- Email: [email protected]
Manganese(II) and nickel(II) complexes of some 2-(polyhydroxyalkyl) thiazolidine-4-carboxylic acid derivatives
Polyhedron Vol. 11, NO. Ll, pp. 2237-2243, Printed in Great Britain
1992 0
0277-5387192 $5.00+.00 1992 Pergamon Press Ltd
MANGANESE(H) AND NICKEL@) COMPLEXES OF SOME 2(POLYHYDROXJ!ALKYL)THIAZOLIDINE4CARBOXYLIC ACID DERIVATIVES TAM&
GAJDA, NORBERT
NAGY and KALMAN BURGER*
BUZAS, LASZLO
Department of Inorganic and Analytical Chemistry, Attila J6zsef University, H-6701 Szeged, P.O. Box 440, Hungary (Received 27 January 1992 ; accepted 11 May 1992)
Abstract-The manganese(I1) and nickel(I1) ion coordination equilibria of some 2-(polyhydroxyalkyl)thiazolidine-4-carboxylic acid (PHTAC) derivatives were studied by potentiometric titration in the pH range 2-l 1. Nickel(I1) parent complexes with (1, 1,O) and (1, 2, 0) compositions and manganese(I1) complexes with (1, 1, 0) composition were formed. In both systems, mixed-ligand complexes involving hydroxide ion coordination and/or further deprotonation of the alcoholic hydroxy groups of the sugar moieties were observed at pH > 6. EPR measurements indicated that in alkaline solution all the manganese(II)PHTAC complexes are dimeric. The magnitudes of the complex-formation constants were shown to depend on the conformation of the hydroxy groups on the first carbon atoms of the polyol chains.
In recent years, research concerning the synthesis of glycopeptides has been directed towards the development of highly receptor-selective and specific derivatives for clinical use. The reactions of aldehydes with /?-aminothiols, and particularly with cysteine, lead to the formation of a thiazolidine ring [eq. (l)] :
boxylic acid is capable of inducing reverse transformation in tumour cell~,~and this compound was selected for the chelation of metal ions from their protein complexes in the plasma membrane. ‘@I2It is interesting to note that such compounds do not
R’
R’
I H-C-SH
I
I H&-NH,
+
HAC=O u,/-
-
-
Hmi-s>C(H H-C-NH
+ .R”
H,O
(1)
!,
b
These reactions have been the subject of numerous previous studies I because of their relevance to the binding of carbonyl compounds to proteins containing sulphydryl and amino groups in close proximity.2 The condensation of sulphydryl-containing amino acids with naturally occurring monosaccharides3-6 takes place under mild conditions. Lote and co-workers isolated a similar type of oligopeptide, galactose7 and glucose’ being linked to cysteine as the N-terminal amino acid. Gosilvez and co-workers reported that thiazolidine-4-car-
*Author to whom correspondence should be addressed.
poison cells. Fazakerley et al. I3 have studied thioproline-transition metal(I1) ion systems. Recently, 2-(polyhydroxyalkyl)thiazolidine-4-carboxylic acids were tested as protective agents against acetaminophen(N-4-hydroxyphenylacetamide)-induced hepatoxicity in a mouse model. I4 The results discussed suggest that a study of the complex formation of these compounds is of importance. The complex formation of six such derivatives was studied by Weitzel et a1.,6 but only in the pH range 2-6. They did not find any correlation between the protonation or complex-formation constants and the structure of the polyol chain.
2237
T. GAJDA
2238
et al.
D-ribose (Ribcys, VI), L-arabinose (Laracys, I) and L-rhamnose (Ramcys, V)], the ligands were prepared by the method of Bog& et aL3 while the hexoses [D-mannose (Mancys, IX), D-glucose (Glucys, III) and D-galactose (Galcys, IV)] were prepared according to Weitzel et a1.6 After recrystallizations (at neutral pH), racemic 2(S) and 2(R) mixtures were formed in a 1: 1 ratio, as revealed by our NMR investigations and also reported previously,‘7 but the proportions of the 2(S) and 2(R) compounds were shown to depend on the pH of the solution. The structures of the ligands are depicted in Fig. 1. The analytical data for the characterization of the ligands are given in our previous paper. ’ 5
Recently, we studied the proton and zinc(I1) complexes of a large number of such compounds,” as well as the transition metal coordination of 2(R59D-galacto(l’,2’,3’,4’-tetrahydropentyl-5’-carboxy) thiazolidine-4(R)-carboxylic acid. I6 It was found that both protonation and complex-formation constants depend on the structure of the sugar moiety. In the case of the protonation constants, this is due to the rearrangement of the intramolecular hydrogen-bonding network, while the complexformation constants depend on the conformation of the hydroxy groups on the first carbon atoms of the polyol chains. The present paper reports on coordination chemical studies of the nickel(I1) and manganese(I1) complexes of a series of such compounds.
pH-metric
EXPERIMENTAL
The manganese(I1) and nickel(I1) coordination equilibria were investigated by potentiometric titration at 25.0+ O.l”C, under a nitrogen atmosphere, in aqueous solutions of constant ionic strength (0.1 mol drne3 NaClOJ. Changes in pH were followed using a G 222B Radiometer glass electrode and an OP-2801 Radelkis silver-silver chloride reference electrode. The titrations were performed with a computercontrolled on-line automatic titration apparatus constructed in our laboratory. ’ 8 For quantitative evaluation of the data, the following correlation between the experimental EMF values (E) and the
Materials
Manganese(I1) perchlorate chlorate were Fluka products. were obtained from Reanal. chlorate stock solutions were plexometrically.
and nickel(I1) perAll other reagents The metal(I1) perstandardized com-
Synthesis
In the cases of pentoses [D-lyxose (Lyxcys, VIII), D-xylose (Xylcys, II), D-arabinose (Daracys, VII),
S'
measurements
,3NH
Y R
m
zm
pm
P
Fig. 1. Schematic structures of the ligands studied.
