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The potentiality of vanadium in medicinal applications
Inorganica Chimica Acta 504 (2020) 119445
Contents lists available at ScienceDirect
Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica
Review article
The potentiality of vanadium in medicinal applications
T
Dieter Rehder Chemistry Department, University of Hamburg, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Diabetes Anti-tumour Antiviral/antibacterial Parasitic diseases Decavanadate
Light is thrown on the impact of vanadium compounds in medicinal issues, including simple inorganic vanadates, such as vanadates stabilized (and thus possibly modified) by organic counter-ions. The main fields of potential medications (and limits thereof) based on vanadium so far do not (yet) enjoy official pharmacological application. However, several sectors of the potentially successful treatment of pathological symptoms with vanadium (coordination) compounds have been thoroughly and mostly successfully investigated during the past two or three decades. The main issues dealt with in the present overview are directed towards (type 2) diabetes, anti-tumour therapy, and the implication of vanadium compounds in (tropical) diseases caused by bacteria, viruses, flagellates or amoeba, such as tuberculosis, sleeping sickness and Chagas disease, leishmaniasis and amoebiasis. The investigations directed towards medicinal applications of vanadium compounds have commonly been carried out, in vitro and in vivo, with experimental animals. Most promising perhaps in the field of potential applications of vanadium-based medications is the antidiabetic effect of rather simple coordination compounds such as VO(maltol)2, a complex that has been checked in clinical tests I and II.
1. Introduction and general aspects Vanadium is an omnipresent element in Earth’s crust (0.019%, 21st most abundant element), in seawater and in ground water (up to 100 µg l−1), and – accordingly – also in living organisms. Of particular interest in this context is the presence of vanadium in various marine macro-algae (where vanadium is in the active centre of haloperoxidases) and in medicinal plants[1a], such as wild thyme [1b] with an average vanadium content of 0.5 mg V per kg dry matter. Vanadium can also stimulate plant growth [1c]. For humans, the common daily intake amounts to 0.01–0.02 mg. Nutritional intake takes place in the form of oxidovanadium(IV) or -(V) compounds, or – more predominant – as vanadate H2VO4− (at physiological pH). Excretion essentially occurs via the urine (hydrogenvanadate) and faeces (in the form of VO2+/ 3+ hydroxides). Microbial control of the vanadium contents in the environment, i.e. removal of vanadium by reduction of easily soluble vanadate to insoluble oxidovanadium(IV)hydroxide, as well as resupply of vanadate via oxidation of VO2+ to vanadate, is an important environmental factor in the context of the overall vanadium balance [1d] (for details, see Section 4). Small amounts of vanadium, taken in via nutrients and drinking water, supposedly are beneficial, while excessive vanadium amounts (high local vanadium concentrations originating from natural deposits or human input [2a], or inhaled vanadium oxides present in the breathing air in industrial areas) are toxic. For a general overview of the potential ecotoxicity of vanadium, see Ref. [3a]. The threshold limit value for breathing air is 0.05 mg m3 [2b]. The main transporter for the VO2+ ion in the blood system is transferrin; to some extent, albumin also comes in as a transporter. Most of the “modern” https://doi.org/10.1016/j.ica.2020.119445 Received 3 January 2020; Accepted 11 January 2020 Available online 14 January 2020 0020-1693/ © 2020 Elsevier B.V. All rights reserved.
medicinal applications based on vanadium employ vanadium incorporated into organic ligand systems. These coordination compounds are, in several cases, subject to degradation (with the formation of vanadate and/or oxidovanadium(IV/V)) at physiological conditions [3b], a fact that can be responsible for off-target toxicity. Vanadate can act as a phosphate analogue, thus interfering with phosphate dependent activities. Examples are the inhibition of the extra/intracellular transporter (ATPase) for Na+ and K+ [4a]), and the interaction with phosphate-based structures such as DNA. In addition, vanadate can partially replace phosphate in bone structures [4b]. However, this non-specific (in contrast to phosphate) bioactivity can also cause objectionable side effects, essentially due to the fact that vanadate forms stable covalent bonds to functionalities within physiologically relevant biomolecules, while the respective interaction between phosphate and functions such as {N}, {O} and {S} is reversible and thus intermediate in nature. Further, vanadium compounds eventually can interfere – based on the ease of change in oxidation state (VIV ⇆ VV) – with oxidative stress [5a] caused by superoxide and peroxide; in its VO2+ state, vanadium can be an effective antioxidant [5b]. On the other hand, peroxovanadates such as H2V(O2)O3− can eventually form, and exert oxidative stress. It should be noted that vanadium is categorized (category 2) as a cancer generating/genotoxic substance. In addition, adverse outcomes within the scope of prenatal exposure to excessive vanadium concentrations have been associated with anthropogenic activities [6]. In the present overview, the main emphasis is laid upon beneficial aspects with (potential) medicinal applications. For a summary of the health benefits of vanadium compounds see also Ref. [7]; for a more
Inorganica Chimica Acta 504 (2020) 119445
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Fig. 1. Selection of vanadium coordination compounds VOL that have been shown to exhibit insulin-mimetic properties. The bidentate ligands are ethyl-maltolate (1) [8], 3-hydroxypicolinate (2a) [12b], 2,5-dipicolinate (2b) [12c], adenosine monophosphate (3) [13], orotate (4)[14a], and aminotris(phenolate) (5) [14b] An effective transporter for the maltolato complex in the blood system is albumin [15].
