EQUILIBRIUM STUDIES OF ORGANOTIN(IV) COMPLEXES OF PEPTIDES

Abdul Aziz ΑΙ-Najjar1, Mohamed R. Shehata2, Mahmoud M. A. Mohamed2 and Mohamed M. Shoukry*1

1 Department of Applied Sciences, Faculty of Technological Studies, PO Box 42325, 70654 Shuwaikh, Kuwait

2 Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt

Summary The interaction of dimethyltin(IV), diethyltin(IV) and trimethyltin(IV) with some selected peptides

was investigated at 25°C and ionic strength 0.1 Μ N a N 0 3 by a Potentiometrie technique. The peptides are bound to dialkyltin(IV) by carboxylate, deionized amide and amino groups. However, peptides are bound to tr imethyltin(IV) by the amino group. The effect of the pKa values of the peptides on the stability constants of their complexes were elucidated. The concentration distribution of the complexes in solution was evaluated.

Introduction A consideration of the published screening data for all tin derivatives has revealed that many more

diorganotin compounds exhibit anti tumor activity than the corresponding mono-, tri- and tetra-organotins, or the inorganic tin chemicals, while within the diorganotin class, the highest activity was given by the diethyltin d e r i v a t i v e s ' T h i s would suggest that the activity of the diorganotins, R 2 SnX 2 , in general is controlled by the nature of the R2Sn moiety. This is not really surprising since the Sn-X (X = halogen, O, N, S) bonds present in these compounds are susceptible to hydrolysis and so all of the diorganotin derivatives would ultimately yield analogous hydrolyzed R2Sn species, which would then be responsible for the ant i tumor activity observed. It has been demonstrated'2 ' that, for metal glycyl^lycinate complexes , the observed ant i tumor activity was not attributable to the coordinated ligand Glygly"", or to its configuration when chelating to a metal center. The coordinated ligand favors in some way the transport of the drugs into cells and that, for the diorganotins, the antitumor activity arises from R2Sn(IV) moieties released by s low hydrolysis of the complexes. Thus, for the diorganotin compounds, R 2 SnX 2 (X = halogen, N, S), it would appear that the function of the X2 moiety is to aid transport of the active R 2Sn species to the site of action, where it is released by hydrolysis. This mechanism helps to explain the variations in activity seen for a series of diorganotin derivatives in which R is kept constant and X is varied. If the compound is hydrolytically unstable, the R2Sn moiety will be released too soon, and if it is too stable, it may be released slowly and consequently less activity will be seen. Such a mechanism also adds weight to the proposit ion for the R 2SnX 2L 2 adducts, where it was shown that relatively long Sn-N bonds were a requirement for activity, and that the predissociation of the ligand, L2 may be an important feature of the mode of action of this particular class of compounds. Therefore, there is a relationship between the stability of the organotin compounds and their anti tumöTaetivity. With this in mind and in conjunction with our previous studies on organotin(IV) complexes'3 '9 ' , the present paper aims to study the dimethyltin(IV) and diethyltin(IV) complex formation equilibria with peptides of different configurations with the hope that such types of coordinating ligands might possess favorable properties, possibly as carriers in body fluids. The complex formation equilibria of trimethyltin(IV) complexes with the peptides will also be investigated to know the behavior of the tin derivative in biological fluids.

Experimental Materials and Reagents

Dimethylt in(IV) chloride (DMT), diethyltin(IV) chloride (DET) , and tr imethytin(IV) chloride (TMT) were f rom Merck Chem. Co. The ligands (L) used were glycinamide, glycylglycine, glycylalanine, glycylphenylalanine, glycylleucine, glycylvaline, glycylglutamic acid, leucylalanine, carnosine, and N-(2-acetamido)iminodiacetic acid. These materials were from Sigma Chem. Co. Sodium hydroxide stock solutions were prepared by diluting the content of BDH concentrated volumetric solutions vials. These solutions were systematically checked by titration against potassium hydrogen phthalate. The solutions were prepared in deionized water.

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Procedure and Measuring techniques The Potentiometrie titrations were performed using a Metrohm 686 titroprocessor equipped with a

665 dosimat (Switzerland-Herisau). The titroprocessor and electrode were calibrated with standard buffer solutions, prepared according to NBS specifications"0 ' . The titrations were carried out in a purified nitrogen atmosphere using a titration vessel described previously"". The temperature was maintained constant by a colora ultrathermostat.

