VANADIUM COMPLEXES, THEIR THERAPEUTIC AND CATALYTIC POTENTIALITY

Abstract

Vanadium, named after the Nordic Goddess "Vanadis", has been reported to be an essential bio-element for certain organisms, including tunicates, bacteria and some fungi but this has not been clearly proved for human. Blood cells of several ascidians accumulate very high concentrations of vanadium in lower oxidation states. Amavadine, a naturally occurring vanadium(IV) complex has been isolated from Amanita muscaria and other members of the genus Amanitae. It is also presentat very low concentrations (<10"8 M) in the cells of plants and animals. The structural analogy between vanadate (H2V04~") under physiological conditions and phosphate (HP042-) possibly is the basis for many regulatory, inhibitory and stimulating functions of vanadium towards phosphate metabolising. Vanadium chemistry has attracted attention of researchers worldwide due to its medicinal inputs. In fact, in early 1900s vanadium compounds were used for treating tuberculosis, anaemia and diabetes and were present in antiseptics or tonics. Medicinal aspects of vanadium compounds were increased with the discovery of insulin-mimetic property of vanadium ions in 1979 / 1980. Oxidation state of metal ion, interaction of complexes with human serum albumin (HSA) and design of ligands have been indicated to play an important role inmodifying the biological effects ofmetal based drugs. Vanadium with atomic number 23 and electronic configuration [Ar]3d 4s , exhibits formal oxidation states from +V down to -III. The most stable oxidation states under normal conditions are IV and V, and readily form V-0 bonds. Vanadium in these oxidation states comfortably binds with O, N and S donor ligands. In fact, much attention was focused on oxovanadium(IV) complexes in mid 70s. The discovery of vanadium(V) in vanadium based enzymes e.g. vanadate-dependent haloperoxidases, attracted attention of researcher to develop coordination chemistry of vanadium(V) in search of good models for vanadium-containing biomolecules. Vanadium compounds have also been found to promote a peroxide-driven oxidation of organic substrates. All these clearly indicated the need for further development of coordination chemistry of vanadium that provides: (i) structural and functional models of Ill haloperoxidases, and (ii) medicinal as well as catalytic potentials. The present thesis is, therefore, aimed to describe the coordination chemistry of vanadium considering biologically important ligand. Emphasis has been given to provide structural as well functional model of haloperoxidases. Catalytic potential of some of these complexes for the oxidation reactions have also been explored. Though vanadium complexes are known for their good insulin mimetic activity, some of the complexes reported here have been explored for their possible antiamoebic drugs. For convenience, the present thesis has been divided into four chapters. First chapter is introductory one and deals with general remarks on vanadium, their occurrence in nature, potential applications of vanadium complexes, and interaction and speciation of vanadium complexes in biofluids. General coordination chemistry developed through various synthetic precursors has also been included. Second chapter describes the syntheses, characterization and reactivity of ryOL-H20], [K(H20)][V02L], [{VOLJ^-O] and [VO(OMe)(MeOH)L] type of complexes. H2L are the hydrazones, H2sal-nah I or H2sal-fah H; sal =salicylaldehyde, nah = nicotinic acid hydrazide and fah = 2-furoic acid hydrazide. Reaction of [VO(acac)2] with ligands I and H in methanol leads to the formation of oxovanadiurnOV) complexes [VOLH20] (H2L =I: 1, H2L =II: 4). Aerial oxidation of the methanolic solutions of 1 and 4 yields the dinuclear oxo-bridged monooxovanadium(V) complexes [{VOLJ^O] (H2L = I: 2, H2L = H: 5). These dinuclear complexes slowly convert, in excess methanol, to [VO(OMe)(MeOH)L] (H2L =I: 9, H2L =U: 10), the crystal and molecular structures ofwhich have been determined, confirming the ONO binding mode of the dianionic ligands in their enolate form. Reaction ofaqueous KrV03] with the ligands at pH ca. 7.5 results in the formation of [K(H20)][V02L] (H2L =I: 3, H2L = H: 6). The overall coordination environment is represented by an 04N donor set: the ONO ligand, the doubly bonded oxo group and an aqua, methoxo or bridging oxo ligand. The complexes, thus, model iv structural features of the vanadate-dependent haloperoxidases isolated from marine algae (such as Ascophyllum nodosum and Corallina officinalis) and the fungus Curvularia inaequalis. The model character extends tothe simulation ofthe functions of the enzymes in that