Complexes of hydroxamates VI: Binary and ternary complexes involved in the palladium(II) monohydroxamic acids—glycylglycine systems

m r

. . . .

Complexes of Hydroxamates VI: Binary and Ternary Complexes Involved in the Palladium(II) Monohydroxamic Acids- Glycylglycine Systems Hayat M. Marafie, Nadia M. Shuaib, Roghaieh Ghodsian, and Mohamed S. EI-Ezaby Chemistry Department~ Faculty o f Science, Kuwait University, Safat, Kuwait

ABSTRACT Binary complexes of VL-serine-, L-histidine-, glycine-, aceto-, and methionine- hydroxamic acids as ,#ell as glycylglycine (Glygly) with PdfIr) have been studied in solution. Only Pd(II) complexes with met.~ionine hydroxamic (MX) acid were successfully studied potentiometrically because the other hydrox~.mic acids formed instant black precipitates. The potentiometric data for Pd(II)-MX were assessed by the SUPERQUAD program. The formation constants of only two species were determined in a limited pH range. The ternary complexes o f Pd(II) with Glygly and MX were also studied, in which only two species were formed. It has been possible to determine only one species for the binary interaction of Pd(II) with Glygly, which is not usually simple to obtain in the absence of MX. The differential pulse polarographic te.chldque was applied to the binary and ternary complexes involved in the system of Pd(II)-MX-Glygly in a wider pH range tha,~ that in the potentiometric study.

INTRODUCTION t I y d r o x a m i c acids havv b e e n shown to have m a n y biologic activities [I]. S o m e o f t h e m inhibit proteolytic e n z y m e s , sc-,."n~act as sequestering agents in metal overload, and s o m e act as agents for lowerit.,~, b l o o d a m m o n i a level in s o m e m a m m a l s [2]. It has b e e n also r e p o r t e d that low m o l e c u l a r weight m o n o h y d r o x a m i c acids w e r e used Address reprint requests t¢: Professor M. S. EI-Ezaby and Dr. H. M. Marafie, University of Kuwait, P.O. Box 5969, ! 3060 Safat, Kuwait. Part V of ",his series appeared in J. im,rg. Biochem. 33, 161 (1988).

Journal of Inorganic Biochemistry 38, 27-36 (1990)

27 lcJ=)0Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, NY, NY 10010 0162-0134/90/$3.50

28

H . M . M a r a f i e et ai.

therapeutically as urease inhibitors in hepatic c o m a [3]. It has b e e n suggested that their m o d e o f action involves binary and/or ternary metal c o m p l e x formation. Binary c o m p l e x e s o f these ligands have attracted attention for the last two decades. H o w e v e r , studies o f the t e r n a r y metal c o m p l e x e s involving one o r m o r e hydroxamates with other biologic m o l e c u l e s are scarce [3]. F u r t h e r m o r e , their interactions with e n z y m e s and proteins have not b e e n studied. The aim o f this w o r k is to study the possible interaction o f s o m e Pd(II) hydroxamat¢ c o m p l e x e s with g l y c y l g l y c i n e (Glygly), a m o d e l for the interaction o f metal hydroxamates with protein.

EXPERIMENTAL Materials T h e Iigands DL-methionine- ( M X ) , DL-serine- (SX), L-histidine- (HX), glycine- (GX), and aceto- (AX) h y d r o x a m i c acids ( > 9 8 % , S i g m a , St. Louis, M O ) were used without further purification. The concentrations o f the stock solutions o f all hydroxamic acids w e r e 0.1 M in 0 . 1 - M HCI with the exception o f H X , w h i c h was in 0 . 2 - M HCI. T h e concentration o f the stock solution o f g l y c y l g l y c i n e ( > 9 9 % , B D H ) was 0.1 M in 0 . 1 - M HCI. T h e ligands w e r e kept in ~ ¢ool, d a r k place. A stock solution o f Pd(II) chloride was m a d e acidic by adding HC! o f at least five times its concentration. T h e concentration was checked by gravirnetric m e t h o d s as Pd (dimethylglyoxime).

