Oxidovanadium complexes for the consumption of alkylating toxins

Article abstract of DOI:10.1002/ejic.200800949

Carcinogens found in cooked foods, tobacco smoke, and vehicle exhaust undergo metabolic activation to pernicious alkylating toxins, yield damaged DNA, and promote cancerous growth. Vanadium has been shown to decrease the occurrence of cancers, possibly by

Full text of DOI:10.1002/ejic.200800949

SHORT COMMUNICATION
DOI: 10.1002/ejic.200800949
Oxidovanadium Complexes for the Consumption of Alkylating Toxins
Jessica M. Fautch,[a] Phillip E. Fanwick,[a] and Jonathan J. Wilker*[a]
Keywords: Bioinorganic chemistry / Vanadates / Alkylation / Hydrolysis / Substituent effects
Carcinogens found in cooked foods, tobacco smoke, and ve-
hicle exhaust undergo metabolic activation to pernicious al-
kylating toxins, yield damaged DNA, and promote cancerous
growth. Vanadium has been shown to decrease the occur-
rence of cancers, possibly by intercepting such toxins before
DNA damage can occur. According to recent results, nucleo-
ethyl sulfate were treated with a series of new oxidovana-
dium complexes of the salicylidenehydrazide ligand, [VO2-
(salhyph(R)2)]–. These complexes consumed a collection of
alkylating agents and brought about transformation to
alcohols. Changing the ligand substituents (R = –OCH3,
–CH3, –H, –NO2) yielded a series of compounds with varied
philic oxido salts of vanadium can prevent this DNA alky- degrees of electron density. Kinetic experiments indicated
lation. Although effective at detoxification and preventing
DNA damage, vanadate salts equilibrate in solution to mul-
tiple coexisting species and can exhibit toxicity. Ligand-en-
forced coordination geometries may minimize such equili-
brations, thereby decreasing toxicity and providing a means
to control reactivity. As part of our efforts to detoxify alkylat-
ing agents, here we are studying reactions between oxidova-
nadium complexes and toxins. Alkylating agents such as di-
that there may be a correlation between electron density and
reactivity with alkylating toxins. The design and reactivity of
these compounds indicate that we may be able to exert con-
trol over interactions between carcinogens and metal com-
plexes. Such principles may be helpful in developing new
compounds for the prevention of cancer.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
consuming the toxin prior to the onset of DNA dam-
age.[17,18] Although a new mechanism for preventing DNA
damage is exciting, concentrating efforts on simple metal-
oxido salts will not permit control over reactivity and toxic-
ity. Problems with using simple salts include solution equili-
bration to multiple coexisting species, thus enhancing toxic-
ity and complicating mechanistic studies. Introduction of
chelating ligands to the metal-oxido moiety will minimize
such equilibria and also facilitate the design of chemoprev-
entative metal complexes with controllable chemistry.
A rich history surrounds complexes in which vanadium is
bound by organic ligands. Perhaps the most widely known
examples are those of the insulin mimetic vanadium com-
pounds.[19–22] Other prominent examples of oxidovanadium
complexes include oxidation catalysts, photocatalysts, and
model complexes for vanadium-containing enzymes.[23–27]
Use of organic ligands to bind metals can provide control
over the compound charge, nuclearity, metal coordination
number, nature of the ligand donor atoms, and the extent
of ligand electron donation to the metal center. Occupation
of multiple coordination sites about vanadium centers mini-
mizes unwanted reactions and interconversions (e.g., mono-
mer ↔ dimer ↔ trimer), consequently simplifying the
mechanistic chemistry at hand. Greater complex stability
may also reduce toxicity by preventing vanadium from
mimicking phosphate [i.e., (VO4)3– vs. (PO4)3–] and in-
hibiting phosphate-processing enzymes.[28] Proper choice
and design of ligands provides us with inroads to de-
veloping cancer preventing complexes with controlled reac-
Introduction
We are constantly exposed to carcinogens resulting from
the combustion of organic matter. Cooked food, tobacco
smoke, and vehicle exhaust all contain alkylating carcino-
gens such as the polycyclic aromatic hydrocarbons (PAHs)
and nitrosamines.[1–3] Toxicity of these compounds is a re-
sult of enzymatic oxidation into electrophiles that attack
nucleophilic positions on DNA. The resulting alkylated
bases can mispair during replication, yield mutations, and
bring about cancerous growth.[4,5] In order to develop new
approaches to cancer prevention, we are focusing attention
on ways to minimize such DNA damage. Recent studies
have shown that salts of vanadium[6–10] and selenium[11–13]
prevent cancers induced by alkylating toxins. In aqueous
solutions vanadium[14,15] and selenium[16] equilibrate to an-
ionic metal-oxido species such as (H2VO4)– and (SeO4)2–.