The protonation constants of the ligands were determined by titrating 40 ml of ligand solution (2.5x10"J M). The hydrolysis constants of organotin(IV) were determined by titrating 40 ml of organotin(IV) solution (2.5x10"3 M). The formation constants of organotin(IV) complexes were determined by titrating 40 ml of solution containing the ligand (2.5x10" M) and organotin(IV) with concentrations (1.0x10 M), (5 .0x l0 3 M), (2.5x10° Μ), (1 .25xl0 3 M) and (6.25xl0"4 M). The ionic strength was adjusted to 0.1 Μ by NaN0 3 .

The equilibrium constants were evaluated from titration data, defined by Eq. (1) and Eq. (2).

pM + qL + rH - M p L q H r (1) | M p L q H r l

p p q r " i M i W W ™ ( 2 )

The formation of the hydroxo species is characterized by the equilibrium process (3) while the formation constants for these generalized species are given by Eq. (4).

P MpLqH-r

PM + <1L — MpLqH-r + rH

f^MpLq(OH)r

pM + qL + rOH MpLq(OH)r (3)

| M p L q H . r | [ H | r / W q H - r = l M , P , L ] « l

| M p L q ( O H ) r | K r

[ M [ p | L | q | O H | r

w - R ' M p L q ( O H ) r Λ ( 4 )

where M, L and Η represent organotin(IV), ligand and proton respectively. Kw is the autoprotolysis of water. The calculations were performed using the computer program" MINIQUAD-75 by means of an IBM 486 computer. The stoichiometries and stability constants of the complexes formed were determined by trying various possible composition models. The model selected gave the best statistical fit and was chemically consistent with the titration data without giving any systematic drifts in the magnitudes of various residuals, as described elsewhere"2 ' . The fitted model was tested by comparing the experimental titration data points and the theoretical curve calculated from the values of acid dissociation constant of the ligand and formation constants of the corresponding complexes. Table 1 lists the formation constants together with their standard deviations and the sum of square of residuals as was obtained from the program MINIQUAD-75. The Concentration distribution diagrams were obtained using the program SPECIES .

Results and Discussion The acid dissociation constants of the ligands were determined under the experimental conditions

Τ = 25°C and 0.1 Μ N a N 0 3 which are used for determining the stability constants of the organotin(IV) complexes. The data obtained were compared with literature values"4 '. The difference was not more than 0.1 pK unit.

The organotin(IV) cation may undergo hydrolysis, the acid-base chemistry of dimethyl and diethyltin(IV) was characterized by fitting the Potentiometrie data (mixture B) to various acid-base models. The fitted model was found to be consistent with the formation M(OH), M(OH)2, M(OH)3 , [M(OH)]2, and M2(OH)3 . This model resembles that obtained in the diethyltin(IV) system previously investigated by Arena et al(l5). The polymeric species as M2(OH)4, M3(OH)2, M4(OH)5 and M4(OH)6 reported by Natsume et. ai(l6)

were rejected. This may be explained on the premise that the concentration range of organotin(IV) is low to

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al low the formation of these polymeric species. The difference between the hydrolys is constants for the d imethyl t in( IV) ion and diethylt in(IV) ion reflects the smaller electron density caused by the less indue effect of the methyl group compared with the corresponding diethylt in(lV) ion.

T a b l e I. F o r m a t i o n C o n s t a n t s of O r g a n o t i n ( I V ) N i t r a t e C o m p l e x e s wi th s o m e Selec ted P e p t i d e s .