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic acid derivatives equilibrium hydrogen ion concentrations, used : E = E,,+ 7
[H+], was
log[H+]+j,[H+]+joHIH+]-‘Kw;
(2) where ju and JOHare fitting parameters in acidic and alkaline media for the correction of experimental errors, mainly due to the liquid junction and to possible alkaline and acidic errors of the glass electrode ; K, is the autoprotolysis constant of water ( 1O- ’ 3.7‘). In the complex-formation studies, the titrations were carried out in systems with six different metal-to-ligand ratios, varying from 1 : 5 to 1:15. Calculations The species of various compositions formed in the systems studied can be characterized by the general equilibrium process [Eq. (3)] (charged omitted) : pM+qL+rHeM,L,H,.
(3)
The formation constant for this generalized reac[MPLQHII The fipqrvalues were caltion is bp4’=
[MlptLlqWl”
culated from the pH-metric titration data with the PSEQUAD computer program. I9 EPR measurements The EPR spectra were recorded in aqueous solutions of 2.85 x lop3 moldmw3 metal and 2.85 x lo-* mol dmp3 ligand concentrations in standard quartz cells with the JEOL-JES-PE spectrometer at room temperature. In work with solutions sensitive to oxygen, the cells were sealed. The microwave power was set at 15 mW, and the modulation frequency and amplitude were 100 kHz and 10 G, respectively. RESULTS AND DISCUSSION
As has already been pointed out, on the basis of the previous equilibrium study’ 5 of the zinc(I1) complex formation of the same ligands, the complexes can be divided into four groups ; this is of help towards an explanation of the stability differences in terms of the different structures of the polyhydroxy chain linked to the thiazolidine ring. In order to control the validity of this observation in other systems, we determined the formation constant of transition metal(I1) ions forming complexes of higher and lower stability than those of the zinc
2239
(II) ion. Investigation of the copper(I1) complexes was prevented by the redox reactions between the ligands and the copper(I1) ion. In accordance with the Irving-Williams complex stability series, therefore, we chose nickel(I1) and manganese(I1) ions for these investigations. The formation curves in both cases indicated that the complex-formation reactions are not complete up to pH 6 [Weitzel et al6 measured the cobalt(I1) and zinc(I1) systems only up to this point] and further complexes are formed in the interval pH 6 11. The observed formation curves reflected the simultaneous formation of mononuclear parent and mixed-ligand complexes (hydroxide ion coordination) in the systems, but further deprotonation of alcoholic hydroxy groups of the ligands could not be excluded either. Earlier studies of the coordination of thiaproline by bivalent transition metal ions have shown that amino-N and carboxyatoms are the coordination centres.1°-13 It is obvious that analogous coordination can be expected in the present case. Our equilibrium studies revealed that in slightly acidic solution nickel(I1) parent complexes with 1 : 1 and 1 : 2 compositions and manganese(I1) parent complexes with 1 : 1 compositions are formed beside mixed-ligand complexes, and in the case of manganese(I1) polynuclear complexes. The same results were also obtained for the manganese(II)- and nickel(H)-thiaproline systems.*’ The overall formation constants (log p values) of the parent and mixed-ligand complexes and the corresponding stepwise stability constants (log K, and log K,), together with some literature data, are presented in Tables 1 and 2. The equilibrium data on the nickel(I1) complexes clearly reflect the effect of the structure of the sugar moiety on the stability of the complexes. From a comparison of the structures (Fig. 1) and the stability constants, it is obvious that the conformation of the OH group on C(1’) has a great influence on the stability,, as demonstrated for the corresponding zinc(I1) complexes studied earlier. ” The similar effect is much less pronounced for the manganese(I1) complexes, which have lower stabilities. The fact that the hydroxy group on the first carbon atom of the sugar moiety plays an important role in the metal-ligand interaction indicates that, besides the carboxylate-oxygen, the amino-nitrogen atom of the ligand is also coordinated to the metal ion, forming a five-membered chelate ring. ’ 2 In Laracys the OH group on C(l’) is close to the amino group as the rotation is hindered (cis position), and this OH group can also be bound to the metal ion. In this way two five-membered chelate rings are formed, resulting in an enhancement
2240
T. GAJDA et
al.
Table 1. Formation constants (log values) for complexes (Ni”“),(aHTAC),(proton), Ligands
No.
Laracys
I
5.94t_0.03
Ramcys
V
4.29 +
Daracys
VII
0.03
3.1940.04
9.79kO.05 (3.85) 7.84kO.07 (3.55) 5.74kO.12 (2.55)
0.09 Jto.07 (4.05) -0.67kO.18 (5.24) -2.6.5+0.19 (5.36)
220 -11.07*0.28 (3.35) -12.19kO.28 (4.21)
280 220
Thiaproline, log K, = 3.93” ; log Kz = 3.28; log I(, = 1.62. On= number of experimental points.
of the stability of the complex (Fig. 2). In Daracys the C( 1’) OH group is too far from the amino group (trans position) to be bound by the metal ion (which is already chelated by the amino and carboxylato groups). Consequently, the formation of a second chelate ring in the latter system is not possibfe. This is the reason for the lowest stability of the Daracys complexes in the series of systems studied. Finally, in Ramcys the OH group on C(I’) is in a suitable position for the formation of a second chelate ring, but the OH on the neighbou~ng carbon atom gives rise to steric hindrance, resulting in the lower stability of the chelate rings than in the Laracys complex, but higher than that in the Daracys complex (Figs 3 and 4).
Table 2. notation
constants (log values) for complexes (~n2+)~~ligand)~~roton~,
No.