From a mechanistic perspective, however, few detailed in-
sights are available to explain the anticancer properties of
vanadium or selenium. We have previously proposed, and
provided evidence to show, that the cancer preventing prop-
erties of vanadium may result from a “carcinogen intercep-
tion” process.[17] Nucleophilic metal-oxido species can react
directly with electrophilic alkylating carcinogens, thereby
[a] Department of Chemistry, Purdue University,
560 Oval Drive, West Lafayette, IN 47907-2084, USA
Fax: +1-765-494-0239
E-mail: wilker@purdue.edu
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
Eur. J. Inorg. Chem. 2009, 33–37
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
33

J. M. Fautch, P. E. Fanwick, J. J. Wilker
SHORT COMMUNICATION
tivity toward toxins. In this report we describe a series of
These results indicate that this oxidovanadium com-
new oxidovanadium complexes and reactions with alkylat- pound can promote detoxification by transforming this al-
ing agents.
kylating agent into an alcohol. Such reactivity appears to
be a general phenomenon for [VO2(salhyph)]–. Analogous
experiments showed that the alkylating agents CH3CH2–I,
CF3SO2O–CH2CH3, NH2CON(NO)–CH3, and CH3SO2O–
CH3 were each consumed by [VO2(salhyph)]– and yielded
the less toxic alcohols CH3OH or CH2CH3OH. A proposed
mechanism is electrophilic attack of an alkyl cation onto a
nucleophilic terminal oxido of [VO2(salhyph)]–. Support
for this mechanism comes from observations of the
VO(OCH2CH3)(salhyph) intermediate at δ = 1.56 and
Results and Discussion
Dioxidovanadium(V) compounds of the salicylidene-
hydrazide (“salhyph”) ligand provide an excellent entry into
alkylation studies of oxidovanadium compounds
(Scheme 1). Two terminal oxido ligands are present for re-
actions with alkylating agents and, overall, [VO2(salhyph)]–
is anionic, thereby indicating potential nucleophilicity. The
starting K[VO2(salhyph)]·CH3OH[29] was combined 1:1
with the alkylating toxin diethyl sulfate, (CH3CH2O)2SO2.
Diethyl sulfate is a reagent used commonly in carcinogene-
sis studies.[30] This reaction was carried out in distilled [D6]-
1
5.62 ppm in the H NMR spectra.[31] Subsequent proton-
ation from residual water may then release CH3CH2OH.
In order to gain insights on the vanadium-containing
product of this process, a reaction was run in acetone and
then ether was diffused therein. Large, red-brown crystals
resulted and were examined by single-crystal X-ray diffrac-
tion methods (see Supporting Information). The structure
found was that of {[VO(salhyph)]2O}, a known compound
prepared previously via an unrelated route.[32] Scheme 1
shows a proposed reaction in which {[VO(salhyph)]2O} is
produced from [VO2(salhyph)]– and (CH3CH2O)2SO2. This
reaction product resembles a dimer of the starting [VO2-
(salhyph)]–, however one oxygen short. This “missing” oxy-
gen was likely extracted during formation of the ethanol
product. Such results are consistent with our prior work
1
DMSO and monitored by H NMR spectroscopy. Figure 1
shows a 1H NMR spectrum of this reaction in progress, fo-
cusing on the aliphatic resonances. Full spectroscopic data
are provided in the Supporting Information. The starting
(CH3CH2O)2SO2 was consumed while the products
–
(CH3CH2O)SO3 and CH3CH2OH were formed. Methanol
was also observed, persisting from the crystallization of the
starting K[VO2(salhyph)]·CH3OH. Control solutions of
(CH3CH2O)2SO2 in [D6]DMSO did not yield CH3CH2OH
on a comparable time scale.
–
wherein simple vanadates such as (V3O9)3– [i.e. (VO3 )3] re-
acted with alkylating agents to yield alcohols and
–
(V5O14)3– [i.e. one oxygen “missing” from (VO3 )5].[17,33] In-
clusion of a ligand system here preserves the nucleophilic
reactivity of the oxidovanadium moiety and provides a plat-
form for subsequent modifications.