System ρ q r a logß b S c

D i m e t h y l t i n ( I V ) c h l o r i d e 1 0 -1 -3 .08(0.01: 3 .5E-8 1 0 -2 -8 .50(0.02; 1 0 -3 -19.05(0.02 ) 2 0 -2 -3 .33(0 .03 ' 2 0 -j -8 .16(0.05

Die thy l t i n ( IV) c h l o r i d e 1 0 -1 -3 .02(0.0 Γ 1.5E-8 1 0 -2 -8.45(0.01< 1 0 -J -19.00(0.02 ) 2 0 -2 -3.23(0.03; 2 0 -j -8 .10(0.04

T r i m e t h y l t i n ( I V ) c h l o r i d e 1 0 -1 -5 .89(0.01; 1.2E-7 1 0 -2 -16.46(0.04 ) 2 0 -1 -3.32(0.09;

D M T - g l y c i n a m i d e 0 1 1 1 1 1

1 7 .88(0.00) 4 .6E-8 D M T - g l y c i n a m i d e 0 1 1 1 1 1

0 -1

7 .97(0 .02) 3 .38(0 .01)

5 .7E-9

D E T - g l y c i n a m i d e 1 1 1 1

0 7.74(0.03) 4 .3E-9 D E T - g l y c i n a m i d e 1 1 1 1 -1 3 .09(0.02)

T M T - g l y c i n a m i d e 1 1 1 1

0 4.60(0 .04) 2 .3E-9 T M T - g l y c i n a m i d e 1 1 1 1 -1 -2 .85(0.03)

DMT-g lycy lg lyc ine 0 1 1 7 .94(0.01) 2 .5E-8 0 1 2 10.80(0.01) 1 1 0 8.18 ( .07) 8 .3E-7 1 1 1 11.67(.08)

2 .99( .07) 1 1 -1 11.67(.08) 2 .99( .07)

DET-g lycy lg lyc ine 1 1 1 1

0 8.11 ( .04) 9 .7E-8 DET-g lycy lg lyc ine 1 1 1 1 1 11.31 ( .09) 1 1 -1 2 .97( .05)

5 .13( .07) T M T - g l y c y l g l y c i n e

1

0 2.97( .05) 5 .13( .07) 5 .4E-7 T M T - g l y c y l g l y c i n e

1 1

-1 11.11 ( .06) -2 .65( .08)

D M T - g l y c y l a l a n i n e 0 1 0 1

1 8 .21(0.01) 4 .4E-8 D M T - g l y c y l a l a n i n e 0 1 0 1 2 11.01(0.02) 1 1 1 1 1 1

0 1

-1

8 .19( .07) 11.73(.10) 3 .23( .07)

5 .7E-7

D E T - g l y c y l a l a n i n e 1 1 1 1 1 1

0 8.06( .07) 9 .6E-8 D E T - g l y c y l a l a n i n e 1 1 1 1 1 1

1 -1

11.64(.07) 2 .61( . l 1)

T M T - g l y c y l a l a n i n e 1 1 1 1

0 1

5.10( .09) 11.14(.07)

4 .4E-7

1 1 D M T - g l y c y l p h e n y l a l a n i n e 0 1

-1 1

-2.11 ( .05) 8 .24(0.01) 1.1 E-7

1 1 D M T - g l y c y l p h e n y l a l a n i n e 0 1

2 11.71(0.02) 1 1 1 1

0 1

8 .34(0.04) 12.42(0.03)

1.0E-7

1 1 -1 2 .30(0 .05) D E T - g l y c y l p h e n y l a l a n i n e 1 1

1 1

0 8.28(0.02) 3 .2E-8 D E T - g l y c y l p h e n y l a l a n i n e 1 1

1 1 1

-1 12.27(0.02)

1.68(0.09) T M T - g l y c y l p h e n y l a l a n i n e 1 1

1

0 5.25(0.08) 1.4E-7 T M T - g l y c y l p h e n y l a l a n i n e 1 1

1 1

-1 10.90(0.07) -2 .45(0 .08)

DMT-g lycy l l euc ine 0 1 1 7 .96(0.01) 2 .0E-7 DMT-g lycy l l euc ine 0 1 2 11.28(0.02)

1 1 1 1 1 1

0 1

-1

8 .25(0.06) 12.36(0.05)

2 .55(0 .06)

2 .6E-7

D E T - g l y c y l l e u c i n e 1 1

1 1

0 8.15( .06) 4 .6E-6 D E T - g l y c y l l e u c i n e 1 1

1 1 1

-1 11.78(.14) 2 .38( .14)

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Vol. 22, No. 4, 1999 Equilibrium Studies of Organotin(IV) Complexes of Peptides