Measurements T h e pH titrations w e r e carried out using an O r i o n R e s e a r c h Ionalyzer m o d e l 901 in the pH m o d e , e q u i p p e d with Orion glass (91-01) and calomel (90-05-00) electrodes. T h e ion m e t e r was calibrated before use with R a d i o m e t e r buffers o f pH 4 . 0 1 0 and 6 . 8 7 0 at 2 5 ° C . T h e autoburette used was R a d i o m e t e r A B U I 2 accurate to :L-0.001 m L . All titrations w e r e carried out in a thermostated cell at 25 ° -4-0.1°C. Purified nitrogen saturated with humidity was p u r g e d through the solutions in the cell during the titrations. T h e ionic strength was kept constant at 0.15 M. T h e titrant was 0 . 1 0 ? - M K O H (carbonate free) in 0 . 1 5 - M KCI. T h e titration was followed in the pH range o f 2.0 to 8.0 for the system of ( M X : G l y g l y : P d ) , having the ratios o f > 2 : > 2 : 1 (TMx:Tc;lygty:Tpd), w h e r e T is the initial concentration. Differential pulse p o l a r o g r a m s (DPPs) w e r e obtained using M e t r o h m P l a r e c o r d E 506 provided with a t h r e e - e l e c t r o d e a r r a n g e m e n t : d r o p p i n g m e r c u r y indicator electrode, saturated calomel r e f e r e n c e e l e c t r o d e , and c o u n t e r platinum-wire electrode. The settings o f the polarograph w e r e as follows: the voltage range was either 0 . 0 to - 1 . 5 or - 0 . 6 to - 1 . 6 volt, pulse amplitude was --40 m V , the droptime was 1 s, the r e c o r d e r s p e e d was 2 m m / s . T h e p H - r a n g e u s e d was 2.4 to 10.0. T h e solution was d e o x y g e n a t e d by passing pure humidified nitrogen through it b e f o r e taking the p o l a r o g r a m s . T h e ionic strength was 0 . 1 5 - M C I - . T h e concentration o f Pd 2+ was either 5.0 x 10 -4 M or 1.0 x 1 0 - : M and the concentration o f M X was at least 10 times that o f the metal ions. The p o l a r o g r a m s w e r e taken at r o o m t e m p e r a t u r e (23 ° ± IoC). The absorption spectra w e r e taken using a H e w l e t t Packard photodiode array spect r o p h o t o m e t e r in the wavelength range o f 200 to 300 n m and pH range o f 2.9 to 3.5. T h e ligand concentrations w e r e in the range o f 1 to 2 × 10 -3 M and that o f PdCl2 was fixed at I × 10 -4 M.

PALLADIUM(II) MONOHYDROXAMIC ACIDS-GLYCYLGLYCINE

29

RESULTS

Potentiometric and Spectral Study Binary systems. The addition of SX, HX, GX, AX, or Glygly (Figure 1) to Pd(II) chloride solution resulted in the formation o f black precipitates at pH ~-. 3.0; with MX, a pale yellow precipitate was observed. The addition o f KCI solution to the latter precipitate was found to dissolve it instantaneously. In order to successfully perform the pH metric titration, Pd(II) chloride was added to the KCI ionic strength adjuster prior to the addition of the required M X concentration, which was always twice that of the Pd(II) chloride. No sign of precipitation was shown in the pH range 2.00 to 7.00. However, the precipitation o f a pale yellow product occurred at pHs _> 7.0.

Ternary systems. The addition of Pd(II) chloride to the solution mixture of Glygly and MX produced a pale yellow precipitate, which again was dissolved by the addition o f the KCI ionic strength adjuster. The precipitate formed by the addition of MX solution to the Pd(II) chloride solution was not dissolved by the addition of the required amount of Glygly. However, by adding the KCI ionic strength adjuster, dissolution occurred and a clear solution was obtained for thc titratit~n. It seems that the order o f addition is important when a successful pH metric titration of the ternary system is to be studied. The titration was followed in the pH range of 2.0 to 8.0 for systems o f TMX:TGlysly:Tpd having the ratios > 2 : > 2 : 1 (TMx, TOlygly and Tpd are the initial concentrations). At pH 8.0 a precipitate appeared which was dissolved gradually until the pH was approximately 11.0. Figure 2 shows the absorption spectra o f the Pd(II)MX-Glygly system. The addition of M X to the Pd(II) causes a hypsochromic shift with respect to that of Pd(II), with a considerable increase in the intensity. Further FIGURE 1. R~

Structure of some hydroxamic acids and glycylglycine. /NHz

R =

H/C~c--o

H

. glycine--

-~- C H = O H I

--- C H z -

H'~N~oH

, serine-C , i

C I

=

H N~.c.~N H

histidine-

H

= CH=CHz--S--CH s , methionine--

Aminohydroxamic

H~

H f ~.C..~- 0

H/C

H

I

I H

"~OH

Acetohydroxamie

aeid

acid

H OOC-- CH=--N--C-II O

CHz-- NH z

Glyeylglycine

30

H . M . Marafie et al.