critical view and potential health hazards of vanadium Ref. [8]. A positive impact of vanadium has also been reported in the context of the downregulation of inflammation and in immunotherapy[9a], while a positive response on the athletic performance, such as propagated by, inter alia, “vanadyl fuel” (containing oxidovanadium sulphate) and “vanadium water” (from the Fuji region, containing H2VO4−) has not unambiguously been accredited. These “vanadyl fuels” are not to be mistaken for vanadyl petroporhyrines present in crude oil [9b]. 2. Treatment of diabetes The first anti-diabetic vanadium compound, a maltolato complex of composition VO(maltolate)2 (=oxido-bis(ethylmaltolato)vanadium (IV)) had been introduced into phase IIa clinical tests [10] (and abandoned thereafter due to sporadic (mild) renal problems with some of the test persons). Ethylmaltol (see 1 in Fig. 1) derives from the naturally occurring methyl variant, present e.g. in pine needles and malt. Various other oxidovanadium coordination compounds have since been subjected to in vitro and in vivo studies – commonly with test animals – for their ability to lower elevated blood glucose (and lipid) levels in the case of type II and – to some extent – also type I diabetes mellitus [11]. In the case of insufficient insulin supply, the uptake of glucose by – and degradation within – cells is hampered. A few selected examples of vanadium coordination compounds VOL that have been proven potentially valid insulin-mimetic compounds are collated in Fig. 1. The actually active species under in vivo conditions supposedly is vanadate H2VO4−, which forms – essentially extracellularly – via (oxidative) hydrolysis of the applied vanadium coordination compound. For a likely course of action, see Fig. 2. In this context, the hypoglycemic effect of a tea/vanadate decoction orally delivered to diabetic rats, and inducing long-term glycaemic stability, is of some interest[12a]. Vanadate can enter the intracellular space via phosphate channels (scenario 2 in Fig. 2) integrated in the cellular membrane, and interact with (and thus lock off) protein tyrosine phosphatase, in such a way preventing dephosphorylation of the intracellular tyrosine phosphate attached to the insulin receptor. Signalling towards the mechanism for glucose intake – otherwise initiated as insulin docks to the insulin receptor (scenario 1. in Fig. 2) – is thus restored. Since other members of the phosphatase family are equally sensitive to vanadate, vanadium compounds can be expected to also have unfavourable side effects. Most in vivo animal studies have been carried out with Wistar rats having induced diabetes (for a recent review see [16]), employing
Fig. 2. Proposed mechanism for the impact of vanadium coordination compounds VOL (for L see Fig. 1) on the cellular uptake of glucose in the case of absence/critical shortage of insulin. If disposable, insulin docks to the insulin receptor (1.), thus initiating the intake (followed by degradation) of glucose. In the case of insulin undersupply, PTP (PTP = protein tyrosine phosphatase) hydrolytically dephosphorylates the tyrosine, thus blocking off signalling for glucose intake. As vanadate enters the cellular interior (2.), it coordinates to the sulphide of a cysteinyl residue of PTP, forming {PTP}CH2SVO4H2−, in such a way inhibiting the PTPase [17,18] and restoring the signalling path (2.) for the uptake of glucose.
streptozotocin (STZ, glucosamine nitrosourea) [19] or alloxan (a pyrimidine derivative) [20]. Streptozotocin and alloxan deactivate the pancreatic β cells, inducing a severe form of diabetes type I (where the pancreatic β cells are non-productive with respect to insulin). They are hence of restricted relevance for the direct treatment of diabetes in humans, where at least 90% of the individuals suffer from type II diabetes, i.e. a relative lack of and/or resistance towards insulin. On the other hand, administration of vanadium compounds in case of the treatment of diabetes has been shown to induce weight loss [21], a fact that – in any case – is of relevance when counteracting the prevalence of diabetes. 3. Anti-tumour and anticancer therapy For a comprehensive overview of the chemistry and biology of vanadium compounds in cancer therapeutics see, e.g., Ref. [22]. Simple inorganic vanadium compounds such as the oxidovanadium(IV) cation 2
Inorganica Chimica Acta 504 (2020) 119445
D. Rehder
Fig. 3. Selected vanadium coordination compounds that have shown anti-cancer effects in vitro and in vivo. The ligands are based on ethylenediamine diacetic acid (the peroxide complex 1) [24], silibinin (2) [25], cyclopentadienide(1-) and selenocyanate (3) [28], an indolyl-catecholate (4) [29] and pyridoxal (5) [30]. Compounds 6 [31] is effective in promoting oncoviral propagation.
VO2+, or the anionic species hydrogenvanadate H2VO4− and peroxidovanadate HVO3(O2)2− can exhibit anti-tumour effects due to their ability to induce the activation of liver enzymes, such as γ-glutamyl transpeptidase [23], that effectively inhibits tyrosine phosphatases (see also above) and activate tyrosine phosphorylases. Vanadium compounds containing the peroxido ligand (see, e.g., compound 1 in Fig. 3), and thus disposing of the potential to generate reactive oxygen species, can cause oxidative damage and even apoptosis more efficiently in fast growing cancer cells than in healthy cell tissues. Among the naturally occurring products exhibiting cyto-protection (and thus the capability in fighting cancer), silibinin, a flavonoid from the thistle Silybum marianum, is noteworthy since its antioxidant (and thus cyto-protective) properties are enhanced when coordinated to VO2+. The coordination compound VO(silibinin)2 (2 in Fig. 3) effectively thwarts osteosarcomas [25]. Similarly, [VO(chrysin)2(C2H5OH)]2 [26], containing the naturally occurring – in the passion flower Passiflora – flavone chrysin, is cytoprotective. Non-oxido vanadium compounds can be equally effective. Thus, vanadocene Cp2VCl2 has been shown as early as 1979 to be active in the medication of Ehrlich ascites tumour cells (cultured in vivo) by causing morphological changes in these cells [27]. Other vanadocenes, such as the selenocyanato-vanadium(IV) complex Cp′2V(NCSe)2 (3 in Fig. 3, Cp′ is p-methoxiphenyl) [28] display in vivo toxicity against renal cancer cells, possibly