Ligand
I
Laracys
2.43If:0.06
n
Xylcys
2.34 f 0.05
III
Glucys
2.35 _t 0.07
IV
Galcys
2.3lkO.06
V
Ramcys
2.24kO.07
VI
Ribcys
2.17f0.08
VII
Daracys
1.92t0.07
VIII
Lyxcys
2.20 20.07
Ix
Mancys
2.12IfrO.08
Thiaproline, log K, = 1.91. ’ 3 = number of experimental points.
an
A comparison of the log K values For nickel(II)and manganese(II)-thiaproline (Tables 1 and 2) with the corresponding values for the complexes formed with Laracys and Ramcys confirms the existence of the two five-membered chelate rings discussed above. Both the log K, and log lya values for the nickeI(I1) complexes and the log K, values for the manganese(U) complexes of ligands with the OH groups on C(1‘) in the cis position are significantly larger than the corresponding values for the thiapro~ne systems, due to the double chelate effect in the former complexes. Daracys, which cannot be bound in a tridentate manner because of the trans position of its OH on C(l’), exhibited a log K, value for the manganese(I1) complex equal to
-0.32f0.10 (11.00) -0.47*0.10 (10.94)
-9.41 kO.01 (4.66) -9.31+0.16 (4.91)
-29.66k0.25 (7.25) - 29.40+ 0.25 (7.41)
-0.47f0.12 (10.93) -0.66+0.08 (10.78) -0.55fO.11 (10.96) -0.46+_0.12 (11.12) -0.59f0.15 (11.24) -0.49f0.10 (11.06) -0.55+0.12 (11.08)
- 10.21 ho.18 (4.01) - 10.3o_to.15 (4.11) - 10.53 t 0.20 (3.77) -9.85It:O.I8 (4.30) - 10.17t0.20 (4.17) -10.34Ifro.17 (3.90) - 10.43 f 0.20 (3.87)
-3O.lOf0.22 (7.61) - 30.40 f 0.22 (7.40) -31.00&0.20 (7.03) -29.90+0.2X (7.45) -30.77+0.30 (6.90) -30.60+0.25 (7.24) -30.90+0.30 (7.03)
300 240 280 250 240 270 300 240 250
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic
M = Ni,Mn
2241
acid derivatives
4
6
6
4
6
8
II 0
Fig. 2. Suggested structures of manganese(II)- and nickel(II)-Laracys and -Ramcys complexes.
that for the corresponding thiaproline complex. In the nickel(I1) complex, the log K, value was even smaller than that of the corresponding thiaproline complex, probably because of the steric effect of the polyol chain. Both manganese(I1) and nickel(I1) complexes
PH 4
I
6
IO
8
Fig. 4. Species distribution in manganese(II)-Laracys, -Ramcys and -Daracys systems as a function of pH. [Mn’+] = 1.4x 10m3 mol dm-‘, [L] = 1.4x IO-’ mol dm-‘, T = 298 K, Z = 0.1 mol drnm3 NaClO,.
Lb)
4
6
IO
8
PH (Cl
2
3
4
5
6
7
8
9
IO
I
Fig. 3. Species distribution in the nickel(II)-Laracys, -Ramcys and -Daracys systems as a function of pH. [Ni2+] = 2.00 x lop3 mol dmp3, [L] = 1.00 x 10m2 mol dm-‘, T=298K,Z=O.l moldm-3NaC10,.
have been prepared in the solid state from methanolic solution and characterized by IR spectroscopy. The IR spectra of the ligands are very similar to each other in that the v(NH*+) band lay at 3080 - ‘. The appearance of the asymmetric stretching %rations of the carboxylate groups at 160&1660 cm- ’ and that of the symmetric vibrations indicated that all of the ligands studied here have a zwitterion structure. The OH region in the IR spectra of the free ligands reflected the presence of several hydrogen-bonded alcoholic hydroxy groups. The composite structure of the OH bands pointed to the presence of an inter- and intramolecular hydrogenbonding network. In the range 640-620 cm-l, characteristic of the C-S stretching vibration, the complex formation resulted in small shifts. The IR spectra of the complexes are more simple than those of the ligands. As a consequence of com-
2242
T. GAJDA
plex formation, the v(NH2+) vibrations disappeared. The appearance of a new shoulder at 3180 cm- ‘, assigned to the NH group, and the shifts in the v,,(COO-) and v,,,(COO-) bands indicate that manganese(I1) and nickel(I1) coordinate to the carboxylic and NH group of the thiazolidine ring. The local structure was determined by means of the extended X-ray absorption fine structure (EXAFS) method. 21*22It was found that the Laracys and Ramcys complexes of both metal ions are hexa-coordinated. The Ni-0,N and Mn-0, N bond distances are 202 and 216 pm, respectively, in good agreement with those observed for hexa-coordinated nickel(I1) and manganese(I1) complexes. The average Ni . . . C, Mn . . . C, Ni . . * S and Mn. **S distances are 287, 306, 380 and 370 pm, respectively. The carbon atoms are located in the second and the sulphur atoms in the third coordination shell (Fig. 2). These results confirm that the OH groups on C( 1’) of the polyhydroxy moiety could also be coordinated to the central metal ions, forming an elongated octahedral structure. The percentage distributions of the total manganese(I1) and nickel(I1) concentrations in the different complexes are presented in Figs 3 and 4, respectively. In the manganese(I1) complexes, the formation of dimeric species was revealed by the equilibrium measurements (see Table 2 and Fig. 4). This statement was confirmed by the EPR measurements. The typical six-line pattern of manganese(I1) in the aqueous solution of pH < 5.5 containing 3 x lop3 mol dmp3 manganese(I1) and 1.5 x lop2 mol dmp3 ligand decreased and finally disappeared when the pH of the solution was increased above pH 6 (Fig. 5). This change in the EPR signal indicates that dimeric manganese(I1) complexes are formed (in accordance with the equilibrium measurements) with magnetically interacting manganese(I1) centres, resulting in a decrease in the number of unpaired electrons. This behaviour is analogous to that observed for the manganese(II)-saccharose,23 -maltitol24 and -gluconate2’ systems. The equilibrium studies indicated further deprotonation processes after coordination of the organic ligands (Tables 1 and 2 and Figs 3 and 4). These may be due to the deprotonation of the OH group on C(l’) of the polyol, or (and) to coordination of the OH- ions by the metal, i.e. in the two chelate ring-containing systems the substitution of the sugar OH group by a hydroxide ion. Carbohydrates are very weak acids ; the first acidity constants are in the range 10-‘4-10-‘2 mol dm- 3.26 In the presence of metal ions a sugar becomes more acidic. For instance, ribose protons are ordinarily neutralized at around pH - 12-14,
et al.