TMT-glycyl leucine

DMT-glycylval ine

DET-glycylval ine

TMT-glycylval ine

DMT-glycylglutamic acid

DET-glycylglutamic acid

TMT-glycylg lutamic acid

DMT-leucylalanine

DET-leucylalanine

TMT-Ieucylalanine

DMT-carnosine

DET-carnosine

TMT-carnos ine

DMT-N-(2-acetamido) imino-diacetic acid

DET-N-(2-acetamido)imino-diacetic acid TMT-N-(2-acetam ido)im ino-

tic acid giacet ic;

1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 1 1 1 0 0 1 1 1 1 I 1 1 1 1 0 0 0 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 1

0 1

-1 1 2 0 1

-1 0 1

-1 0 ]

-1 1 2 3 0

-1 0

-1 0 1

-1 1 2 0 1

-1 0 1

-1 0 1

-1 1 2 3 0 1

-1 0 1

-1 0 1

-1 1 2 0

-1 0

-1 0

5.08(.08) 10.S8C.08) -2.34(.06) 7.99(0.01)

11.34(0.02) 8.18(0.05)

12.37(0.04) 2.53(0.05) 8.04(0.03)

12.00(0.03) 2.17(0.04) 5.15(0.08)

10.50(0.10) -2.45(0.08) 8.59(0.02)

12.95(0.04) 15.08(0.07) 8.46(0.02) 4.03(0.01) 8.42(0.05)

3.32(0.05) 5.48(0.03)

11.29(0.02) -2.62(0.02) 8.05(0.01)

10.95(0.01) 8.21(0.02)

11.52(0.03) 3.30(0.02) 7.85(0.02)

11.24(0.02) 2.60(0.02) 5.44(0.06)

10.97(0.06) -2.02(0.06) 9.03(0.01)

15.61(0.02) 17.70(0.04) 11.46(0.01) 15.74(0.02) 3.22(0.02) 10.34(0.03) 15.45(0.02) 3.55(0.05) 8.92(0.08)

15.33(0.06) 1.56(0.08) 6.82(0.01) 9.16(0.02) 7.44(0.05) 2.10(0.09) 7.14(0.03) 1.74(0.07) 4.01(0.07)

-2.10(0.03)

2.4E-6

1.5E-7

5.0E-7

6.5E-8

6.2E-7

6.0E-7

1.9E-8

6.0E-7

1.1E-7

8.7E-8

3.6E-8

2.7E-8

2.0E-7

1.2E-7

9.5E-9

1.2E-8

3.0E-7

5.0E-8

5.3E-7

1.5E-7

7.1E-8

p , q a n d r a r e t h e s t o i c h i o m e t r i c c o e f f i c i e n t c o r r e s p o n d i n g t o o r g a n o t i n ( I V ) , p e p t i d e a n d H + r e s p e c t i v e l y . b S t a n d a r d d e v i a t i o n s a re g i v e n in p a r e n t h e s e s . c S u m o f s q u a r e o f r e s i d u a l s .

The hydrolysis of trimethyltin(IV) ion was previously investigated"7 '81 and the results were contradictory. The acid-base chemistry of trimethyltin(IV) has been investigated. The fitted model was found to be consistent with the formation of M(OH), M(OH)2 and M2(OH) species. This model is in agreement with the recent literature data"8 ' .

The Potentiometrie titration curves of the glycylglycine in the presence and absence of equimolar solution of dimethylt in(IV) or trimethyltin(IV), taken as a representative example, are given in Figure 1. The complex titration curves start at pH = 2.9 for DMT-Glygly and 3.0 for TMT-Glyg ly and is significantly lower than the ligand curve. This may be conceived as a visual indication of complex formation through release of hydrogen ions.

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Moles of base added per moles of ligand

Fig. I. Potentiometrie titration curves of glycylglycine

and its complexes withTMT and DMT.