because the Cp2V fragment (forming from Cp2VL2 by hydrolytic loss of the ligands L) binds – via vanadium – to the phosphate residues of DNA, thus deactivating replication and hence cell growth. More generally, vanadocenes are potent cytotoxic compounds against testicular cancer. Another example of a non-oxido complex that exhibits significant antiproliferative activity against various cancer cell lines, again through strong binding to DNA and hence mitochondrial damage, is the catecholate complex 4 [29] in Fig. 3. The pyridoxal based oxidovanadium(IV) complex 5 in Fig. 3 induces ca. 90% mortality in human melanoma cells via induction of apoptosis, again by an increase of reactive oxygen species [30]. Vanadate and oxidovanadium(V) are also effective in increasing viral replication of non-pathogenic viruses that kill cancer cells (oncolytic viruses such as rhabdovirus VSVΔ51; oncolytic viruses have available a DNA or RNA genome). Efficient precursor compounds in this
respect are dioxido-picolinato vanadates of composition [VO2(p-dipicX)]− (6 in Fig. 3 [31]) where X is H, Cl or OH, which – in the cell culture medium – hydrolyse to provide VO2+ and H2VO4−. 4. Antiviral, antibacterial and anti-parasitic issues Fig. 4 provides an overview of selected vanadium coordination compounds that have been shown to be effective in fighting infectious diseases, viz. tuberculosis and diseases caused by parasitic protozoa, bacteria and viruses that are essentially native in tropical regions (amoebiasis, leishmaniasis, sleeping sickness and Chagas disease). For a survey, see, e.g., Ref. [7b]. Amoebiasis (counteracted by compound 1 in Fig. 1) goes back to an infection with Entamoebae such as E. histolytica, commonly in the case of sanitation problems; bloody diarrhoea is one of the typical symptoms. Tuberculosis (2) is caused by mycobacteria (Mycobacterium tuberculosis) and transferred between individuals via aerosol droplets. Leishmaniasis (3) is induced by a flagellate (belonging to the genus Trypanosoma) and spread via the bite of sand-flies (such as Phleobotumus and Lutzomyia). Typical symptoms are skin ulcers. Sleeping sickness (4), also known as African trypanosomiasis, goes back to Trypanosomas brucei, a flagellate transferred by the tsetse fly. Symptoms include fever and problems with coordination. Chagas disease (5) (also known as American trypanosomiasis) is spread by the kissing bug (or assassin bug, belonging to the Triatominae). Symptoms include fever and headache. A potential target for these compounds is DNA, i.e. the mode of action of these compounds (or degradation products thereof formed at physiological conditions) may root in the inhibition of DNA replication of the parasitic DNA, via direct (hydrophobic) interaction between the aromatic environment of the drug and the aromatic residues of the nucleobases of DNA. Alternatively, coordination to (and thus deactivation of) the phosphate linkages by hydrolysis products of the original vanadium complexes comes in (see also Section 1). Biological activity (and thus pharmacological effects) against, e.g., human cancer cell lines, have also been reported for decavanadates (for a review see [37]), in particular for decavanadate with organic cations as counter-ions [38]. Anti-bacterial potential has been established for decavanadate [H2V10O28]4− with counter-ions such as nicotinamide 3
Inorganica Chimica Acta 504 (2020) 119445
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Fig. 4. Vanadium complexes that have been tested for their potentiality in the treatment of diseases based on viral, bacterial or parasitic infections, viz. amoebiasis (1; the ligand derives from 5,5′-methylene-bis(salicylaldehyde) and S-methyldithiocarbazide [32]), tuberculosis (2; the ligands are salicylglycine and 8-hydroxyqhinoline [33]), leishmaniasis (the salophen complex 3 [34]), trypanosomiasis (sleeping disease, 4; the ligands are bipyridine and a derivative of salicylaldehyde semicarbazone [35]), and Chagas disease (5; a coordination compound with epoxyphenathroline [36]).
monovanadate as the actually active species. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] (a) I.A. Owolabi, K.L. Mandiwana, N. Panichev, S. Afr, J. Chem. 69 (2016) 67; (b) D.S.W. Antal, C.A. Dehelean, C.M. Canciu, M. Anke, Anal. Univers. Oradea, Fasc. Biol. 16 (2009) 5; (c) A. García-Jiménez, L.I. Trejo-Téllez, D. Guillén-Sánxhez, F.C. Gómez-Merino, PLOS One (2018), https://doi.org/10.1371/journal.pone0201908; (d) J.-H. Huang, F. Huang, L. Evans, S. Glasauer, Chem. Geol. 417 (2015) 68. [2] (a) Y. Yu, J. Yang, Chemosphere 215 (2019) 294; (b) Ch. 6.12 in: WHO Regional Office for Europe, Copenhagen, Denmark, 2000. [3] (a) J.P. Gustafsson, Appl. Geochem. 102 (2019) 1; (b) A. Levina, P.A. Lay, Chem. Asian J. 12 (2017) 1692. [4] L.C. Cantley, M.D. Resh, G. Guidotti, Nature 272 (1978) 552. [5] (a) A. Ścibior, J. Llopis, A.A. Holder, M. Altamirano-Lozano, Oxid. Med. Cellul. Longevity (2016); (b) A. Ścibior, J. Kurus, Curr. Med. Chem. 26 (2019) 5456. [6] J. Hu, et al., Lancet Planet Health 1 (2017) 230. [7] (a) C. Ulbricht, et al., J. Diet. Suppl. 9 (2012) 223; (b) D. Rehder, Fut. Med. Chem. 8 (2016) 325. [8] C. Wong, http:///www.verywellhealth.com/the-benefits-of-vanadium. [9] (a) O. Tsave, S. Petanidis, E. Kioseoglou, M.P. Yavropoulou, J.G. Yvos, D. Anestakis, A. Tsepa, A. Salifoglou, Ox. Med. Cell Long. ID (2016) 4013639; (b) D. Mannikko, S. Stoll, Energy Fuels 33 (2019) 4237. [10] K.H. Thompson, C. Orvig, J. Inorg. Biochem. 100 (2006) 1925. [11] G. Boden, Proc. Assoc. Am. Phys. 111 (1999) 241. [12] (a) T.A. Clark, C.E. Heyliger, M. Kopilas, A.L. Edel, A. Junaid, F. Aguilar, D.D. Smyth, J.A. Thliveris, M. Merchant, H.K. Kim, G.N. Pierce, Metabolism 61 (2012) 742; (b) T. Koleša-Dobravc, K. Maejima, Y. Yoshikawa, A. Meden, H. Yasui, F. Perdih, New. J. Chem. 42 (2018) 3619; (c) J. Gätjens, B. Meier, Y. Adachi, H. Sakurai, D. Rehder, Eur. J. Inorg. Chem. (2006) 3575. [13] A.M. Naglah, M.A. Al-Omar, M.A. Bhat, A.S. Al-Wasidi, A.M.A. Alsuhaibani, A.M. El-Didamony, N. Hassa, S.A. Taleb, M.S. Refat, Crystals 9 (2019) 208. [14] (a) A.M. Naglah, M.A. Al-Omar, A.A. Almehizia, M.A. Bhat, W.M. Afifi, A.S. AlWasidi, J.Y. Al-Humaidi, M.S. Refat, BioMed. Res. Int. (2018) 1;
Fig. 5. A decavanadate salt, (3-Hpca)]4[H2V10O28]⋅2(3-pca)⋅2H2O, that is active in fighting intestinal infections [39].
