Vanadium compounds in medicine

Abstract

Vanadium is a transition metal that, being ubiquitously distributed in soil, crude oil, water and air, also found roles in biological systems and is an essential element in most living beings. There are also several groups of organisms which accumulate vanadium, employing it in their biological processes. Vanadium being a biological relevant element, it is not surprising that many vanadium based therapeutic drugs have been proposed for the treatment of several types of diseases. Namely, vanadium compounds, in particular organic derivatives, have been proposed for the treatment of diabetes, of cancer and of diseases caused by parasites. In this work we review the medicinal applications proposed for vanadium compounds with particular emphasis on the more recent publications. In cells, partly due to the similarity of vanadate and phosphate, vanadium compounds activate numerous signaling pathways and transcription factors; this by itself potentiates application of vanadium-based therapeutics. Nevertheless, this non-specific bio-activity may also introduce several deleterious side effects as in addition, due to Fenton's type reactions or of the reaction with atmospheric O₂, VCs may also generate reactive oxygen species, thereby introducing oxidative stress with consequences presently not well evaluated, particularly for long-term administration of vanadium to humans. Notwithstanding, the potential of vanadium compounds to treat type 2 diabetes is still an open question and therapies using vanadium compounds for e.g. antitumor and anti-parasitic related diseases remain promising.

Keywords: Antiparasitic activity; Biological properties; Cancer therapy; Insulin-enhancing agents; Vanadium.

Fig. 1

Uptake and distribution of vanadium compounds in the body.

Fig. 2

Some vanadium compounds that have been reported to exhibit insulin-like effects .

Fig. 3

(A) Distribution diagram of V^IVO hydrolysis at 10 nM concentration. (B) The same but including the possibility of forming a V^IVO(L) complex (concentration of L = 100 nM) with a conditional stability constant of 10⁹; β values of the hydrolytic V^IV-species were obtained from Ref. .

Fig. 4

Analogy between phosphate and vanadate. Besides monovanadate being structurally similar to phosphate, the acid-base equilibria operating and other types of reactions (e.g. V and/or P ‘ester’ formation) are similar. However, there are also some structural and pK_a differences (see text) , .

Fig. 5

Two distinct proposed types of binding for V^IVO(carrier)₂ complexes to hTF. The possibility of the Type 1 binding to a protein was recently confirmed by the x-ray diffraction characterization of a lysozyme-V^IVO(pic)₂ adduct .

Fig. 6

Several additional insulin-enhancing vanadium compounds , , , .

Fig. 7

Scheme depicting how in vivo blood circulation monitoring-electron paramagnetic resonance (BCM-EPR) studies on rats are carried out . The method was used to measure the real-time disposition of spin probes in the circulating blood of rats.

Fig. 8

Simplified sketch of the possible mechanism of action of VCs. The internalization of glucose by the glucose transporter GLUT4, is triggered by the phosphorylated insulin receptor (IR). In the absence of insulin or insufficient insulin response, protein tyrosine phosphatase 1B (PTP-1B) dephosphorylates the IR, and the glucose intake is stopped. By binding to PTP-1B vanadate may block PTP-1B, this restoring the signaling path. (1) Phosphate remaining bound to IRβ, the insulin receptor substrate (IRS), the phosphatidylinositol 3-kinase (PI3K, which activates protein kinase B, PKB, also known as Akt) remain phosphorilated, thus the signaling path is kept active and (2) activation of the glucose transporter remains in operation, as well as (3) translocation of GLUT4, and (4) cellular uptake of glucose by GLUT4.

Fig. 9

Several anti-tumor vanadium complexes or compounds which form anti-tumor vanadium complexes , , , , , , , , , , , , , , .

Fig. 10

Structural formulae of V^IVO-oda compounds .

Fig. 11

Structure of V^V-hydroxylamido-amino acid complexes .

Fig. 12

Polypyridyl compounds selected as bidentate potentially intercalating ligands: dipyrido[3,2-a: 2′,3′-c]phenazine (dppz), 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), 5-amine-1,10-phenanthroline (aminophen), 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), 1,10-phenanthroline-5,6-dione (phendione), [1,2,5]thiadiazolo[3,4-f][1,10]phenanthroline (tdzp), included in complexes with T. cruzi activity.

Fig. 13

Schematic general structure of the two newly synthesized V^IVO families of compounds , , , , , .

Fig. 14

AFM images showing the modifications suffered by pBR322 plasmid DNA (a) due to the interaction with (b) [V^IVO(SO₄)(H₂O)₂(tdzp)] .

Fig. 15

Tridentate salicylaldehyde semicarbazone derivatives selected as coligands in [V^IVO(L-2H)(NN)] compounds , , .

Fig. 16

Graphical comparison of the IC₅₀ values on T. cruzi of the five families of [V^IVO(L-2H)(NN)] compounds: (a) NN = bipy, dppz and phen, IC₅₀ Nfx (Nifurtimox) (Dm28c strain) 6.0 μM; (b) NN = epoxyphen and aminophen, IC₅₀ Nfx (Tulahuen 2 strain) 7.7 μM.

Fig. 17

Schematic representation of carbon source metabolism in trypanosomes.

Fig. 18

V^IVO- and V^VO₂-complexes of the bioactive tridentate ligand 2-(benzothiazol-2-yl-hydrazonomethyl) phenol (L6) .

Fig. 19

Oxidovanadium(IV) N-acylhydrazone complexes where L7 = LASSBio1064 = (E)-N′-(2-hydroxybenzylidene-4-chlorobenzohydrazide .

Fig. 20

V^VO₂-complexes of binucleating bis(dibasic ONS donor ligands) showing activity in vitro on E. histolytica.

Fig. 21

V^IVO-porphyrin complex with anti-HIV properties .

Fig. 22

V^IVO-xylylbicyclam anti-HIV compounds .

Fig. 23

Structure of 35 [VO(acac)(L8-H)], where L8 = 2-acetylpyridine-N(4)-phenylthiosemicarbazone and acac = acetylacetonate .

Fig. 24

8-Hydroquinoline anti-TB bioactive vanadium compounds .