Electron donating (–OCH3, –CH3) and withdrawing
(–NO2) substituents were placed onto the salhyph ligand
framework.[34] The resulting new K[VO2(salhyph(R)2)]
compounds, where R = H is the parent [VO2(salhyph)]–,
were prepared and are depicted in Figure 2. Substituent
electron donation into the aromatic rings may then increase
electron density on the O and N ligand donor atoms. The
central metal ion would exhibit enhanced electron density
and may then increase nucleophilicity of the terminal
oxygen ligands. As a consequence, reactivity toward alkylat-
ing agents could be enhanced. Given the long distances be-
tween added substituents and the terminal oxidos, such
electronic effects are expected to be subtle, but may
serve to indicate that limited control over reactivity is pos-
sible.
Scheme 1. Proposed alkylation reaction of [VO2(salhyph)]–.
1
Figure 1. A H NMR spectrum in [D6]DMSO of the 1:1 reaction,
in progress at approximately 8 h, between K[VO2(salhyph)]·
CH3OH and (CH3CH2O)2SO2. Arrows indicate peak intensity Figure 2. Electron-donating and -withdrawing substituents on
changes during the course of the reaction.
[VO2(salhyph(R)2)]–.
34
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2009, 33–37

Oxidovanadium Complexes for Consumption of Alkylating Toxins
Each of the substituted [VO2(salhyph(R)2)]– compounds
reacted readily with (CH3CH2O)2SO2, as well as all of the
other alkylating agents mentioned above. Product charac-
Conclusions
Here we have shown that a family of oxidovanadium
complexes reacts with alkylating carcinogens and yields
alcohols. Introduction of ligands can be a useful tool in
moderating the nucleophilicity of metal oxides. Thus
changes in ligand architecture may provide an avenue to-
ward nucleophilic compounds for consuming toxins.
1
terization by H NMR spectroscopy showed formation of
CH3CH2OH from ethylating toxins or CH3OH from meth-
ylating toxins, similar to experiments with the parent, un-
substituted [VO2(salhyph)]– compound. Next we examined
kinetics of the reactions between the [VO2(salhyph(R)2)]–
compounds and (CH3CH2O)2SO2. Pseudo-first-order con-
ditions were employed with a 10 : 1 [VO2(salhyph(R)2)]–/
(CH3CH2O)2SO2 ratio and concentrations of 200 m and
20 m, respectively. Rate constants, each determined in
triplicate, were obtained by following the reduction of reso-
nances from (CH3CH2O)2SO2 and plotting concentration
vs. time. The methylene resonances of (CH3CH2O)2SO2
were monitored owing to a clear baseline on either side of
the peak. Two processes may be noted in the plot (see Sup-
porting Information), one of which is background hydroly-
sis of (CH3CH2O)2SO2 in distilled [D6]DMSO, measured
independently to be kobsd. = 1.1ϫ10–5 s–1. Although rea-
gent decomposition is significant under these conditions,
use of dmso was dictated by finding one solvent in which
all derivatives of [VO2(salhyph(R)2)]– are soluble. Kinetic
data were fit to a biexponential containing a fixed compo-
nent to account for the hydrolysis. Figure 3 shows typical
kinetic data along with a curve fit. The rate constants pre-
Experimental Section
H2salhyph(OCH3)2: This compound was prepared by modifying a
published procedure for the unsubstituted salhyph ligand.[35] In a
round-bottomed
flask,
4-methoxybenzhydrazide
(1.734 g,
10.44 mmol) was dissolved in 1-propanol (40 mL) and 2-hydroxy-
5-methoxybenzaldehyde (1.30 mL, 10.43 mmol) was added with
stirring. The yellow reaction mixture was heated at reflux for 17 h,
cooled, and left to stand for 6 h. Light yellow crystals precipitated,
were removed by gravity filtration, and dried under vacuum (2.80 g,
89.6%). 1H NMR (200 MHz, [D6]DMSO, 22 °C): δ = 3.72 (s, 3
H, –OCH3), 3.82 (s, 1 H, –OCH3), 6.85 (br. m, 2 H, ar), 7.05 (br.