pH = 10.3
Fig. 5. The change of the EPR spectrum of the manganese(II)-Laracys complex with the pH of the solution. [manganese(R)] = 2.85 x lop3 mol dme3, [Laracys] = 2.85 x lo-* mol dmp3. but on chelation with copper(I1) their deprotonations shift by about 2 pH units. In our systems, the formation of new species starts at around pH 6. It is hard to believe that complexation could shift the deprotonation of sugar hydroxy groups to such a low pH. Thus, the process mentioned above is probably due to the coordination of OH- ions. In those systems which contain two five-membered chelate rings (tridentate coordination of the ligand), the OH- ion coordination results in the opening of the chelate ring containing the alcoholic OH group and one or (at higher pH) two OH- ions coordinate to the central metal ion, completing the octahedral coordination sphere. This process needs a higher hydroxide ion concentration than the formation of the mixed-ligand (OH--containing) complex in those systems which contain only one chelate ring with amine-nitrogen and carboxylate-oxygen donor atoms. In the complexes containing ligands bound in a tridentate way, the OH- concentration required by the mixed-ligand complex formation depends on the bonding energy of the polyol OH groups in the chelate. This is the reason why the pH needed for this process increases in the sequence Daracys < Ramcys < Laracys. Acknowledgement-This
of the Hungarian 84/1991).
work was supported by a grant Research Foundation (OTKA
REFERENCES 1.
M. P. Schubert, J. Biol. Gem. 1935,111,671; 1936, 114, 341; S. Ratner and H. T. Clarke, J. Am. Gem. Sot. 1937,53, 1690.
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic 2. R. G. Kollen, J. Am. Chem. Sot. 1971, 93, 6236 ; M. V. Buell and R. E. Hansen, J. Am. Chem. Sot. 1960, 82, 6042; J. Heller, Biochemistry 1968, 7, 2914. 3. R. Bognar, Z. GyGrgydeLk, K. Szilagyi and L. Somogyi, Liebigs Ann. Chem. 1970,737,68. 4. R. Bognar, L. Somogyi and Z. GyBrgydeak, Liebigs Ann. Chem. 1975,1637. 5. R. Bog&r, Z. Gyiirgydeak, L. Szilagyi, G. Horvath, C. Czira and L. Radics, Liebigs Ann. Chem. 1976, 450. 6. G. Weitzel, I. E. Engelmann and A. M. Fretzdorf, 2. Physiol. Chem. 1969,315,236. 7. C. J. Lote and J. B. Weiss, Biochem. J. 1971, 25. 8. J. B. Weiss, C. J. Lote and H. Babinski, Nature, New Biol. 1971, 234, 25. 9. M. Gosalvez, L. Pecci and C. Vivero, Biochem. Sot. Trans. 1978,6,635 ; A. Burgarolas and M. Gosalvez, Lancet 1980, 1, 68. 10. Z. X. Huang, P. M. May, D. R. Williams and M. Gosalvez, Znorg. Chim. Acta 1981, 56,41. 11. R. Radomske, T. Tatarowski, J. P. Morawiec and H. Kozlowski, Znorg. Chim. Acta 1985,106, L29; M. Nagase, Y. Yukawa, Y. Inowata and T. Takenchi, Znorg. Chim. Acta 1988, 152, 211. 12. T. Tatarowski, M. Kubiak, T. Glowiak, J. P. Morawiec, H. Kozlowski and M. Gosblvez, Znorg. Chim. Acta 1984,93, L3 and refs therein. 13. G. V. Fazakerley, G. E. Jackson and P. W. Lindner, Znorg. Nucl. Chem. 1976,38, 1397. 14. J. C. Roberts, H. T. Nagasowa, R. T. Zeerea, R. F.
15. 16. 17. 18.
19.
20.
21.
22. 23. 24. 25. 26.
acid derivatives
2243
Ficke and D. J. W. Goon, J. Med. Chem. 1987, 30, 1981. T. Gajda, L. Nagy and K. Burger, J. Chem. Sot., Dalton Trans. 1990,3 155. T. Gajda, L. Nagy, N. Rozlosnik, L. Korecz and K. Burger, J, Chem. Sot., Dalton Trans. 1992,475. J. Radomski and A. Temeriusz, Carbohydr. Res. 1989,187,223. K. Trogmayer-Malik, I. Horvath, K. Burger, G. Condos, L. Gera and M. Bartok, Znorg. Chim. Acta, 1987,138, 155. L. Zekany and I. Nagypal, in ComputationalMethods for the Determination of Stability Constants (Edited by D. Legget). Plenum Press, New York (1985). A. P. G. Kieboom, K. M. A. Bum-mans, L. K. von Leeuven and H. J. Benschop, Reel. Trans. Chim. Pays-Bas 1979,98, 393. L. Nagy, T. Gajda, N. Buzbs, S. Yamashita, M. Nomura, T. Yamaguchi and H. Wakita, J. Chem. Sot., Dalton Trans., to be published. L. Nagy, S. Yamashita, M. Nomura, T. Gajda, T. Yamaguchi and H. Wakita, Znorg. Chem., submitted. L. Nagy, T. Gajda, T. Pali and K. Burger, Znorg. Chim. Acta 1986,123,35. L. Nagy, T. Gajda, T. Pali and K. Burger, Acta Chim. Hung. 1988,125,403. M. E. Bodini, L. A. Willis, T. L. Riechel and D. T. Sawyer, Znorg. Chem. 1976, 15, 1538. K. Burger and L. Nagy, in Biocoordination Chemistry (Edited by K. Burger), Ch. VI, pp. 236-284. Ellis Horwood, Chichester, NY (1990).