T h e resul ts of d io rgano t in ( IV) c o m p l e x e s show the fo rmat ion of the c o m p l e x e s ( R 2 S n ) L H , ( R 2 S n ) L and (R 2 Sn)LH. i . C o n s e q u e n t l y the c o m p l e x fo rma t ion may be exp la ined by the f o l l o w i n g equi l ibr ia :

R 2 S n 2 + + H L ^ — ( R 2 S n ) L H 2 + (5)

R 2 S n 2 + + L — ( R 2 S n ) L / (6)

K a

( R 2 S n ) L + — | ( R 2 S n ) L H . , | + H + (7)

T h e p K a of M L H complex (pK a = logßMLH - logßML)"9 ' is 3 .49 for D M T - g l y c y l g l y c i n e c o m p l e x . Th i s va lue is in fa i r a g r e e m e n t with p K a g lycy lg lyc ine carboxyl ic g r o u p (2 .86) . T h i s m a y indica te tha t the a m i n o g r o u p o f g lycy lg lyc ine is the b i n d i n g site in M L H complex . It is k n o w n tha t the pep t ide a m i d e g r o u p is very d i f f i cu l t to ionize (pk a> 13). H o w e v e r in presence of s o m e metal ions and t h r o u g h c o m p l e x fo rmat ion , the a m i d e p ro ton is easi ly i on ized l 9 .The p K a of the ionized amide g r o u p of the pep t ide c o m p l e x ( p K a = logßviL - logßMLH ) is ca lcula ted . The va lues are g iven in Tab le 2. T h e s l ight difference in the s ide cha in of the pept ides has an e f fec t on the ionizat ion of the a m i d e g roup . T h e g l y c i n a m i d e c o m p l e x has t he sma l l e s t p K a va lue and g lycy lpheny la lan ine c o m p l e x has the h ighes t pK a va lue . T h i s is exp la ined based o n the a s s u m p t i o n tha t the m o r e bu lky subs t i tu ted g r o u p on the pep t ide m a y serve to h inde r the ioniza t ion of the a m i d e g r o u p . T h e d ime thy l t i n ( lV) c o m p l e x e s are more s table than the co r r e spond ing d ie thy l t in ( IV) c o m p l e x e s . T h i s m a y be d u e to the s ter ic interact ion be tween the bu lky ethyl g r o u p and the pep t ide l igand.

T h e par t ic ipa t ion of the te rmina l a m i n o group , carboxylate o x y g e n and a m i d e n i t rogen ; and based on p r e v i o u s structural s tud ies of d ia lky l t in ( IV) complexes wi th pept ides as g lycy lg lyc ine , the c o m p l e x is a s s u m e d to h a v e the fo l l owing structure:

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Ο II

/ c \ ο c h 2

R I 2+ I

- T V h 2 n c h 2

( R 2 S n ) L H . ,

Further structural investigation of the complexes in solution may provide a solid evidence for the structural configuration of the complexes.

T a b l e II. p K a of ion ized a m i d e g r o u p in d i a l k y l t i n ( I V ) - p e p t i d e c o m p l e x e s

Pept ide pKa of ( C H 3 ) 2 S n ( I V ) C o m p l e x p K a of ( C z H . ^ S n Q V ) C o m p l e x

G l y c i n a m i d e 4 . 5 9 4 . 6 5 G l y c y l g l y c i n e 5 .19 5 . 1 4 G l y c y l a l a n i n e 4 .96 5 .45 G l y c y l p h e n y l a l a n i n e 6 . 0 4 6 . 6 0 G l y c y l l e u c i n e 5 . 7 0 5 .77 G l y c y l v a l i n e 5 .56 5 .97 G l y c y l g l u t a m i c ac id 4 .43 5 . 1 0 L e u c y l a l a n i n e 4 .91 5 .25 C a r n o s i n e 5 . 3 4 5 . 4 0 N- (2 -ace tam ido)im ino- 5 .25 5 . 5 0 d iacet ic ac id

The Potentiometrie titration curves of trimethyltin(IV)-peptide complexes are lower than the corresponding peptide titration curve, Figure 1. This reveals that the complex formation occurs through release of hydrogen ion. All peptides except glycinamide, may coordinate either by amino group nitrogen or carboxylate oxygen atom. The stability constant values of glycinamide complex are in fair agreement with stability constant values of other peptides. This indicate that the peptides are coordinating by the amino group. The stability constant values of trimethyltin(IV) complexes of coefficients 110 (Me3SnL) are less than those corresponding to dimethyltin(IV) and diethyltin(IV) complexes (table I). This reveals that the peptides are bound to tin(lV) as monodentate in case of trimethyltin(IV) complexes and as bidentate in case of dialkyltin(lV) complexes.