3-20

pH -4

(I)

2.90

,Tpd-

1 x 10

(2)

3-53

,TMx=2X = 20

Q U

(3)

¢1 II ,Q 1 . 6 0

3-53

M=

Tpd

, TMX = t X 163M

=TGlygly

$,4

163

M

= 10

Tpd

o

~..

,~=

2,3

10 mm

1

0-00'-~200

250

F I G U R E 2.

Absorption spectra o f the Pd(II)-MX-Glygly system at equilibrium.

F I G U R E 3.

The DPP of PdCI2 in the pH range of 2.4 to 5.5.

Wavelength

300

(nm)

24 16 8

<¢ 0 -

"o

~ 8

-16 4 ) L_ t._

-3

Tpd -

--24

-

--32

-

--40

i

--I-5

= 1.0

x 10

.,u : O - 1 5 M

CI

pH

I

--I-2

t. 2.

2.3~ 3.50

3.

5.54 m,

! --0'9

Potentiol

I --0.6

(V)

1I --0'3

0

P A L L A D I U M ( ! I ) M O N O H Y D R O X A M I C ACIDS-~,L'~ C V L G I , Y C ! N E

3_11

--2

TMX=

1.0 x 1 0

Tpd

= 5.0

F

=

--4

x I0

o.I~

M

~1

c~

pH

pH

! = 2-48

4(

M

!5 =

4"59

2=3-01

6 =5"15

3 = 3.55 4=4-59

7

=

6"54

3 3 -I:

24

~s.Na=

16

a0

o

I-4

8

N 4.a

gl

O

O 1,4

r~

7

-8 -16 '5

-24 I -

1.2

I

I - o. s

- o

Potential F I G U R E 4.

' - o.3

.s

o

(V)

The DPP of Pd(II)-MX system in the pH range 2.5 to 6.5.

addition of Glygly to the Pd(Ir)-MX solution caused a slight bathochrornic shift with respect to the binary system, with an increase in the absorption b a n d in the 210 to 2 2 0 - n m wavelength range. Polarographie

Study

Differential pulse p o l a r o g r a m s o f the PdCI2 solution w e r e taken in the pH range o f 2.4 to 7.0 (Figure 3). T h e potential at m a x i m u m differential" farada/c currer~ (~i), E m ~ , was found at 324 inV. A l t h o u g h the m a g n i t u d e o f the pulse is negative, the 6i is anodic rather t h a n cathodic. It is w o r t h mentioning that at l o w e r p H s a slight black precipitate a p p e a r e d o n the surface o f the a c c u m u l a t e d m e r c u r y droplets while

32

W. M. Murafie

et al.