1992 0
0277-5387192 $5.00+.00 1992 Pergamon Press Ltd
MANGANESE(H) AND NICKEL@) COMPLEXES OF SOME 2(POLYHYDROXJ!ALKYL)THIAZOLIDINE4CARBOXYLIC ACID DERIVATIVES TAM&
GAJDA, NORBERT
NAGY and KALMAN BURGER*
BUZAS, LASZLO
Department of Inorganic and Analytical Chemistry, Attila J6zsef University, H-6701 Szeged, P.O. Box 440, Hungary (Received 27 January 1992 ; accepted 11 May 1992)
Abstract-The manganese(I1) and nickel(I1) ion coordination equilibria of some 2-(polyhydroxyalkyl)thiazolidine-4-carboxylic acid (PHTAC) derivatives were studied by potentiometric titration in the pH range 2-l 1. Nickel(I1) parent complexes with (1, 1,O) and (1, 2, 0) compositions and manganese(I1) complexes with (1, 1, 0) composition were formed. In both systems, mixed-ligand complexes involving hydroxide ion coordination and/or further deprotonation of the alcoholic hydroxy groups of the sugar moieties were observed at pH > 6. EPR measurements indicated that in alkaline solution all the manganese(II)PHTAC complexes are dimeric. The magnitudes of the complex-formation constants were shown to depend on the conformation of the hydroxy groups on the first carbon atoms of the polyol chains.
In recent years, research concerning the synthesis of glycopeptides has been directed towards the development of highly receptor-selective and specific derivatives for clinical use. The reactions of aldehydes with /?-aminothiols, and particularly with cysteine, lead to the formation of a thiazolidine ring [eq. (l)] :
boxylic acid is capable of inducing reverse transformation in tumour cell~,~and this compound was selected for the chelation of metal ions from their protein complexes in the plasma membrane. ‘@I2It is interesting to note that such compounds do not
R’
R’
I H-C-SH
I
I H&-NH,
+
HAC=O u,/-
-
-
Hmi-s>C(H H-C-NH
+ .R”
H,O
(1)
!,
b
These reactions have been the subject of numerous previous studies I because of their relevance to the binding of carbonyl compounds to proteins containing sulphydryl and amino groups in close proximity.2 The condensation of sulphydryl-containing amino acids with naturally occurring monosaccharides3-6 takes place under mild conditions. Lote and co-workers isolated a similar type of oligopeptide, galactose7 and glucose’ being linked to cysteine as the N-terminal amino acid. Gosilvez and co-workers reported that thiazolidine-4-car-
*Author to whom correspondence should be addressed.
poison cells. Fazakerley et al. I3 have studied thioproline-transition metal(I1) ion systems. Recently, 2-(polyhydroxyalkyl)thiazolidine-4-carboxylic acids were tested as protective agents against acetaminophen(N-4-hydroxyphenylacetamide)-induced hepatoxicity in a mouse model. I4 The results discussed suggest that a study of the complex formation of these compounds is of importance. The complex formation of six such derivatives was studied by Weitzel et a1.,6 but only in the pH range 2-6. They did not find any correlation between the protonation or complex-formation constants and the structure of the polyol chain.
2237
T. GAJDA
2238
et al.
D-ribose (Ribcys, VI), L-arabinose (Laracys, I) and L-rhamnose (Ramcys, V)], the ligands were prepared by the method of Bog& et aL3 while the hexoses [D-mannose (Mancys, IX), D-glucose (Glucys, III) and D-galactose (Galcys, IV)] were prepared according to Weitzel et a1.6 After recrystallizations (at neutral pH), racemic 2(S) and 2(R) mixtures were formed in a 1: 1 ratio, as revealed by our NMR investigations and also reported previously,‘7 but the proportions of the 2(S) and 2(R) compounds were shown to depend on the pH of the solution. The structures of the ligands are depicted in Fig. 1. The analytical data for the characterization of the ligands are given in our previous paper. ’ 5
Recently, we studied the proton and zinc(I1) complexes of a large number of such compounds,” as well as the transition metal coordination of 2(R59D-galacto(l’,2’,3’,4’-tetrahydropentyl-5’-carboxy) thiazolidine-4(R)-carboxylic acid. I6 It was found that both protonation and complex-formation constants depend on the structure of the sugar moiety. In the case of the protonation constants, this is due to the rearrangement of the intramolecular hydrogen-bonding network, while the complexformation constants depend on the conformation of the hydroxy groups on the first carbon atoms of the polyol chains. The present paper reports on coordination chemical studies of the nickel(I1) and manganese(I1) complexes of a series of such compounds.
pH-metric
EXPERIMENTAL
The manganese(I1) and nickel(I1) coordination equilibria were investigated by potentiometric titration at 25.0+ O.l”C, under a nitrogen atmosphere, in aqueous solutions of constant ionic strength (0.1 mol drne3 NaClOJ. Changes in pH were followed using a G 222B Radiometer glass electrode and an OP-2801 Radelkis silver-silver chloride reference electrode. The titrations were performed with a computercontrolled on-line automatic titration apparatus constructed in our laboratory. ’ 8 For quantitative evaluation of the data, the following correlation between the experimental EMF values (E) and the
Materials
Manganese(I1) perchlorate chlorate were Fluka products. were obtained from Reanal. chlorate stock solutions were plexometrically.
and nickel(I1) perAll other reagents The metal(I1) perstandardized com-
Synthesis
In the cases of pentoses [D-lyxose (Lyxcys, VIII), D-xylose (Xylcys, II), D-arabinose (Daracys, VII),
S'
measurements
,3NH
Y R
m
zm
pm
P
Fig. 1. Schematic structures of the ligands studied.