and isonicotinamide, Fig. 5 [39]. These compounds have been shown to efficiently exhibit growth inhibitory activity against bacterial stems such as Giardia intestinales and pathogenic varieties of Escherichia coli (otherwise a coliform bacterium in the gut microbiota responsible for, e.g., the production of vitamin K). G. intestinales is a flagellated parasite in the small intestines, the trophozites of which cause giardiasis (beaver fever), accompanied by diarrheal diseases. The mechanism of action of decavanadate remains to be elucidated, though. Decavanadate by itself is not stable in aqueous media at physiological (and hence rather low) concentrations. The counter-cation in the original medication, or counter-ions eventually provided in the physiological broth, might protect decavanadate – via interaction of the decavanadate with these organic ions – to the effect that [H2V10O28]n− is transported to the locus agendi, where it successively provides 4
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[15] [16] [17] [18] [19] [20]
[21] [22]
[23] [24] [25]
[26] [27] [28] [29] [30]
Physiol. 228 (2013) 2202. [31] A. Bergeron, K. Kostenkova, M. Selman, H.A. Murakami, E. Owens, N. Haribabu, R. Arulanandam, J.-S. Diallo, D.C. Crans, Biometals 32 (2019) 545. [32] M.R. Maurya, C. Haldar, A.A. Khan, A. Azam, A. Salahuddin, A. Kumar, J.C. Pessoa, Eur. J. Inorg. Chem. (2012) 2560. [33] I. Correia, P. Adão, S. Roy, M. Wahba, C. Matos, M.R. Maurya, F. Marques, F.R. Pavan, C.Q.F. Leite, F. Avecilla, J. Costa Pessoa, J. Inorg. Biochem. 141 (2014) 83. [34] P. de Almeida Machado, V.Z. Mota, A.C. de Lima Cavalli, G.S.G. de Carvalho, A.D. da Silva, J. Gameiro, A. Cuin, E.S. Coimbra, Acta Trop. 148 (2015) 120. [35] M. Fernández, L. Becco, I. Correia, J. Benítez, O.E. Piro, G.A. Echeverria, A. Madeiros, M. Comini, M.L. Lavaggi, M. Gonzáles, H. Cercetto, V. Moreno, J. Costa Pessoa, B. Garat, D. Gambino, J. Inorg. Biochem. 127 (2013) 150. [36] J. Benítez, I. Correia, L. Becco, M. Fernández, B. Garat, H. Gallardo, G. Conte, M.L. Kuznetsov, A. Neves, V. Moreno, J. Costa Pessoa, D. Gambino, Z. Anorg. Allgem. Chem. 639 (2013) 1417. [37] M. Aureliano, Oxid. Med. Cell Longev. (2016) 6103457. [38] E. Kioseoglu, C. Gabriel, S. Petanidis, V. Psycharis, C.P. Raptopoulou, A. Terzis, A. Salifoglou, Z. Anorg, Allgem. Chem. 639 (2013) 1407. [39] J.M. Missina, B. Gavinho, K. Postal, F.S. Santana, G. Valdameri, E.M. de Souza, D.L. Hughes, M.I. Ramirez, J.F. Soares, G.G. Nunes, Inorg. Chem. 57 (2018) 11930.
(b) L. Reytman, O. Braitbard, J. Hochman, E.Y. Tshuva, Inorg. Chem. 55 (2016) 610. H. Ou, L. Yan, D. Mustafi, M.W. Makinen, M.J. Brady, J. Biol. Inorg. Chem. 10 (2001) 874. D.C. Crans, L. Henry, G. Cardiff, B.I. Posner, Met. Ions Life Sci. 19 (2019) 203–230. G. Huyer, S. Liu, J. Kelly, J. Moffat, P. Payette, B. Kennedy, G. Tsaprailis, M.J. Gresser, C. Ramachandran, J. Biol. Chem. 272 (1997) 843. (a) E. Irving, A.W. Stoker, Molecules 22 (2017) 2269; (b) S. Shehzad, Biohorizons 6 (2013) 1. M. Xie, D. Chen, F. Zhang, G.R. Willsky, D.C. Crans, W. Ding, J. Inorg. Biochem. 136 (2014) 47. S. Trevino, E. Brambila-Colombres, D. Válesquez-Vásquez, E. Sánchez-Lara, E. Gonzales-Vergara, A. Diaz-Fonseca, J.Á. Flores-Hernandez, A. Pérez-Benitez, E.B. Colombes, E.G. Vergara, Oxid. Med. Cell Longev. (2016) 60. H. Sakurai, Chem. Rec. 2 (2002) 237. (a) K. Gruzewska, A. Michno, T. Pawelczyk, H. Bielarczyk, J. Physiol. Pharmacol. 65 (2014) 603; (b) A.A. Holder, P. Taylor, A.R. Magnusen, E.T. Moffett, K. Meyer, et al., Dalton Trans 42 (2013) 11881. E. Kioseoglou, S. Petanidis, C. Gabriel, A. Salifoglou, Coord. Chem. Rev. 301–302 (2015) 87. F. Chen, Z. Gao, C. You, H. Wu, Y. Li, X. He, Y. Zhang, Y. Zhan, B. Sun, Dalton Trans. 48 (2019) 15160. I.E. León, J.F. Cadavid-Vargas, I. Tiscornia, V. Porro, S. Castelli, P. Katkar, A. Desideri, M. Bollati-Fogolin, S.B. Etcheverry, J. Biol. Inorg. Chem. 20 (2015) 1175. I.E. Leon, A.L. di Virgilio, V. Porro, L. Muglia, G. Naso, P.A.M. Williams, M. BollatiFogulin, S.B. Etcheverry, Dalton Trans. 42 (2013) 11868. (a) P. Köpf-Meier, H. Köpf, Z. Naturforsch. 34b (1979) 805; (b) P. Köpf-Meier, H. Köpf, Chem. Rev. 87 (1987) 1137. J. Fichtner, J. Claffey, A. Deally, B. Gleeson, M. Hogan, M.R. Markelova, H. MüllerBunz, H. Weber, M. Tacke, J. Organomet. Chem. 695 (2010) 1175. K. Dankhoff, A. Ahmad, B. Weber, B. Biersack, R. Scobert, J. Inorg. Biochem. 194 (2019) 1. M. Strianese, A. Basile, A. Mazzone, S. Morello, M.C. Turco, C. Pellecchia, J. Cell.
Dieter Rehder: Born 22. 02. 1941 in Hamburg (Germany). www.chemie.uni-hamburg.de/ac/rehder/index.html. 1961 – 1970 Studies of Chemistry and Astronomy (19671970) at the University of Hamburg. 1967 Diploma in Chemistry (Topic: CyanovanadiumComplexes) with Prof. Dr. R. Nast. 1970 Dr. rer. nat. at the of (Topic: “Mixed Carbonyl,- Cyano- and Cyclopentadienyl Complexes of V(+I), V(0) and V(-I)”) with Prof. Dr. R. Nast. 1968 – 1973 Assistant at the Chemistry Department, University of Hamburg. 1970 – 1972 Lecturer at the College for Tobacco Technology and BioEngineering in Hamburg-Bergedorf. 1973 – 1975 Lecturer at the College of Arts Science & Technology and at the Institute for Sugar Technology in Kingston/Jamaica. 1975 – 1979 Habiltation at the University of Hamburg (Topic: “51V Nuclear Magnetic Resonance”) and appointment (1979) as “Privatdozent” (equivalent to Assistant Professor). Since 1983 Full Professor, University of Hamburg.