the polarograms were taken in the potential range of 0.0 to - 1.5 V. The differential faradaic current and the maximum potential are nearly independent of pH in the range 2.4 to 7.0 (Figure 3). The DPP of the Pd(II)-MX binary system is quite different, although MX has no DPP under the experimental conditions used in this work (Figure 4). Several DPP peaks appear as a function o f pH in the potential range of 0.0 to -1.5 V. At pHs less than 3.0, two overlapped pea’ks appeared in the polarogram at potentials greater than -0.60 V. On the other hand, NO separated peaks appeared at pHs greater -0.60 with ca*hodic 6i, and the other at than ~3.0, one at potentials @CStCi dhIi At pHs greater than ~3.5, the httei potentials less than -0.60. peak (C-O.60 V) shows both anodic and cathodic 6i. Furthermore, the peak at voltages greater than. -0.60 V gradually disappeared as the pH was increased. The peak at potentials less than -0.60 V shifted to more negative potentials (from -0.984 to -1.070 V) as the pH was increased (from -6.0 to lO.O), with an increase in 6i up to pH 6.0. However Si becomes constant above pH 6. DISCUSSION Table 1 depicts the stoichiometries and the apparent formation constants (fiapp) of the binary and the ternary complex species involved in the Pd(II)-MX-Glygly-H system, calculated by using the SUPERQUAD program [6). Under the experimental conditions of this work (I = 0.15-M Cl-), it is assumed that the metal species is the tetrachloro complex of Pd(II), PdCla-. The true formation constants CBcorr)for the following equilibrium reaction: IMX + pGlygly + yPd*+ + rH+ * MXrGlygly,Pd,H, have been corrected (Table 2). taking into consideration the chloro-complex equilibria of Pd(II) in solution. Analogous with Pd(II)-MX complexes [7], it is expected that MX may also form six-membered chelate ring complexes with Pd(II), in which the amino nitrogen and the ether sulfur are the ligating sites. In the case of the 1: 1:0 species (MX:Pd:H), Pd(II) is surrounded by two Cl- ions in addition to the MX species. Although there is a possibility that Pd(II) coordinates through the amino nitrogen and the hydroxamate groupings to give a five-membered chelate ring, the softness of Pd(I1) favors more the sulfirr moiety. However, in the case of the 2:1:0 species (MX:Pd:H), Pd(II) is surroiclnded by two six-membered MX rings. HONH

o=

e

CIJB .

NH2

’

yN\

/

s-T2 CH2

H2C \

,‘2,

&

H&-S I CH3

IG( y=o

HkOH

PALLADIUM(II) MONOHYDROXAMIC ACIDS-GLYCYLGLYCINE

°~

O

9 C

O

0

°~

0

~L o

o

~d

~

0

0

0

~

0

u~ e.. o~

t-

I.,

i

'

a.a

°

e-*

3,3

34

W. M. Marafie

TABLE

et at.

2. Corrected Values of the Formation Constants of the Binary and Ternary Complexes of Pd(Il) with MX and GIygIy at I = 0.15 = M (Cl-)

Reaction

loI3 P,,,”

Pd2+ tMX+2ClT= PdClzMX Pd*+ +2MX = Pd(MX)z Pd* + + Glygly + 2Cl - = PdC12Glygly Pd* + + MX + Glygty = PdMXGlygly Pd2 + + MX + Giygly = PdMXGlyglyH

- < 24.34b < 34.44c - ~20.27~ . ~32.17~ < 35.4BC

a Al-Salem b PdCL2a

et al. [5]. + MX or Glygly

“2

PdCbMX

11

Pdz+ + 4Cl-

+ MX or Glygly

(or Glygly) K 11

&orr = PdCl*MX

(or Glygly)

+ 2 Cl-

&,=&l.I3l’K-I c PdCLz-

@npP + MX + Glygly (or MX) f H * PdCbMX

P.! IL Pd* + + 4C1- + MX + Glygly

(or MX)

Glygiy (or MX)H K’ II

&JhT + PdClpSlygly

(or MX) + 4 Cl -

Pcom=B.w-P4-K’-’

formation is the true formation constant, PEWis the SUPERQUAD where &, formation constant of PdCb2and K and K’ are the formation constants of: Pdz+ -t4 Cl- +MX Pd2’ -t-4Clrespectively

(or Glygly)

+ MX or Glygly

=

PdC12MX (or Glygly)

+2Cl-

constant,

& is the

and

(or MX) = PdC12Glygly (or MX) -k?Cl-,

_

“he potentiometric work given in Table 1 shows that only one unprotonated binary [Glygly:Pd(II):H] 1: 1 :O complex species exists in solution in the pH range of 1.9 to 4.3. The formation constant (log fiapp) was calculated from the ternary MX-GlyglyPd(II) system, since a slight black precipitate was formed at a pH of -3.6 in the binary Glygly-Pd(IX) system, which may be attributed to the reduction of Pd(IE). The preserlce of a deprotonated complex species in which the proton is removed from the peptidic linkage was not confirmed, as -was previously reported [S] in the pH range of 3.0 to 4.0. Table 1 shows that only two ternary complex species were obtained, namely 1: 1:l:O and 1: 1: 1: 1 (MX:Glygly :Pd(II):H). In both cases, Glygly ligates to Pd(I1) through the terminal NH2 and COOH groups to form an eight-membered chelate ring or through the terminal NH2 and the peptidic oxygen to form a five-membared ring, whereas MX forms a six-membered chelate ring with Pd(I1) as mentioned before. Moreover, in the protonated ternary species the proton may be located on the MX moiety. The formation of both binary and ternary complex species has been confirmed from the occurrence of spectral hypsochromic shifts with respect to that of Pd(I1) species (Figure 2). The appearance of the black precipitate on the accumulated mercury droplets in the potential range of 0.0 to -1.5 V in the DPP of PdCli- solution may be explained if the cell potential is calculated for the following reaction: PdCl$-