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic acid derivatives equilibrium hydrogen ion concentrations, used : E = E,,+ 7
[H+], was
log[H+]+j,[H+]+joHIH+]-‘Kw;
(2) where ju and JOHare fitting parameters in acidic and alkaline media for the correction of experimental errors, mainly due to the liquid junction and to possible alkaline and acidic errors of the glass electrode ; K, is the autoprotolysis constant of water ( 1O- ’ 3.7‘). In the complex-formation studies, the titrations were carried out in systems with six different metal-to-ligand ratios, varying from 1 : 5 to 1:15. Calculations The species of various compositions formed in the systems studied can be characterized by the general equilibrium process [Eq. (3)] (charged omitted) : pM+qL+rHeM,L,H,.
(3)
The formation constant for this generalized reac[MPLQHII The fipqrvalues were caltion is bp4’=
[MlptLlqWl”
culated from the pH-metric titration data with the PSEQUAD computer program. I9 EPR measurements The EPR spectra were recorded in aqueous solutions of 2.85 x lop3 moldmw3 metal and 2.85 x lo-* mol dmp3 ligand concentrations in standard quartz cells with the JEOL-JES-PE spectrometer at room temperature. In work with solutions sensitive to oxygen, the cells were sealed. The microwave power was set at 15 mW, and the modulation frequency and amplitude were 100 kHz and 10 G, respectively. RESULTS AND DISCUSSION
As has already been pointed out, on the basis of the previous equilibrium study’ 5 of the zinc(I1) complex formation of the same ligands, the complexes can be divided into four groups ; this is of help towards an explanation of the stability differences in terms of the different structures of the polyhydroxy chain linked to the thiazolidine ring. In order to control the validity of this observation in other systems, we determined the formation constant of transition metal(I1) ions forming complexes of higher and lower stability than those of the zinc
2239
(II) ion. Investigation of the copper(I1) complexes was prevented by the redox reactions between the ligands and the copper(I1) ion. In accordance with the Irving-Williams complex stability series, therefore, we chose nickel(I1) and manganese(I1) ions for these investigations. The formation curves in both cases indicated that the complex-formation reactions are not complete up to pH 6 [Weitzel et al6 measured the cobalt(I1) and zinc(I1) systems only up to this point] and further complexes are formed in the interval pH 6 11. The observed formation curves reflected the simultaneous formation of mononuclear parent and mixed-ligand complexes (hydroxide ion coordination) in the systems, but further deprotonation of alcoholic hydroxy groups of the ligands could not be excluded either. Earlier studies of the coordination of thiaproline by bivalent transition metal ions have shown that amino-N and carboxyatoms are the coordination centres.1°-13 It is obvious that analogous coordination can be expected in the present case. Our equilibrium studies revealed that in slightly acidic solution nickel(I1) parent complexes with 1 : 1 and 1 : 2 compositions and manganese(I1) parent complexes with 1 : 1 compositions are formed beside mixed-ligand complexes, and in the case of manganese(I1) polynuclear complexes. The same results were also obtained for the manganese(II)- and nickel(H)-thiaproline systems.*’ The overall formation constants (log p values) of the parent and mixed-ligand complexes and the corresponding stepwise stability constants (log K, and log K,), together with some literature data, are presented in Tables 1 and 2. The equilibrium data on the nickel(I1) complexes clearly reflect the effect of the structure of the sugar moiety on the stability of the complexes. From a comparison of the structures (Fig. 1) and the stability constants, it is obvious that the conformation of the OH group on C(1’) has a great influence on the stability,, as demonstrated for the corresponding zinc(I1) complexes studied earlier. ” The similar effect is much less pronounced for the manganese(I1) complexes, which have lower stabilities. The fact that the hydroxy group on the first carbon atom of the sugar moiety plays an important role in the metal-ligand interaction indicates that, besides the carboxylate-oxygen, the amino-nitrogen atom of the ligand is also coordinated to the metal ion, forming a five-membered chelate ring. ’ 2 In Laracys the OH group on C(l’) is close to the amino group as the rotation is hindered (cis position), and this OH group can also be bound to the metal ion. In this way two five-membered chelate rings are formed, resulting in an enhancement
2240
T. GAJDA et
al.
Table 1. Formation constants (log values) for complexes (Ni”“),(aHTAC),(proton), Ligands
No.
Laracys
I
5.94t_0.03
Ramcys
V
4.29 +
Daracys
VII
0.03
3.1940.04
9.79kO.05 (3.85) 7.84kO.07 (3.55) 5.74kO.12 (2.55)
0.09 Jto.07 (4.05) -0.67kO.18 (5.24) -2.6.5+0.19 (5.36)
220 -11.07*0.28 (3.35) -12.19kO.28 (4.21)
280 220
Thiaproline, log K, = 3.93” ; log Kz = 3.28; log I(, = 1.62. On= number of experimental points.
of the stability of the complex (Fig. 2). In Daracys the C( 1’) OH group is too far from the amino group (trans position) to be bound by the metal ion (which is already chelated by the amino and carboxylato groups). Consequently, the formation of a second chelate ring in the latter system is not possibfe. This is the reason for the lowest stability of the Daracys complexes in the series of systems studied. Finally, in Ramcys the OH group on C(I’) is in a suitable position for the formation of a second chelate ring, but the OH on the neighbou~ng carbon atom gives rise to steric hindrance, resulting in the lower stability of the chelate rings than in the Laracys complex, but higher than that in the Daracys complex (Figs 3 and 4).
Table 2. notation
constants (log values) for complexes (~n2+)~~ligand)~~roton~,
No.