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Contents lists available at ScienceDirect
Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica
Review article
The potentiality of vanadium in medicinal applications
T
Dieter Rehder Chemistry Department, University of Hamburg, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Diabetes Anti-tumour Antiviral/antibacterial Parasitic diseases Decavanadate
Light is thrown on the impact of vanadium compounds in medicinal issues, including simple inorganic vanadates, such as vanadates stabilized (and thus possibly modified) by organic counter-ions. The main fields of potential medications (and limits thereof) based on vanadium so far do not (yet) enjoy official pharmacological application. However, several sectors of the potentially successful treatment of pathological symptoms with vanadium (coordination) compounds have been thoroughly and mostly successfully investigated during the past two or three decades. The main issues dealt with in the present overview are directed towards (type 2) diabetes, anti-tumour therapy, and the implication of vanadium compounds in (tropical) diseases caused by bacteria, viruses, flagellates or amoeba, such as tuberculosis, sleeping sickness and Chagas disease, leishmaniasis and amoebiasis. The investigations directed towards medicinal applications of vanadium compounds have commonly been carried out, in vitro and in vivo, with experimental animals. Most promising perhaps in the field of potential applications of vanadium-based medications is the antidiabetic effect of rather simple coordination compounds such as VO(maltol)2, a complex that has been checked in clinical tests I and II.
1. Introduction and general aspects Vanadium is an omnipresent element in Earth’s crust (0.019%, 21st most abundant element), in seawater and in ground water (up to 100 µg l−1), and – accordingly – also in living organisms. Of particular interest in this context is the presence of vanadium in various marine macro-algae (where vanadium is in the active centre of haloperoxidases) and in medicinal plants[1a], such as wild thyme [1b] with an average vanadium content of 0.5 mg V per kg dry matter. Vanadium can also stimulate plant growth [1c]. For humans, the common daily intake amounts to 0.01–0.02 mg. Nutritional intake takes place in the form of oxidovanadium(IV) or -(V) compounds, or – more predominant – as vanadate H2VO4− (at physiological pH). Excretion essentially occurs via the urine (hydrogenvanadate) and faeces (in the form of VO2+/ 3+ hydroxides). Microbial control of the vanadium contents in the environment, i.e. removal of vanadium by reduction of easily soluble vanadate to insoluble oxidovanadium(IV)hydroxide, as well as resupply of vanadate via oxidation of VO2+ to vanadate, is an important environmental factor in the context of the overall vanadium balance [1d] (for details, see Section 4). Small amounts of vanadium, taken in via nutrients and drinking water, supposedly are beneficial, while excessive vanadium amounts (high local vanadium concentrations originating from natural deposits or human input [2a], or inhaled vanadium oxides present in the breathing air in industrial areas) are toxic. For a general overview of the potential ecotoxicity of vanadium, see Ref. [3a]. The threshold limit value for breathing air is 0.05 mg m3 [2b]. The main transporter for the VO2+ ion in the blood system is transferrin; to some extent, albumin also comes in as a transporter. Most of the “modern” https://doi.org/10.1016/j.ica.2020.119445 Received 3 January 2020; Accepted 11 January 2020 Available online 14 January 2020 0020-1693/ © 2020 Elsevier B.V. All rights reserved.
medicinal applications based on vanadium employ vanadium incorporated into organic ligand systems. These coordination compounds are, in several cases, subject to degradation (with the formation of vanadate and/or oxidovanadium(IV/V)) at physiological conditions [3b], a fact that can be responsible for off-target toxicity. Vanadate can act as a phosphate analogue, thus interfering with phosphate dependent activities. Examples are the inhibition of the extra/intracellular transporter (ATPase) for Na+ and K+ [4a]), and the interaction with phosphate-based structures such as DNA. In addition, vanadate can partially replace phosphate in bone structures [4b]. However, this non-specific (in contrast to phosphate) bioactivity can also cause objectionable side effects, essentially due to the fact that vanadate forms stable covalent bonds to functionalities within physiologically relevant biomolecules, while the respective interaction between phosphate and functions such as {N}, {O} and {S} is reversible and thus intermediate in nature. Further, vanadium compounds eventually can interfere – based on the ease of change in oxidation state (VIV ⇆ VV) – with oxidative stress [5a] caused by superoxide and peroxide; in its VO2+ state, vanadium can be an effective antioxidant [5b]. On the other hand, peroxovanadates such as H2V(O2)O3− can eventually form, and exert oxidative stress. It should be noted that vanadium is categorized (category 2) as a cancer generating/genotoxic substance. In addition, adverse outcomes within the scope of prenatal exposure to excessive vanadium concentrations have been associated with anthropogenic activities [6]. In the present overview, the main emphasis is laid upon beneficial aspects with (potential) medicinal applications. For a summary of the health benefits of vanadium compounds see also Ref. [7]; for a more
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Fig. 1. Selection of vanadium coordination compounds VOL that have been shown to exhibit insulin-mimetic properties. The bidentate ligands are ethyl-maltolate (1) [8], 3-hydroxypicolinate (2a) [12b], 2,5-dipicolinate (2b) [12c], adenosine monophosphate (3) [13], orotate (4)[14a], and aminotris(phenolate) (5) [14b] An effective transporter for the maltolato complex in the blood system is albumin [15].
