Hydroxycarboxylate Complexes - American Chemical Society

Chapter 27

Synthetic and Structural Studies of Aqueous Vanadium(IV,V) Hydroxycarboxylate Complexes Downloaded by UCSF LIB CKM RSCS MGMT on August 29, 2014 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch027

Athanasios Salifoglou Department of Chemical Engineering, Laboratory of Inorganic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece and Chemical Process Engineering Research Institute, Thermi, Thessaloniki 57001, Greece

Vanadium has been amply established as a competent inorganic cofactor in biological systems. Among vanadium's various functions its insulin mimetic capacity stands out and constitutes a challenge to bioinorganic chemists. Prompted by the need to comprehend the insulin mimetic action of vanadium and its interaction with biomolecular targets, extensive synthetic reactivity studies were carried out with V(IV,V) in the presence of low molecular mass ligands in aqueous solutions. Through meticulous synthetic pHdependent efforts, new V(IV,V) soluble binary and ternary species arose that delineate the aqueous speciation and reflect the chemical reactivity of insulin mimetic vanadium involved in interactions with physiological substrates.

Introduction Vanadium is an element widely established in abiotic and biological applications. Its employment as an inorganic cofactor in biological systems has received considerable attention in the past couple of decades due to its presence in enzymes (1,2), such as nitrogenase (J), haloperoxidases (4,5,6), and others. Beyond, however, its role in active sites of metalloenzymes outstanding has been its involvement in biochemical processes that affect the physiology of an organism. Characteristic to that end have been its roles in mitogenicity (7,8), © 2007 American Chemical Society

In Vanadium: The Versatile Metal; Kustin, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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Downloaded by UCSF LIB CKM RSCS MGMT on August 29, 2014 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch027

378 antitumorigenicity (9,10) and more recently its insulin mimetic action (11,12). The latter biological function has propelled vanadium into the sphere of challenging scientific endeavors invoking multidisciplinary research in biology, medicine and chemistry. The insulin mimetic action of vanadium has spurred considerable research activities in chemistry, in hopes of finding vanadium drugs that could be of help to patients suffering from Diabetes mellitus II. Key to this challenging feat is in depth understanding of the type of interactions involved in vanadium (bio)chemistry, once the latter element is recognized and internalized by the cell. Such interactions entail chemical reactivity of the biologically relevant oxidation states of vanadium (V(IV), V(V)) with physiological substrates of both low and high molecular mass. Consequently, the existence of well-characterized, water soluble species arises as an important goal in pursuing vanadium metallodrugs capable of insulin mimetic action. Moreover, such vanadium drugs should be further characterized by ideally no toxicity, and fully accounted for physicochemical profiles linking the bioactive vanadium species with cellular organic ligands-substrates. Prompted by the need to understand the primary chemical interactions of vanadium initially with low molecular mass physiological and physiologically relevant ligands, we launched efforts targeting synthetic complexes of V ( V ) and V(IV) with the physiological ligands a-hydroxycarboxylic acids. Prominent representatives of such substrates are citric acid and malic acid. They both exist in cellular fluids, with citric acid being present at a concentration of -0.1 m M (13,14). Our synthetic efforts were a) based on information on aqueous solution studies and b) guided by the need to develop pH-dependent reactivity methodologies in binary and ternary systems of V ( V ) and V(IV) with cthydroxycarboxylic acids and hydrogen peroxide, all of them components of species purported to exhibit insulin mimetic properties.

Experimental Section Materials and methods A l l experiments were carried out in the open air. Nanopure quality water was used for all reactions. V 0 , V O S 0 , VC1 , anhydrous citric acid, and H 0 30% were purchased from Aldrich. Ammonia, potassium and sodium hydroxide were supplied by Fluka. FT-Infrared spectra were recorded on a Perkin Elmer 1760X FT-infrared spectrometer. UV/Visible measurements were carried out on a Hitachi U2001 spectrophotometer in the range from 190 to 1000 nm. A ThermoFinnigan Flash E A 1112 C H N S elemental analyser was used for C,H,N analysis. 2

5

4

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2

2

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Results Binary V(V)/V(IV)-(a-hydroxycarboxylase) systems Both V(V) and V(IV) oxidation states were investigated in the presence of citric acid in aqueous solutions at specific pH values. The general methodology involved the pH-dependent synthesis of V(V,IV)-citrate complexes over the entire pH range. The isolated crystalline products were characterized by elemental analysis, spectroscopically (FT-IR, V - , C - M A S N M R ) , and structurally by X-ray crystallography. Chemical reactivity studies were carried out on all new complexes through acid-base chemistry, thermal and non-thermal transformations, at various pH values.