3
m, 3 H, ar), 7.90 (d, JH–H = 8.6 Hz, 2 H, ar), 8.58 (s, 1 H, N=C–
H), 10.78 (br. s, 1 H, –OH), 11.99 (br. s, 1 H, –NH) ppm.
H2salhyph(CH3)2: In 1-propanol (40 mL), p-toluic hydrazide
(1.803 g, 12.0 mmol) was dissolved slightly and 2-hydroxy-5-meth-
ylbenzaldehyde (1.633 g, 12.0 mmol) added with stirring. The reac-
sented in Table 1 indicate subtle differences in reactivity be- tion mixture was heated at reflux for 21 h. The solution was cooled
and left to stand for 19 h. Off-white crystals precipitated and were
removed by gravity filtration and dried under vacuum (2.70 g,
83.8%). 1H NMR (300 MHz, [D6]DMSO, 22 °C): δ = 2.24 (s, 3
tween these complexes. The degree of electron donation or
withdrawal from the aryl ring substituents may correlate
with alkylation reactivity.
3
H, –CH3), 2.37 (s, 1 H, –CH3), 6.82 (d, JH–H = 8.4 Hz, 1 H, ar),
3
3
7.09 (d, JH–H = 8.1 Hz, 1 H, ar), 7.35 (m, 3 H, ar), 7.84 (d, JH–H
= 8.1 Hz, 2 H, ar), 8.58 (s, 1 H, N=C–H), 11.1 (br. s, 1 H, –OH),
12.0 (br. s, 1 H, –NH) ppm.
H2salhyph(NO2)2: To a solution of 4-nitrobenzhydrazide (1.812 g,
10.0 mmol) in 1-propanol (40 mL), 2-hydroxy-5-nitrosalicylalde-
hyde (1.672 g, 10.0 mmol) was added with stirring. The reaction
mixture was heated at reflux for 5 h, cooled, and left to stand over-
night. A yellow solid was removed by gravity filtration and dried
under vacuum (3.48 g, 90.4%). 1H NMR (200 MHz, [D6]DMSO,
3
22 °C): δ = 7.09 (d, JH–H = 8.8 Hz, 1 H, ar), 8.15 (br. m, 3 H, ar),
3
8.36 (d, JH–H = 8.2 Hz, 2 H, ar), 8.58 (s, 1 H, ar), 8.73 (s, 1 H,
N=C–H), 12.2 (br. s, 1 H, –OH), 12.43 (br. s, 1 H, –NH) ppm.
K[VO2(salhyph(OCH3)2)]: This compound was prepared as de-
scribed previously for the unsubstituted K[VO2(salhyph)] com-
pound.[29] Potassium metavanadate, KVO3 (0.5518 g, 4.0 mmol),
was stirred in methanol (50 mL) to which H2salhyph(OCH3)2
(1.202 g, 4.0 mmol) was added and the mixture was heated at reflux
for 5 h. Crude yellow product was collected by gravity filtration
from the hot reaction mixture and dried under vacuum (1.01 g,
60.1%). Needle-like crystals were obtained when the crude product
was dissolved in N,N-dimethylformamide, followed by slow vapor
diffusion of diethyl ether for ten days. Crystals were isolated by
Figure 3. Plot of (CH3CH2O)2SO2 concentrations vs. time for
the 10:1 (200:20 m) reaction of [VO2(salhyph(H)2)]– and
(CH3CH2O)2SO2.
Table 1. Pseudo-first-order rate constants for the alkylation reac-
tions of [VO2(salhyph(R)2)]– compounds with (CH3CH2O)2SO2.
Substituent
R
Hammett value
σ
Rate constant[a]
kobsd. [s–1]
1
gravity filtration, rinsed with diethyl ether, and dried in vacuo. H
–NO2
–H
–CH3
–OCH3
+0.78
0
–0.17
–0.27
(4.3Ϯ0.7)ϫ10–5
(5.5Ϯ1.5)ϫ10–5
(6.3Ϯ1.1)ϫ10–5
(6.5Ϯ0.3)ϫ10–5
NMR (300 MHz, [D6]DMSO, 22 °C): δ = 3.72 (s, 3 H, –OCH3),
3
3.81 (s, 3 H, –OCH3), 6.70 (d, JH–H = 9.3 Hz, 1 H, ar), 6.9–7.0
3
3
(m, 3 H, ar), 7.11 (d, JH–H = 3.0 Hz, 1 H, ar), 7.93 (d, JH–H
=
8.7 Hz, 2 H, ar), 8.88 (s, 1 H, C=N–H) ppm. K[C16H14N2O6V]
(420.34): calcd. C 45.72, H 3.36, N 6.66; found C 45.43, H 3.38, N
6.53.