+ 2Hg *Hg;+

+Pd +4Cl-

PALLADIUM(H)

MONOHYDROXAMIC

ACIDS-GLYCYLGLYCINE

35

-ioa

- 2oa

>

E E

w

-4oc

-5oc I

2

3

4

5

6

7

PH

FIGURE 5.

The variation of E,,,

with pH for the Pd(Ii)-MX

and Pd(II)-MX-Gjygly

systems.

Although the differential faradaic current and the maximum potential in the case of Pd(I1) are nearly independent of the pH {Figure 3) and MX has no DPP, that of the binary MX-Pd(II) system is pH dependent (Figure 4). The differential pulse polarograms shown in Figure 4 may be attributed to the various species of binary complexes with MX. The two overlapped peaks at pHs 2.48 and 3.01 may be due to the 1: 1:O and 2: 1:O (MX:Pd:H) species detected by the potentiometric titration in the same pH range. The third peak, which started to appear at more negative potentials, may be attributed to the formation of further deproronated or hydroxide species rhat could not be detected by potentiometric calculations. Furthermore, we have not been able to determine other complex species in the pH range of 4.0 to 10.0 using potentiometric techniques, since the ligand concentration was not greater than five times that of Pd(II). In the DPP technique, vie have used a concentration of ligand at least 10 times that of the metal ions.

36

N. M. Matqfie

et al.

The above mentioned results, shown in Figure 4, could be rationalized on the basis hydrolyzed species may be formed at higher pHs (3.55 to 6.54) and are likely monomeric, since changing the pH of the solution from a basic medium back to an acidic medium produced the same DPP results that were initially found in the acidic medium. Another explanation is based on the deprotonation of the N-H proton of the hydroxamic acid, which is not usually dissociating in the absence 0: metal ions. In both types of complexes, Pd(II) is pentacoordinated, the fifth ligating group being either a hydroxy ion or the nitrogen of the hydroxamic acid group. Actually, what is surprising is the appearance of anodic as well as cathodic peaks in a manner that is similar in part to the DPP of PdC12 solution. The addition of Glygly to a solution of MX-Pd(I1) usually produced the same DPP pattern as the MX-Pd(I1) system except that more negative shifts were observed with respect to those of the MX-Pd(II). Figure 5 shows the variation of b for the binary and ternary systems with PH. This emphasizes the enhancement effect of ternary complex formation on the DPP hax.

that several

The authors would like to thank Kuwait University _for the provision No. SC036 and KFAS for resenrch grant No. 86-07-09.

of restxzxh gmnt

REFERENCES 1. H. Kehl, Ed.,

Chemistry

and Biology of Hydnxamic

Acids, Ch. 1, S. Karger. New

York, 1982. 2. D. A. Brown, M. V. Chidambaram,

S. J. Clarke, and D. M. McAleese,

Broinorg. Chem.

9, 255 (and the references therein) (1978). 3. t’l. N. Fishbem, C. L. Streeter, and J. E. Daly, J. Phirrmacol Exp. Ther. 186, 173 (1973). 4. L. G. Sillen and A, E. Mar-tell, Stability Constants of the Metal-Ion Complexes. Special publication

5. N. A. Al-Salem,

No. 25, The Chemical Society, London (1971). M. S. El-Ezaby, H. M. Maratie, and H. M. Abu Soud, Polyhedwn

633 (1986).

6. P. Gans, A. Sabatini, and A. Vacca, J. Chem. Sot. Dalton mans. 1195 (1985). 7. H. M. Marafie, N. M. Shuaib, and M. S. El-Ezaby, Polyhedron 6, 1391 (1987). 8. E. W. Wilson, Jr., and R. B. Martin, Inorg. :?hem. 9, 528 (1970). Rerzivtxi January 30, 1989; acceptad May 5, 1P89

5.