in theanalogous copper(r1) complexes, in which the A H + value forthe formation of [Cu{cyclo(-His-His)-)} 2 ] 2 + is less favourablethan that of [Cu{cy~lo(-His-His-)}]~ +; however, this isconsistent with the well known tendency of Zn" to switch froman octahedral to a tetrahedral geometry, as discussed above for[Zn(Him),12+. The enthalpy value for the formation of[Zn{ cyclo(-Hi~-His-)}]~ + would thus also 'contain' theendothermic contribution associated with the change ofgeometry; this would also explain the higher entropycontribution in the first complexation step.In conclusion a detailed thermodynamic study allows us toreveal both the formation of chelate rings of unusual size as wellas the different enthalpy and entropy contributions to th1230 J.CHEM. SOC. DALTON TRANS. 1994stabilization of such macrochelate rings. The ligand featuresprevail on the geometric and electronic requirements of the twometal ions, leading to the formation of macrochelate rings inboth cases.AcknowledgementsWe thank Consiglio Nazionale della Ricerce (P.F. ChimicaFine 11) and Minister0 dell’universita e della RicercaScientifica e Tecnologica (Rome) for partial support.References1 Yu. A. Ovchinnikov and V. T. 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ISSN:1477-9226
DOI:10.1039/DT9940001227
出版商:RSC
年代:1994
数据来源: RSC