Earlier structural studies by means of X-ray, neutron and electron diffraction studies'20', and Mössbauer spectroscopy'2" revealed that the trimethyltin(IV) complexes have a trigonal bipyrimidal configuration with three methyl groups in equatorial and two water molecules in axial positions. Complex formation would then involve ligand substitution of one water molecule. The location of the two trans water molecules prevents the chelation of the ligands as bidentates. Chelation of ligand by substitution of two trans water molecules will result in a strained complex; a similar behaviour was found for (CH3)3Pb(II) complexes'22'. The pK.ai and pKa2 values of water molecules coordinated to (CH3)3Sn(IV) are 5.89 and 10.57 respectively. The first coordinated water molecule is more acidic than the second water molecule, located in trans position, a similar behaviour was found for Pd(picolylamine)(H20)2

2+ complex'23'. This may be explained on the premise that the water molecule is attracted to the tin(IV) center by the ion-dipole interaction. The bond length between Sn(IV) and H20 located at the trans position of OH" should be largely elongated because of the significant increase of the electron density on the central Sn(IV) atom. The pKa values of coordinated water molecule in (CH3):sSn(peptide) complex (pKa = logßno - logßn.i) are lower than pKa2 of (CH3)3Sn(H20)2+ species. This indicates that the elongation of Sn(IV)-H20 bond caused by the coordination of peptide may not be as large as that caused by the coordination of OH".

It is well-known that for metal complexes with a series of structurally-related ligands, a linear relationship holds between the stability constant of the complex and acid dissociation constant of the ligand.

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The importance of these plots is that they afford a means of estimating the stabilities of complexes that have not yet been studied. Figures (2) demonstrate such a relationship for dimethyl-, diethyl- and trimethyl-complexes.

L o g ß , 10

Y=0.73X+2.16 (R=0.95,S=0.12)

6.5

Y=0.82X-1.48 (R=0.97,S=0.12)

T 7.0

Τ 7.5

T 8.0

pK»

DMT-Peptide DET-Peptide-TMT-Peptide

T 8.5

Fig. 2. Correlation of formation constant of organotin(IV)- peptide dissociation constant of the peptide ( R anfd S are the coefficients and the standard errors,

pH Fig. (3) Concentration distribution of various species as a function of pH in the DMT-Glycylglycine

system. Cine system

Estimation of the concentration distribution of various species in solution provides a useful picture of organotin(IV) binding in the biological system. Concentration distribution of various species as a function

DMT D M T - ( O H ) 3

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Vol. 22, No. 4, 1999 Equilibrium Studies of Organotin(IV) Complexes of Peptides

of pH in the equimolar solution mixture of glycylglycine and organotin (IV) ( 2 . 5 x 1 0 M ) are given in Figures (3,4). The concentration of the formed complex increases with increasing pH, thus making the complex formation more favorable in the physiological pH range. The (CH3)2Sn(Glygly) complex reaches the maximum concentration of 8% at pH = 4.3. However, the (CH3)2Sn(Glygly)H-i species predominates with a maximum concentration of 20% at pH 7.0. The trimethyltin(IV) complexes are existing in lower concentration and at relatively high pH. The (CH3)3Sn(Glygly) complex reaches a limiting value of 10% at pH = 7.0 and the corresponding deionized form reaches the maximum concentration of 4% at pH = 9.0.

5Λ £

p H Fig. (4) Concentration distribution of various species as a function of pH in the TMT-Glycylglycine

system

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Lamartina, J. Inorg. Biochem., 25, 229 (1985). 3. M. Gielen, Coord. Chem. Rev., 151, 41 (1996). 4. V. G. Kumar Das (Ed.) "Main Group Elements and Their Compounds-Perspectives in

Materials Science, Chemistry and Biology", Springer-Verlag/Narosa Publishing House (1996). 5. N. O. Hadjiliadis (Ed.), "Cytotoxic Mutagenic and Carcinogenic Potential of Heavy Metals

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Received: October 6, 1998 - Accepted: October 30, 1998 -Accepted in revised camera-ready format: March 8, 1999

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