Ligand
I
Laracys
2.43If:0.06
n
Xylcys
2.34 f 0.05
III
Glucys
2.35 _t 0.07
IV
Galcys
2.3lkO.06
V
Ramcys
2.24kO.07
VI
Ribcys
2.17f0.08
VII
Daracys
1.92t0.07
VIII
Lyxcys
2.20 20.07
Ix
Mancys
2.12IfrO.08
Thiaproline, log K, = 1.91. ’ 3 = number of experimental points.
an
A comparison of the log K values For nickel(II)and manganese(II)-thiaproline (Tables 1 and 2) with the corresponding values for the complexes formed with Laracys and Ramcys confirms the existence of the two five-membered chelate rings discussed above. Both the log K, and log lya values for the nickeI(I1) complexes and the log K, values for the manganese(U) complexes of ligands with the OH groups on C(1‘) in the cis position are significantly larger than the corresponding values for the thiapro~ne systems, due to the double chelate effect in the former complexes. Daracys, which cannot be bound in a tridentate manner because of the trans position of its OH on C(l’), exhibited a log K, value for the manganese(I1) complex equal to
-0.32f0.10 (11.00) -0.47*0.10 (10.94)
-9.41 kO.01 (4.66) -9.31+0.16 (4.91)
-29.66k0.25 (7.25) - 29.40+ 0.25 (7.41)
-0.47f0.12 (10.93) -0.66+0.08 (10.78) -0.55fO.11 (10.96) -0.46+_0.12 (11.12) -0.59f0.15 (11.24) -0.49f0.10 (11.06) -0.55+0.12 (11.08)
- 10.21 ho.18 (4.01) - 10.3o_to.15 (4.11) - 10.53 t 0.20 (3.77) -9.85It:O.I8 (4.30) - 10.17t0.20 (4.17) -10.34Ifro.17 (3.90) - 10.43 f 0.20 (3.87)
-3O.lOf0.22 (7.61) - 30.40 f 0.22 (7.40) -31.00&0.20 (7.03) -29.90+0.2X (7.45) -30.77+0.30 (6.90) -30.60+0.25 (7.24) -30.90+0.30 (7.03)
300 240 280 250 240 270 300 240 250
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic
M = Ni,Mn
2241
acid derivatives
4
6
6
4
6
8
II 0
Fig. 2. Suggested structures of manganese(II)- and nickel(II)-Laracys and -Ramcys complexes.
that for the corresponding thiaproline complex. In the nickel(I1) complex, the log K, value was even smaller than that of the corresponding thiaproline complex, probably because of the steric effect of the polyol chain. Both manganese(I1) and nickel(I1) complexes
PH 4
I
6
IO
8
Fig. 4. Species distribution in manganese(II)-Laracys, -Ramcys and -Daracys systems as a function of pH. [Mn’+] = 1.4x 10m3 mol dm-‘, [L] = 1.4x IO-’ mol dm-‘, T = 298 K, Z = 0.1 mol drnm3 NaClO,.
Lb)
4
6
IO
8
PH (Cl
2
3
4
5
6
7
8
9
IO
I
Fig. 3. Species distribution in the nickel(II)-Laracys, -Ramcys and -Daracys systems as a function of pH. [Ni2+] = 2.00 x lop3 mol dmp3, [L] = 1.00 x 10m2 mol dm-‘, T=298K,Z=O.l moldm-3NaC10,.
have been prepared in the solid state from methanolic solution and characterized by IR spectroscopy. The IR spectra of the ligands are very similar to each other in that the v(NH*+) band lay at 3080 - ‘. The appearance of the asymmetric stretching %rations of the carboxylate groups at 160&1660 cm- ’ and that of the symmetric vibrations indicated that all of the ligands studied here have a zwitterion structure. The OH region in the IR spectra of the free ligands reflected the presence of several hydrogen-bonded alcoholic hydroxy groups. The composite structure of the OH bands pointed to the presence of an inter- and intramolecular hydrogenbonding network. In the range 640-620 cm-l, characteristic of the C-S stretching vibration, the complex formation resulted in small shifts. The IR spectra of the complexes are more simple than those of the ligands. As a consequence of com-
2242
T. GAJDA
plex formation, the v(NH2+) vibrations disappeared. The appearance of a new shoulder at 3180 cm- ‘, assigned to the NH group, and the shifts in the v,,(COO-) and v,,,(COO-) bands indicate that manganese(I1) and nickel(I1) coordinate to the carboxylic and NH group of the thiazolidine ring. The local structure was determined by means of the extended X-ray absorption fine structure (EXAFS) method. 21*22It was found that the Laracys and Ramcys complexes of both metal ions are hexa-coordinated. The Ni-0,N and Mn-0, N bond distances are 202 and 216 pm, respectively, in good agreement with those observed for hexa-coordinated nickel(I1) and manganese(I1) complexes. The average Ni . . . C, Mn . . . C, Ni . . * S and Mn. **S distances are 287, 306, 380 and 370 pm, respectively. The carbon atoms are located in the second and the sulphur atoms in the third coordination shell (Fig. 2). These results confirm that the OH groups on C( 1’) of the polyhydroxy moiety could also be coordinated to the central metal ions, forming an elongated octahedral structure. The percentage distributions of the total manganese(I1) and nickel(I1) concentrations in the different complexes are presented in Figs 3 and 4, respectively. In the manganese(I1) complexes, the formation of dimeric species was revealed by the equilibrium measurements (see Table 2 and Fig. 4). This statement was confirmed by the EPR measurements. The typical six-line pattern of manganese(I1) in the aqueous solution of pH < 5.5 containing 3 x lop3 mol dmp3 manganese(I1) and 1.5 x lop2 mol dmp3 ligand decreased and finally disappeared when the pH of the solution was increased above pH 6 (Fig. 5). This change in the EPR signal indicates that dimeric manganese(I1) complexes are formed (in accordance with the equilibrium measurements) with magnetically interacting manganese(I1) centres, resulting in a decrease in the number of unpaired electrons. This behaviour is analogous to that observed for the manganese(II)-saccharose,23 -maltitol24 and -gluconate2’ systems. The equilibrium studies indicated further deprotonation processes after coordination of the organic ligands (Tables 1 and 2 and Figs 3 and 4). These may be due to the deprotonation of the OH group on C(l’) of the polyol, or (and) to coordination of the OH- ions by the metal, i.e. in the two chelate ring-containing systems the substitution of the sugar OH group by a hydroxide ion. Carbohydrates are very weak acids ; the first acidity constants are in the range 10-‘4-10-‘2 mol dm- 3.26 In the presence of metal ions a sugar becomes more acidic. For instance, ribose protons are ordinarily neutralized at around pH - 12-14,
et al.