critical view and potential health hazards of vanadium Ref. [8]. A positive impact of vanadium has also been reported in the context of the downregulation of inflammation and in immunotherapy[9a], while a positive response on the athletic performance, such as propagated by, inter alia, “vanadyl fuel” (containing oxidovanadium sulphate) and “vanadium water” (from the Fuji region, containing H2VO4−) has not unambiguously been accredited. These “vanadyl fuels” are not to be mistaken for vanadyl petroporhyrines present in crude oil [9b]. 2. Treatment of diabetes The first anti-diabetic vanadium compound, a maltolato complex of composition VO(maltolate)2 (=oxido-bis(ethylmaltolato)vanadium (IV)) had been introduced into phase IIa clinical tests [10] (and abandoned thereafter due to sporadic (mild) renal problems with some of the test persons). Ethylmaltol (see 1 in Fig. 1) derives from the naturally occurring methyl variant, present e.g. in pine needles and malt. Various other oxidovanadium coordination compounds have since been subjected to in vitro and in vivo studies – commonly with test animals – for their ability to lower elevated blood glucose (and lipid) levels in the case of type II and – to some extent – also type I diabetes mellitus [11]. In the case of insufficient insulin supply, the uptake of glucose by – and degradation within – cells is hampered. A few selected examples of vanadium coordination compounds VOL that have been proven potentially valid insulin-mimetic compounds are collated in Fig. 1. The actually active species under in vivo conditions supposedly is vanadate H2VO4−, which forms – essentially extracellularly – via (oxidative) hydrolysis of the applied vanadium coordination compound. For a likely course of action, see Fig. 2. In this context, the hypoglycemic effect of a tea/vanadate decoction orally delivered to diabetic rats, and inducing long-term glycaemic stability, is of some interest[12a]. Vanadate can enter the intracellular space via phosphate channels (scenario 2 in Fig. 2) integrated in the cellular membrane, and interact with (and thus lock off) protein tyrosine phosphatase, in such a way preventing dephosphorylation of the intracellular tyrosine phosphate attached to the insulin receptor. Signalling towards the mechanism for glucose intake – otherwise initiated as insulin docks to the insulin receptor (scenario 1. in Fig. 2) – is thus restored. Since other members of the phosphatase family are equally sensitive to vanadate, vanadium compounds can be expected to also have unfavourable side effects. Most in vivo animal studies have been carried out with Wistar rats having induced diabetes (for a recent review see [16]), employing
Fig. 2. Proposed mechanism for the impact of vanadium coordination compounds VOL (for L see Fig. 1) on the cellular uptake of glucose in the case of absence/critical shortage of insulin. If disposable, insulin docks to the insulin receptor (1.), thus initiating the intake (followed by degradation) of glucose. In the case of insulin undersupply, PTP (PTP = protein tyrosine phosphatase) hydrolytically dephosphorylates the tyrosine, thus blocking off signalling for glucose intake. As vanadate enters the cellular interior (2.), it coordinates to the sulphide of a cysteinyl residue of PTP, forming {PTP}CH2SVO4H2−, in such a way inhibiting the PTPase [17,18] and restoring the signalling path (2.) for the uptake of glucose.
streptozotocin (STZ, glucosamine nitrosourea) [19] or alloxan (a pyrimidine derivative) [20]. Streptozotocin and alloxan deactivate the pancreatic β cells, inducing a severe form of diabetes type I (where the pancreatic β cells are non-productive with respect to insulin). They are hence of restricted relevance for the direct treatment of diabetes in humans, where at least 90% of the individuals suffer from type II diabetes, i.e. a relative lack of and/or resistance towards insulin. On the other hand, administration of vanadium compounds in case of the treatment of diabetes has been shown to induce weight loss [21], a fact that – in any case – is of relevance when counteracting the prevalence of diabetes. 3. Anti-tumour and anticancer therapy For a comprehensive overview of the chemistry and biology of vanadium compounds in cancer therapeutics see, e.g., Ref. [22]. Simple inorganic vanadium compounds such as the oxidovanadium(IV) cation 2
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Fig. 3. Selected vanadium coordination compounds that have shown anti-cancer effects in vitro and in vivo. The ligands are based on ethylenediamine diacetic acid (the peroxide complex 1) [24], silibinin (2) [25], cyclopentadienide(1-) and selenocyanate (3) [28], an indolyl-catecholate (4) [29] and pyridoxal (5) [30]. Compounds 6 [31] is effective in promoting oncoviral propagation.
VO2+, or the anionic species hydrogenvanadate H2VO4− and peroxidovanadate HVO3(O2)2− can exhibit anti-tumour effects due to their ability to induce the activation of liver enzymes, such as γ-glutamyl transpeptidase [23], that effectively inhibits tyrosine phosphatases (see also above) and activate tyrosine phosphorylases. Vanadium compounds containing the peroxido ligand (see, e.g., compound 1 in Fig. 3), and thus disposing of the potential to generate reactive oxygen species, can cause oxidative damage and even apoptosis more efficiently in fast growing cancer cells than in healthy cell tissues. Among the naturally occurring products exhibiting cyto-protection (and thus the capability in fighting cancer), silibinin, a flavonoid from the thistle Silybum marianum, is noteworthy since its antioxidant (and thus cyto-protective) properties are enhanced when coordinated to VO2+. The coordination compound VO(silibinin)2 (2 in Fig. 3) effectively thwarts osteosarcomas [25]. Similarly, [VO(chrysin)2(C2H5OH)]2 [26], containing the naturally occurring – in the passion flower Passiflora – flavone chrysin, is cytoprotective. Non-oxido vanadium compounds can be equally effective. Thus, vanadocene Cp2VCl2 has been shown as early as 1979 to be active in the medication of Ehrlich ascites tumour cells (cultured in vivo) by causing morphological changes in these cells [27]. Other vanadocenes, such as the selenocyanato-vanadium(IV) complex Cp′2V(NCSe)2 (3 in Fig. 3, Cp′ is p-methoxiphenyl) [28] display in vivo toxicity against renal