5 1

13

V(V)-citrate system The chemical reactivity in the aqueous V(V)-citric acid system was studied through reactions of simple reagents at specific molar ratios and pH values. To that end, reactions between V 0 and citric acid with a molar ratio 1:1 and 1:2 were employed throughout this effort and led to the successful synthesis of discrete soluble species. The appropriate base M O H ( M = K , N a , M e N , N H ) was used to adjust the pH of the reaction medium and concurrently provide the necessary counterions for balancing the arising anionic complexes. Representative species of this family of well-characterized complexes include ( N H ) [ V 0 ( C H 0 ) ] 2 H 0 (1) (pH 3.0), ( N H ) [ V 0 ( C H 0 ) ] 4 H 0 (2) (pH 5.0), ( N H ) [ V 0 ( C H 0 ) ] 6 H 0 (3) (pH 8.0) (Figure 1). The employed pH values for the synthesis of 1-3 were optimally set at p H 3, 5, and 8. A representative reaction showing the synthesis of 2 is shown below: 2

5

+

+

+

+

4

+

4

4

2

2

4

6

4

6

6

7

2

2

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2

6

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4

7

2

4

2

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6

5

7

2

2

2

COOH

p H -6.0 V O 2

s

+ 2

OH

HOOC —

+ 4 OH

COOH [ V 0 ( C H 0 ) ] * (2)+ 2

4

6

5

7

2

5H 0 2

In all three cases, the isolated materials were characterized spectroscopically and subsequently structurally by X-ray crystallography.



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Figure 1. pH-structural variants of binary V(V)-citrate species and their pH-dependent acid-base chemistry. (See page 3 of color inserts.)

v

Compounds 1-3 contain a stable planar V 0 core to which attached are two citrate ligands. The latter bind to the planar core through the deprotonated central alkoxide and carboxylate anchors. The terminal carboxylate groups do not participate in the coordination to the core, dangling away from the complex. The fundamental structural composition throughout the family of these complexes is the same, with the main difference between the various p H structural variants being the state of protonation of the non-coordinating citrate terminal carboxylate groups. Specifically, as the p H increases progressively (from 3 to 5 to 7.5-8.0), two protons are released from the complex (one from each citrate) in each p H step, thus raising the charge of the anionic species by 2. In this regard, the acid-base chemistry among the three species establishes their involvement as competent partners in the requisite aqueous binary speciation. In so doing, it emphasizes the significance of pH as a molecular switch dictating a) the (de)protonation chemistry in the periphery of the vanadium(V)-citrate complex, and b) the chemical and geometrical features of the structural assembly of all arising complexes (15,16). 2

2


381 V(IV)-citrate system In the binary V(IV)-citrate system, aqueous reactions between V O S 0 and citric acid with molar ratios 1:1 and 1:2 were carried out in a pH-dependent fashion. The same reactivity was observed when VC1 was used as a starting material. Here as well, the employment of a base (e.g. K O H ) was instrumental in a) adjusting the pH of the reaction medium, and b) concurrently providing the counterion necessary for the neutralization of the charge of the arising anionic species. Specifically, the reaction at pH -4.5 led to the isolation of complex K [V20 (C H407)(C H50 )] 7 H 0 (4) upon ethanol addition. In a similar reaction at pH 8, the material isolated was K ^ X ^ O ^ Q H ^ ^ ] 6 H 0 (5). In this case, use of a base included M O H (M=K , N a , N H ) . A characteristic reaction leading to the synthesis of 5 is shown below: 4

3


3

2

6

6

7

2

+

+

+

2

4

Hydroxycarboxylate Complexes - American Chemical Society

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