pH = 10.3
Fig. 5. The change of the EPR spectrum of the manganese(II)-Laracys complex with the pH of the solution. [manganese(R)] = 2.85 x lop3 mol dme3, [Laracys] = 2.85 x lo-* mol dmp3. but on chelation with copper(I1) their deprotonations shift by about 2 pH units. In our systems, the formation of new species starts at around pH 6. It is hard to believe that complexation could shift the deprotonation of sugar hydroxy groups to such a low pH. Thus, the process mentioned above is probably due to the coordination of OH- ions. In those systems which contain two five-membered chelate rings (tridentate coordination of the ligand), the OH- ion coordination results in the opening of the chelate ring containing the alcoholic OH group and one or (at higher pH) two OH- ions coordinate to the central metal ion, completing the octahedral coordination sphere. This process needs a higher hydroxide ion concentration than the formation of the mixed-ligand (OH--containing) complex in those systems which contain only one chelate ring with amine-nitrogen and carboxylate-oxygen donor atoms. In the complexes containing ligands bound in a tridentate way, the OH- concentration required by the mixed-ligand complex formation depends on the bonding energy of the polyol OH groups in the chelate. This is the reason why the pH needed for this process increases in the sequence Daracys < Ramcys < Laracys. Acknowledgement-This
of the Hungarian 84/1991).
work was supported by a grant Research Foundation (OTKA
REFERENCES 1.
M. P. Schubert, J. Biol. Gem. 1935,111,671; 1936, 114, 341; S. Ratner and H. T. Clarke, J. Am. Gem. Sot. 1937,53, 1690.
2-(Polyhydroxyalkyl)thiazolidine-4-carboxylic 2. R. G. Kollen, J. Am. Chem. Sot. 1971, 93, 6236 ; M. V. Buell and R. E. Hansen, J. Am. Chem. Sot. 1960, 82, 6042; J. Heller, Biochemistry 1968, 7, 2914. 3. R. Bognar, Z. GyGrgydeLk, K. Szilagyi and L. Somogyi, Liebigs Ann. Chem. 1970,737,68. 4. R. Bognar, L. Somogyi and Z. GyBrgydeak, Liebigs Ann. Chem. 1975,1637. 5. R. Bog&r, Z. Gyiirgydeak, L. Szilagyi, G. Horvath, C. Czira and L. Radics, Liebigs Ann. Chem. 1976, 450. 6. G. Weitzel, I. E. Engelmann and A. M. Fretzdorf, 2. Physiol. Chem. 1969,315,236. 7. C. J. Lote and J. B. Weiss, Biochem. J. 1971, 25. 8. J. B. Weiss, C. J. Lote and H. Babinski, Nature, New Biol. 1971, 234, 25. 9. M. Gosalvez, L. Pecci and C. Vivero, Biochem. Sot. Trans. 1978,6,635 ; A. Burgarolas and M. Gosalvez, Lancet 1980, 1, 68. 10. Z. X. Huang, P. M. May, D. R. Williams and M. Gosalvez, Znorg. Chim. Acta 1981, 56,41. 11. R. Radomske, T. Tatarowski, J. P. Morawiec and H. Kozlowski, Znorg. Chim. Acta 1985,106, L29; M. Nagase, Y. Yukawa, Y. Inowata and T. Takenchi, Znorg. Chim. Acta 1988, 152, 211. 12. T. Tatarowski, M. Kubiak, T. Glowiak, J. P. Morawiec, H. Kozlowski and M. Gosblvez, Znorg. Chim. Acta 1984,93, L3 and refs therein. 13. G. V. Fazakerley, G. E. Jackson and P. W. Lindner, Znorg. Nucl. Chem. 1976,38, 1397. 14. J. C. Roberts, H. T. Nagasowa, R. T. Zeerea, R. F.
15. 16. 17. 18.
19.
20.
21.
22. 23. 24. 25. 26.
acid derivatives
2243
Ficke and D. J. W. Goon, J. Med. Chem. 1987, 30, 1981. T. Gajda, L. Nagy and K. Burger, J. Chem. Sot., Dalton Trans. 1990,3 155. T. Gajda, L. Nagy, N. Rozlosnik, L. Korecz and K. Burger, J, Chem. Sot., Dalton Trans. 1992,475. J. Radomski and A. Temeriusz, Carbohydr. Res. 1989,187,223. K. Trogmayer-Malik, I. Horvath, K. Burger, G. Condos, L. Gera and M. Bartok, Znorg. Chim. Acta, 1987,138, 155. L. Zekany and I. Nagypal, in ComputationalMethods for the Determination of Stability Constants (Edited by D. Legget). Plenum Press, New York (1985). A. P. G. Kieboom, K. M. A. Bum-mans, L. K. von Leeuven and H. J. Benschop, Reel. Trans. Chim. Pays-Bas 1979,98, 393. L. Nagy, T. Gajda, N. Buzbs, S. Yamashita, M. Nomura, T. Yamaguchi and H. Wakita, J. Chem. Sot., Dalton Trans., to be published. L. Nagy, S. Yamashita, M. Nomura, T. Gajda, T. Yamaguchi and H. Wakita, Znorg. Chem., submitted. L. Nagy, T. Gajda, T. Pali and K. Burger, Znorg. Chim. Acta 1986,123,35. L. Nagy, T. Gajda, T. Pali and K. Burger, Acta Chim. Hung. 1988,125,403. M. E. Bodini, L. A. Willis, T. L. Riechel and D. T. Sawyer, Znorg. Chem. 1976, 15, 1538. K. Burger and L. Nagy, in Biocoordination Chemistry (Edited by K. Burger), Ch. VI, pp. 236-284. Ellis Horwood, Chichester, NY (1990).