Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications

Abstract

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

Keywords: 2,2′-bipy, 2,2-bipyridine; 6-mepic, 6-methylpicolinic acid; Ad, adenosine; Ala, alanine; Ala-Gly, alanylglycine; Ala-His, alanylhistidine; Ala-Ser, alanylserine; Amino acids; Antidiabetics; Antitumors; Asp, aspartic acid; BEOV, bis(ethylmaltolate)oxovanadium(IV); Chemical speciation; Cys, cysteine; Cyt, citrate; DMF, N,N-dimethylformamide; DNA, deoxyribonucleic acid; EPR, Electron Paramagnetic Resonance; G, Gauss; Glu, glutamic acid; Gly, glycine; GlyAla, glycylalanine; GlyGly, glycylglycine; GlyGlyCys, glycylglycylcysteine; GlyGlyGly, glycylglycylglycine; GlyGlyHis, glycylglycylhistidine; GlyPhe, glycylphenylalanine; GlyTyr, glycyltyrosine; GlyVal, glycylvaline; HIV, human immunodeficiency virus; HSA, albumin; Hb, hemoglobin; His, histidine; HisGlyGly, histidylglycylglycine; Ig, immunoglobulins; Im, imidazole; L-Glu(γ)HXM, l-glutamic acid γ-monohydroxamate; LD50, the amount of a toxic agent (such as a poison, virus, or radiation) that is sufficient to kill 50 percent of population of animals; Lac, lactate; MeCN, acetonitrile; NADH and NAD+, nicotinamide adenine dinucleotide; NEP, neutral endopeptidas; NMR, Nuclear Magnetic Resonance; Ox, oxalate; PI3K, phosphoinositide 3-kinase; PTP1B, protein tyrosine phosphatase 1B; Pic, picolinic acid; Pro, proline; Pro-Ala, prolylalanine; RNA, ribonucleic acid; SARS, severe acute respiratory syndrome; Sal-Ala, N-salicylidene-l-alaninate; SalGly, salicylglycine; SalGlyAla, salicylglycylalanine; Ser, serine; T, Tesla; THF, tetrahydrofuran; Thr, threonine; VBPO, vanadium bromoperoxidases; VanSer, Schiff base formed from o-vanillin and l-serine; Vanadium complexes; acac, acetylacetone; dhp, 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone; dipic, dipicolinic acid; dmpp, 1,2-dimethyl-3-hydroxy-4-pyridinonate; hTf, transferring; hpno, 2-hydroxypyridine-N-oxide; l.m.m., low molecular mass; mal, maltol; py, pyridine; sal-l-Phe, N-salicylidene-l-tryptophanate; salGlyGly, N-salicylideneglycylglycinate; salSer, N-salicylideneserinate; salTrp, N-salicylidene-L tryptophanate; salVal, N-salicylidene-l-valinate; salophen, N,N′-bis(salicylidene)-o-phenylenediamine; saltrp, N-salicylidene-l-tryptophanate; γ-PGA, poly-γ-glutamic acid.

Fig. 1

Formation reaction of a Schiff base that acts as an intermediary species in reactions catalyzed by enzymes containing pyridoxal. Modified from Ref. .

Fig. 2

Species distribution diagram for the system V(III)-H₂Cyt-HPro in 3.0 mol·dm⁻³ KCl at 25 °C using the molar ratio (R = 1:2:1) at metal concentration of 3 mmol·dm⁻³. Modified from Ref. . H₂Cyt and HPro represents, citric acid and proline respectively.

Fig. 3

A) Species distribution diagram for the system V(III)-H₂dipic-H₂cys in KCl 3.0 mol·dm⁻³at 25 °C. B) Species distribution diagram for the system V(III)-H₂dipic-HHis in KCl 3.0 mol·dm⁻³ at 25 °C. In both cases the molar ratio (R = 1:1:1) was used and the V(III) concentration in the medium was 3 mmol·dm⁻³. Modified from Ref. .

Fig. 4

Species distribution diagram for the hydrolysis of vanadium(IV) oxide A) 10 nM of concentration V(IV)O, B) 100 nM of concentration V(IV)O (Modified from Ref. [24]). C) Species distribution diagram for the system VO′-l-Ala considering the conditions [V(IV)O] = 8·10⁻³ mol·dm⁻³ and L/M = 53.9. Modified from Ref. .

Fig. 5

Schematic diagram of possible reactions for the ligand N-salicylideneamino acidato. Modified from Ref. .

Fig. 6

Desulphydration of cysteine. Modified from Ref. .