cancer cells, possibly because the Cp2V fragment (forming from Cp2VL2 by hydrolytic loss of the ligands L) binds – via vanadium – to the phosphate residues of DNA, thus deactivating replication and hence cell growth. More generally, vanadocenes are potent cytotoxic compounds against testicular cancer. Another example of a non-oxido complex that exhibits significant antiproliferative activity against various cancer cell lines, again through strong binding to DNA and hence mitochondrial damage, is the catecholate complex 4 [29] in Fig. 3. The pyridoxal based oxidovanadium(IV) complex 5 in Fig. 3 induces ca. 90% mortality in human melanoma cells via induction of apoptosis, again by an increase of reactive oxygen species [30]. Vanadate and oxidovanadium(V) are also effective in increasing viral replication of non-pathogenic viruses that kill cancer cells (oncolytic viruses such as rhabdovirus VSVΔ51; oncolytic viruses have available a DNA or RNA genome). Efficient precursor compounds in this
respect are dioxido-picolinato vanadates of composition [VO2(p-dipicX)]− (6 in Fig. 3 [31]) where X is H, Cl or OH, which – in the cell culture medium – hydrolyse to provide VO2+ and H2VO4−. 4. Antiviral, antibacterial and anti-parasitic issues Fig. 4 provides an overview of selected vanadium coordination compounds that have been shown to be effective in fighting infectious diseases, viz. tuberculosis and diseases caused by parasitic protozoa, bacteria and viruses that are essentially native in tropical regions (amoebiasis, leishmaniasis, sleeping sickness and Chagas disease). For a survey, see, e.g., Ref. [7b]. Amoebiasis (counteracted by compound 1 in Fig. 1) goes back to an infection with Entamoebae such as E. histolytica, commonly in the case of sanitation problems; bloody diarrhoea is one of the typical symptoms. Tuberculosis (2) is caused by mycobacteria (Mycobacterium tuberculosis) and transferred between individuals via aerosol droplets. Leishmaniasis (3) is induced by a flagellate (belonging to the genus Trypanosoma) and spread via the bite of sand-flies (such as Phleobotumus and Lutzomyia). Typical symptoms are skin ulcers. Sleeping sickness (4), also known as African trypanosomiasis, goes back to Trypanosomas brucei, a flagellate transferred by the tsetse fly. Symptoms include fever and problems with coordination. Chagas disease (5) (also known as American trypanosomiasis) is spread by the kissing bug (or assassin bug, belonging to the Triatominae). Symptoms include fever and headache. A potential target for these compounds is DNA, i.e. the mode of action of these compounds (or degradation products thereof formed at physiological conditions) may root in the inhibition of DNA replication of the parasitic DNA, via direct (hydrophobic) interaction between the aromatic environment of the drug and the aromatic residues of the nucleobases of DNA. Alternatively, coordination to (and thus deactivation of) the phosphate linkages by hydrolysis products of the original vanadium complexes comes in (see also Section 1). Biological activity (and thus pharmacological effects) against, e.g., human cancer cell lines, have also been reported for decavanadates (for a review see [37]), in particular for decavanadate with organic cations as counter-ions [38]. Anti-bacterial potential has been established for decavanadate [H2V10O28]4− with counter-ions such as nicotinamide 3
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Fig. 4. Vanadium complexes that have been tested for their potentiality in the treatment of diseases based on viral, bacterial or parasitic infections, viz. amoebiasis (1; the ligand derives from 5,5′-methylene-bis(salicylaldehyde) and S-methyldithiocarbazide [32]), tuberculosis (2; the ligands are salicylglycine and 8-hydroxyqhinoline [33]), leishmaniasis (the salophen complex 3 [34]), trypanosomiasis (sleeping disease, 4; the ligands are bipyridine and a derivative of salicylaldehyde semicarbazone [35]), and Chagas disease (5; a coordination compound with epoxyphenathroline [36]).
monovanadate as the actually active species. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] (a) I.A. Owolabi, K.L. Mandiwana, N. Panichev, S. Afr, J. Chem. 69 (2016) 67; (b) D.S.W. Antal, C.A. Dehelean, C.M. Canciu, M. Anke, Anal. Univers. Oradea, Fasc. Biol. 16 (2009) 5; (c) A. García-Jiménez, L.I. Trejo-Téllez, D. Guillén-Sánxhez, F.C. Gómez-Merino, PLOS One (2018), https://doi.org/10.1371/journal.pone0201908; (d) J.-H. Huang, F. Huang, L. Evans, S. Glasauer, Chem. Geol. 417 (2015) 68. [2] (a) Y. Yu, J. Yang, Chemosphere 215 (2019) 294; (b) Ch. 6.12 in: WHO Regional Office for Europe, Copenhagen, Denmark, 2000. [3] (a) J.P. Gustafsson, Appl. Geochem. 102 (2019) 1; (b) A. Levina, P.A. Lay, Chem. Asian J. 12 (2017) 1692. [4] L.C. Cantley, M.D. Resh, G. Guidotti, Nature 272 (1978) 552. [5] (a) A. Ścibior, J. Llopis, A.A. Holder, M. Altamirano-Lozano, Oxid. Med. Cellul. Longevity (2016); (b) A. Ścibior, J. Kurus, Curr. Med. Chem. 26 (2019) 5456. [6] J. Hu, et al., Lancet Planet Health 1 (2017) 230. [7] (a) C. Ulbricht, et al., J. Diet. Suppl. 9 (2012) 223; (b) D. Rehder, Fut. Med. Chem. 8 (2016) 325. [8] C. Wong, http:///www.verywellhealth.com/the-benefits-of-vanadium. [9] (a) O. Tsave, S. Petanidis, E. Kioseoglou, M.P. Yavropoulou, J.G. Yvos, D. Anestakis, A. Tsepa, A. Salifoglou, Ox. Med. Cell Long. ID (2016) 4013639; (b) D. Mannikko, S. Stoll, Energy Fuels 33 (2019) 4237. [10] K.H. Thompson, C. Orvig, J. Inorg. Biochem. 100 (2006) 1925. [11] G. Boden, Proc. Assoc. Am. Phys. 111 (1999) 241. [12] (a) T.A. Clark, C.E. Heyliger, M. Kopilas, A.L. Edel, A. Junaid, F. Aguilar, D.D. Smyth, J.A. Thliveris, M. Merchant, H.K. Kim, G.N. Pierce, Metabolism 61 (2012) 742; (b) T. Koleša-Dobravc, K. Maejima, Y. Yoshikawa, A. Meden, H. Yasui, F. Perdih, New. J. Chem. 42 (2018) 3619; (c) J. Gätjens, B. Meier, Y. Adachi, H. Sakurai, D. Rehder, Eur. J. Inorg. Chem. (2006) 3575. [13] A.M. Naglah, M.A. Al-Omar, M.A. Bhat, A.S. Al-Wasidi, A.M.A. Alsuhaibani, A.M. El-Didamony, N. Hassa, S.A. Taleb, M.S. Refat, Crystals 9 (2019) 208. [14] (a) A.M. Naglah, M.A. Al-Omar, A.A. Almehizia, M.A. Bhat, W.M. Afifi, A.S. AlWasidi, J.Y. Al-Humaidi, M.S. Refat, BioMed. Res. Int. (2018) 1;
Fig. 5. A decavanadate salt, (3-Hpca)]4[H2V10O28]⋅2(3-pca)⋅2H2O, that is active in fighting intestinal infections [39].