the complexes [K(H20)][V02L] catalyse the oxidative bromination by H202 of salicylaldehyde to afford 5-bromo and 3,5- dibromosalicylaldehyde, and the oxidation of (oxo transfer to) phenol to yield catechol and p-hydrochinone. The formation of intermediates proposed for the catalytic cycle, i.e. oxo-hydroxo complexes [VO(OH)HL]+ and oxo-peroxo complexes [VO(02)L]", has been made plausible on the basis ofcharacteristics in the UV-Vis spectra of the anionic dioxovanadium precursor compounds [V02L]" treated with acid and hydrogen peroxide, respectively. Penta-coordinated neutral and anionic dioxovanadium complexes containing a ligand system providing a dianionic ONO donor set and thus modelling the active site of vanadate-dependent haloperoxidases have been reported in the third chapter. The ONO ligands employed are hydrazones containing pyridoxal (vitamin B6) and nicotinoylhydrazide, isonicotinoylhydrazide or benzoylhydrazide as components, and thus biogenic molecular moieties. [VO(acac)2] reacts with H2L (H2L are the hydrazones H2pydx-inh I, H2pydx-nh n or H2pydx-bhz ffl; pydx = pyridoxal, inh = isonicotinoylhydrazide, nah = nicotinoylhydrazide, bhz = benzoylhydrazide) in dry methanol to yield the oxovanadium(IV) complexes [VOL] (H2L =1:1, H2L = H: 4)or [VO(pydx-bhz)]. These complexes, when exposed to air, convert tothe corresponding dioxovanadium(V) complexes [V02HL] (H2L = I: 2, H2L = H: 5, H2L = ffl: 7). Aqueous solutions ofvanadate and the ligands atpH 7.5 give rise to the formation of [K(H20)3][V02(pydx-inh)] 3, [K(H20)2][V02(pydx-nh)] 6 and [K(H20)2][V02(pydxbhz)] 8. Treatment of 6 and 8 with H202 generates the oxo(peroxo)vanadium complexes [VO(02)L] (H2L = H: 9, H2L = ffl: 10). Complexes 9 and 10 are capable of transferring an oxo group to PPh3. Acidification of 8 with HC1 afforded an oxohydroxo complex. The crystal and molecular structures of ligand I and complex 3 have been solved by single crystal X-ray diffraction. In the anion 3, vanadium is in a distorted tetragonal-pyramidal environment (r= 0.23). The K+ ion is coordinated to four water molecules (two of which bridge to a neighbouring K+), the pyridine nitrogen of an isonicotinic moiety, the equatorial oxo group of the V02+ fragment, and the alcoholic group of the pyridoxal moiety, which links to adjacent layers in the three-dimensional lattice network. In the presence of KBr/H202, the anionic complexes 3, 6 and 8 catalyse the oxidative bromination of salicylaldehyde in water to 5-bromosalicylaldehyde in ca. 40%yieldswith ca. 87%selectivity. Binuclear, //-6w(oxo)Z>w{oxovanadium(V)}complexes [(VOL)2(//-0)2] (2 and 7) (where HL are the hydrazones Hacpy-nah I or Hacpy-fah II; acpy = 2- acetylpyridine, nah = nicotinoylhydrazide and fah = 2-furoylhydrazide); prepared by the reaction of [VO(acac)2] and the ligands in methanol followed by aerial oxidation are reported in the fourth chapter. The paramagnetic intermediate complexes [VO(acac)(acpy-nah)] (1) and [VO(acac)(acpy-fah)] (6) have also been isolated. Treatment of [VO(acac)(acpy-nah)] and [VO(acac)(acpy-fah)] with aqueous H202 yields the oxoperoxovanadium(V) complexes [VO(02)(acpy-nah)] (3) and [VO(02)(acpy-fah)] (8). Inthe presence of catechol (H2cat) orbenzohydroxamic acid (H2bha), 1 and 6 give the mixed chelate complexes [VO(cat)L] (HL = I: 4, HL = H: 9) or [VO(bha)L] (HL = I: 5, HL = H: 10). Complexes 4, 5, 9 and 10 slowly convert to the corresponding oxo-//-oxo species 2 and 7 in DMF solution. Ascorbic acid enhances this conversion under aerobic conditions, possibly through reduction of these complexes with concomitant removal of coordinated catecholate or benzohydroxamate. Acidification of 7 with HC1 dissolved in methanol affords a hydroxo(oxo) complex. The crystal and molecular structure of 2xH20 has been determined, and the structure of 7 re-determined, by single-crystal X-ray diffraction. Both ofthese binuclear complexes contain the uncommon asymmetrical {VO(//-0)}2 diamond core. The in vitro tests of the antiamoebic activity of ligands I and II and their binuclear complexes 2 and 7 against the protozoan parasite Entamoeba histolytica show that the ligands have no amoebicidal activity while their vanadium complexes 2 and 7 display more effective amoebicidal activity than the most VI commonly used drug metronidazole (7C50 values are 1.68 and 0.45 /M., respectively vs 1.81 /M for metronidazole). Complexes 2 and 7 catalyse the oxidation of styrene and ethyl benzene effectively. Oxidation of styrene, using H202 as an oxidant, gives styrene epoxide, 2-phenylacetaldehyde, benzaldehyde, benzoic acid and 1-phenylethane- 1,2-diol, while ethyl benzene yields benzyl alcohol, benzaldehyde and 1- phenyl-ethane-1,2-diol.