Fig. 7

Cation (B) is removed from the complex (A = [V^IVO(saltrp)(H₂O)]), by the attack of the a pyridine molecule to the β-carbon atom of the tryptophan, in this process the side group would bind again to the β-carbon atom of 10, this would lead to the racemization of the amino acid (see Fig. 5). Modified from Ref. .

Fig. 8

The expected complexes structure of V(IV)O(salophen) derivate. Modified from Ref. .

Fig. 9

XRD structure obtained for vanadium O-N-salicylieneamino acidato complex Modified from Ref. .

Fig. 10

Pourbaix’s diagram of vanadium. Modified from Ref. .

Fig. 11

Speciation diagram of vanadate-maltol system at 25 °C, ionic medium = NaCl 0.150 mol·dm⁻³, [V(V)] = 10 mM, [maltol] = 20 mM. Modified from Ref. .

Fig. 12

Speciation distribution diagram at 25 °C using NaCl 0.150 mol·dm⁻³ as ionic medium for: (A) vanadate-lactate system, [V(V)] = 10 Mm, [lac] = 15 mM (B) vanadate-lactate-H₂O₂ system, [V(V)] = 15 mM, [H₂O₂]⁺ = 20 mM, [lac]⁻ = 135 mM. Modified from Ref. .

Fig. 13

Speciation distribution diagram for vanadate -citrate system at 25 °C using as ionic medium = NaCl 0.150 mol·dm⁻³, [V(V)] = 15 mM, [Cyt] = 45 mM. Modified from Ref. .

Fig. 14

Species distribution diagram for vanadate-adenosine system at 25 °C using as ionic medium = NaCl 0.600 mol·dm⁻³, [V(V)] = 5 mM, [Ad] = 20 mM, (A). Species distribution diagram for vanadate-adenosine-imidazole system at 25 °C using as ionic medium = NaCl 0.600 mol·dm⁻³, [V(V)] = 1.25 mM, [Ad] = 20 mM, [Im] = 320 mM (B). Modified from Ref. .

Fig. 15

Species distribution diagram for vanadate-picolinic acid system at 25 °C using as ionic medium = NaCl 0.150 mol·dm⁻³, [V(V)] = 1 µM, [Ad] = 20 Mm (A). Possible structures of the two main geometric isomers VPic₂⁻ and VPic₂^−* (B). Modified from Ref. .

Fig. 16

Examples of V(V) complexes proposed to be formed with some dipeptides. Modified from Ref. .

Fig. 17

Comparison of geometries of vanadate and phosphate relevant at the physiological level. Modified from Ref. .

Fig. 18

Chemical structures of BMOV (V^IVO(maltolato)₂(H₂O)), BEOV (V^IVO(etilmaltolato)₂(H₂O)), V^IVO(dmpp)₂ (bis(1,2-dimethyl-3-hydroxy-4-pyridinonate)oxovanadium (IV)), V^IVO(Pic)₂ (bis(picolinato)oxovanadium(IV). Modified from Refs. , , .

Fig. 19

Chemical structure of various vanadium compounds with anti-tumor activity. A) Metvan. B) Vanadocene dichloride. Vanadium complexes with: C) Chrysin. D) Morin. E) Naringenin. F) Silibinin G) VO(oda)phen. H) V(III)-l-Cysteine. Based on Refs. , , , , , , , , .

Fig. 20

Representation of cellular targets involved in the antitumor mechanism of the Vanadium(III)-l-cysteine complex or its possible metabolites. Vanadium complex induces apoptosis of cancer cell through change of mitochondrial function, proapoptotic factor release from mitochondria and alteration of genetic expression. PTPB1: protein-tyrosine phosphatase 1B, mTOR: mammalian target of rapamycin, Akt: serine-threonine protein kinase B, ROS: reactive oxygen species, RNS: reactive nitrogen species, MAPKs: mitogen-activated protein kinases, MPTP: mitochondrial permeability transition pore, Bax: Bcl-2-associated X protein, Bcl-2: B-cell lymphoma 2, Cyt c: cytochrome c, Src: homology region 2 domain-containing phosphatase-1, MMP-9: matrix metalloproteinase-9, VEGF-A: vascular endothelial growth factor A. Based on Refs. , , , .

Fig. 21

Chemical structure of polypyridine ligands capable of intercalating with DNA Modified from Ref. .

Fig. 22

Chemical structure of V(IV)O-porphyrin compounds. Modified from Ref. .

Fig. 23

Schematic representation of global vanadium speciation in the body. In blood and in each organ speciation of vanadium occurs. Modified from Ref. .