and isonicotinamide, Fig. 5 [39]. These compounds have been shown to efficiently exhibit growth inhibitory activity against bacterial stems such as Giardia intestinales and pathogenic varieties of Escherichia coli (otherwise a coliform bacterium in the gut microbiota responsible for, e.g., the production of vitamin K). G. intestinales is a flagellated parasite in the small intestines, the trophozites of which cause giardiasis (beaver fever), accompanied by diarrheal diseases. The mechanism of action of decavanadate remains to be elucidated, though. Decavanadate by itself is not stable in aqueous media at physiological (and hence rather low) concentrations. The counter-cation in the original medication, or counter-ions eventually provided in the physiological broth, might protect decavanadate – via interaction of the decavanadate with these organic ions – to the effect that [H2V10O28]n− is transported to the locus agendi, where it successively provides 4
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[15] [16] [17] [18] [19] [20]
[21] [22]
[23] [24] [25]
[26] [27] [28] [29] [30]
Physiol. 228 (2013) 2202. [31] A. Bergeron, K. Kostenkova, M. Selman, H.A. Murakami, E. Owens, N. Haribabu, R. Arulanandam, J.-S. Diallo, D.C. Crans, Biometals 32 (2019) 545. [32] M.R. Maurya, C. Haldar, A.A. Khan, A. Azam, A. Salahuddin, A. Kumar, J.C. Pessoa, Eur. J. Inorg. Chem. (2012) 2560. [33] I. Correia, P. Adão, S. Roy, M. Wahba, C. Matos, M.R. Maurya, F. Marques, F.R. Pavan, C.Q.F. Leite, F. Avecilla, J. Costa Pessoa, J. Inorg. Biochem. 141 (2014) 83. [34] P. de Almeida Machado, V.Z. Mota, A.C. de Lima Cavalli, G.S.G. de Carvalho, A.D. da Silva, J. Gameiro, A. Cuin, E.S. Coimbra, Acta Trop. 148 (2015) 120. [35] M. Fernández, L. Becco, I. Correia, J. Benítez, O.E. Piro, G.A. Echeverria, A. Madeiros, M. Comini, M.L. Lavaggi, M. Gonzáles, H. Cercetto, V. Moreno, J. Costa Pessoa, B. Garat, D. Gambino, J. Inorg. Biochem. 127 (2013) 150. [36] J. Benítez, I. Correia, L. Becco, M. Fernández, B. Garat, H. Gallardo, G. Conte, M.L. Kuznetsov, A. Neves, V. Moreno, J. Costa Pessoa, D. Gambino, Z. Anorg. Allgem. Chem. 639 (2013) 1417. [37] M. Aureliano, Oxid. Med. Cell Longev. (2016) 6103457. [38] E. Kioseoglu, C. Gabriel, S. Petanidis, V. Psycharis, C.P. Raptopoulou, A. Terzis, A. Salifoglou, Z. Anorg, Allgem. Chem. 639 (2013) 1407. [39] J.M. Missina, B. Gavinho, K. Postal, F.S. Santana, G. Valdameri, E.M. de Souza, D.L. Hughes, M.I. Ramirez, J.F. Soares, G.G. Nunes, Inorg. Chem. 57 (2018) 11930.
(b) L. Reytman, O. Braitbard, J. Hochman, E.Y. Tshuva, Inorg. Chem. 55 (2016) 610. H. Ou, L. Yan, D. Mustafi, M.W. Makinen, M.J. Brady, J. Biol. Inorg. Chem. 10 (2001) 874. D.C. Crans, L. Henry, G. Cardiff, B.I. Posner, Met. Ions Life Sci. 19 (2019) 203–230. G. Huyer, S. Liu, J. Kelly, J. Moffat, P. Payette, B. Kennedy, G. Tsaprailis, M.J. Gresser, C. Ramachandran, J. Biol. Chem. 272 (1997) 843. (a) E. Irving, A.W. Stoker, Molecules 22 (2017) 2269; (b) S. Shehzad, Biohorizons 6 (2013) 1. M. Xie, D. Chen, F. Zhang, G.R. Willsky, D.C. Crans, W. Ding, J. Inorg. Biochem. 136 (2014) 47. S. Trevino, E. Brambila-Colombres, D. Válesquez-Vásquez, E. Sánchez-Lara, E. Gonzales-Vergara, A. Diaz-Fonseca, J.Á. Flores-Hernandez, A. Pérez-Benitez, E.B. Colombes, E.G. Vergara, Oxid. Med. Cell Longev. (2016) 60. H. Sakurai, Chem. Rec. 2 (2002) 237. (a) K. Gruzewska, A. Michno, T. Pawelczyk, H. Bielarczyk, J. Physiol. Pharmacol. 65 (2014) 603; (b) A.A. Holder, P. Taylor, A.R. Magnusen, E.T. Moffett, K. Meyer, et al., Dalton Trans 42 (2013) 11881. E. Kioseoglou, S. Petanidis, C. Gabriel, A. Salifoglou, Coord. Chem. Rev. 301–302 (2015) 87. F. Chen, Z. Gao, C. You, H. Wu, Y. Li, X. He, Y. Zhang, Y. Zhan, B. Sun, Dalton Trans. 48 (2019) 15160. I.E. León, J.F. Cadavid-Vargas, I. Tiscornia, V. Porro, S. Castelli, P. Katkar, A. Desideri, M. Bollati-Fogolin, S.B. Etcheverry, J. Biol. Inorg. Chem. 20 (2015) 1175. I.E. Leon, A.L. di Virgilio, V. Porro, L. Muglia, G. Naso, P.A.M. Williams, M. BollatiFogulin, S.B. Etcheverry, Dalton Trans. 42 (2013) 11868. (a) P. Köpf-Meier, H. Köpf, Z. Naturforsch. 34b (1979) 805; (b) P. Köpf-Meier, H. Köpf, Chem. Rev. 87 (1987) 1137. J. Fichtner, J. Claffey, A. Deally, B. Gleeson, M. Hogan, M.R. Markelova, H. MüllerBunz, H. Weber, M. Tacke, J. Organomet. Chem. 695 (2010) 1175. K. Dankhoff, A. Ahmad, B. Weber, B. Biersack, R. Scobert, J. Inorg. Biochem. 194 (2019) 1. M. Strianese, A. Basile, A. Mazzone, S. Morello, M.C. Turco, C. Pellecchia, J. Cell.
Dieter Rehder: Born 22. 02. 1941 in Hamburg (Germany). www.chemie.uni-hamburg.de/ac/rehder/index.html. 1961 – 1970 Studies of Chemistry and Astronomy (19671970) at the University of Hamburg. 1967 Diploma in Chemistry (Topic: CyanovanadiumComplexes) with Prof. Dr. R. Nast. 1970 Dr. rer. nat. at the of (Topic: “Mixed Carbonyl,- Cyano- and Cyclopentadienyl Complexes of V(+I), V(0) and V(-I)”) with Prof. Dr. R. Nast. 1968 – 1973 Assistant at the Chemistry Department, University of Hamburg. 1970 – 1972 Lecturer at the College for Tobacco Technology and BioEngineering in Hamburg-Bergedorf. 1973 – 1975 Lecturer at the College of Arts Science & Technology and at the Institute for Sugar Technology in Kingston/Jamaica. 1975 – 1979 Habiltation at the University of Hamburg (Topic: “51V Nuclear Magnetic Resonance”) and appointment (1979) as “Privatdozent” (equivalent to Assistant Professor). Since 1983 Full Professor, University of Hamburg.
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