[a] Each rate constant is an average of three runs. The error shows
one standard deviation.
Eur. J. Inorg. Chem. 2009, 33–37
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
35

J. M. Fautch, P. E. Fanwick, J. J. Wilker
SHORT COMMUNICATION
K[VO2(salhyph(CH3)2)]: This compound was prepared as described
for K[VO2(salhyph(OCH3)2)], using the appropriate starting ligand,
H2salhyph(CH3)2. After 4 h of reflux the solution was filtered while
hot. Upon standing, yellow needles precipitated. After cooling to
room temperature, crystals of the desired compound were filtered
by gravity and dried in vacuo (1.07 g, 68.9%). 1H NMR (300 MHz,
[D6]DMSO, 22 °C): δ = 2.24 (s, 3 H, –CH3), 2.35 (s, 3 H, –CH3),
6.67 (d, 3JH–H = 8.1 Hz 1 H, ar), 7.15 (d, 3JH–H = 8.1 Hz, 1 H, ar),
7.24 (d, JH–H = 7.8 Hz, 2 H, ar), 7.31 (s, 1 H, ar), 7.88 (d, JH–H
= 8.1, Hz, 2 H, ar), 8.86 (s, 1 H, C=N–H) ppm. K[C16H14N2O4V]
(388.34): calcd. C 49.49, H 3.63, N 7.21; found C 49.11, H 3.62, N
7.06.
Supporting Information (see also the footnote on the first page of
this article): Complete 1H NMR spectra for select alkylation
reactions and controls, and crystal structure data for
{[VO(salhyph)]2O}.
Acknowledgments
3
3
We thank Ian Henry and John Harwood for assistance with the
1
kinetic H NMR experiments. We also thank and Dale Margerum
and Tong Ren for helpful discussions. Generous support was pro-
vided by the Prevent Cancer Foundation and Alfred P. Sloan Foun-
dation (research fellowship).
K[VO2(salhyph(NO2)2)]·H2O: This compound was prepared as de-
scribed for K[VO2(salhyph(OCH3)2)], using the appropriate start-
ing ligand, H2salhyph(NO2)2. The pale yellow slurry was heated at
reflux for 4.5 h and cooled to room temperature. A yellow solid
was filtered by gravity and dried under vacuum (1.59 g, 84.9%).
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1
The product was recrystallized from nearly boiling acetonitrile. H
3
NMR (300 MHz, [D6]DMSO, 22 °C): δ = 6.94 (d, JH–H = 9.3 Hz,
1 H, ar), 8.1–8.4 (m, 5 H, ar), 8.71 (s, 1 H, ar), 9.27 (s, 1 H, C=N–
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{[VO(salhyph)]2O}: Under an inert argon atmosphere, K[VO2-
(salhyph)]·CH3OH (0.393 g, 1.0 mmol), was added to acetone
(20 mL) and diethyl sulfate, (CH3CH2O)2SO2, (131 µL, 1.0 mmol),
was added to the reaction flask. The pale yellow reaction was
stirred under argon for 5 d, resulting in a dark black-brown solu-
tion. A small portion (appoximately 5 mL) of the acetone reaction
mixture was removed. Diethyl ether was vapor diffused into the
solution for 4 d. The vapor diffusion yielded yellow solids and large
(0.4ϫ0.4ϫ0.4 mm), dark brown-black cubes. After gravity fil-
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solids using tweezers. The cubes were then rinsed with hexanes,
dichloromethane, and water to dissolve residual yellow solids. The
resulting X-ray quality crystals, {[VO2(salhyph)]2O}, were dried in
vacuo. Given that only a portion of the reaction solution was sub-
jected to vapor diffusion, an exact yield cannot be determined.
However, back calculation from the approximately 81 mg of brown-
black cubes indicates that {[VO(salhyph)]2O} can be formed and
crystallized with a rough yield of 324 mg, 52%. 1H NMR
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was combined with diethyl sulfate (DES), (CH3CH2O)2SO2, in dis-
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–
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Received: September 26, 2008
Published Online: November 14, 2008
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