A phenolic antioxidant releasing nitric oxide on demand

Article abstract of DOI:10.1002/ejoc.200901207

A novel molecular conjugate (1) that combines radical scavenging properties to light-regulated release of nitric oxide (NO) has been designed and synthesized by a straightforward procedure. This compound integrates a catecholic unit and a suitable NO photodonor, separated by an alkyl spacer, into the same molecular skeleton. The radical scavenging properties of 1 were evaluated by investigating its reactivity toward hydrogen abstraction by tert-butoxy radical by using laser flash photolysis techniques. The catecholic function of 1 is transparent to visible light, which, in contrast, is exclusively absorbed by the NO photodonor, resulting in the photocontrolled release of this radical species, monitored by an ultrasensitive NO electrode. A comparison of the value of the hydrogen abstraction rate constant and the amount of NO photoreleased with those of reference models demonstrates the retention of the single properties into the new molecular entity. This characteristic together with its water solubility make 1 a potential model system in the perspective of multitarget compounds for biomedical research studies.

Full text of DOI:10.1002/ejoc.200901207

FULL PAPER
DOI: 10.1002/ejoc.200901207
A Phenolic Antioxidant Releasing Nitric Oxide on Demand
Elisa Vittorino[a] and Salvatore Sortino*[a]
Keywords: Photochemistry / Nitric oxide / Phenols / Antioxidants / Radicals
A novel molecular conjugate (1) that combines radical scav-
enging properties to light-regulated release of nitric oxide
(NO) has been designed and synthesized by a straightfor-
ward procedure. This compound integrates a catecholic unit
and a suitable NO photodonor, separated by an alkyl spacer,
into the same molecular skeleton. The radical scavenging
properties of 1 were evaluated by investigating its reactivity
toward hydrogen abstraction by tert-butoxy radical by using
laser flash photolysis techniques. The catecholic function of
1 is transparent to visible light, which, in contrast, is exclu-
sively absorbed by the NO photodonor, resulting in the pho-
tocontrolled release of this radical species, monitored by an
ultrasensitive NO electrode. A comparison of the value of the
hydrogen abstraction rate constant and the amount of NO
photoreleased with those of reference models demonstrates
the retention of the single properties into the new molecular
entity. This characteristic together with its water solubility
make 1 a potential model system in the perspective of
“multitarget” compounds for biomedical research studies.
cisely regulated by enzymes and signal transduction ma-
chinery, NO donors with controllable release of NO seem
indispensable for developing potential therapeutic agents.
The easy manipulation of photons associated with the
instantaneous initiation/stopping of photochemical reac-
tions depending on the presence or not of the illumination
make light the most appealing external on/off trigger to ac-
curately regulate the NO dosage. Furthermore, photons of-
fer the additional advantages to make the NO delivery both
spatially and temporally controlled,[9] without affecting im-
portant physiological parameters such as pH, temperature,
ionic strength, and so on, which is advantageous in view of
biomedical applications. As a consequence, the combina-
tion of phenol-like antioxidant centers with suitable NO-
photodonor appendages represents a valuable objective to
pursue. In principle, these compounds would offer the pos-
sibility to act as radical scavengers in the dark with the
additional property of NO delivery with great accuracy of
the dosage, when stimulated by light.
Prompted by our ongoing interest in developing func-
tional NO photoreleasing systems,[10] in this paper we dem-
onstrate the above proof of concept by designing and synthe-
sizing conjugate 1 (Scheme 1) as a potential multitarget
compound. It integrates a catecholic unit as a radical scav-
enging center and a nitroaniline derivative, which we have
recently discovered to be a good NO photodonor.[10b–10g,11]
The rationale behind the choice of catechol as the antioxi-
dant center is that phenols with two ortho-hydroxy groups
are known to be among the most active antioxidants[12]
and, in this case, are also transparent to visible light. This
latter feature makes the nitroaniline derivative the only
chromogenic center absorbing the visible light, resulting in
Introduction
The design and development of multitarget drugs is one
of the most intriguing challenges in the wide arena of bio-
medical research.[1] Namely, these compounds are single
chemical entities able to address simultaneously more than
one target with the aim of enhancing efficacy relative to
drugs that address only a single target and, in principle,
can be used for the treatment of complex diseases.[1–3] This
strategy represents a significant step forward with respect
to the “one-target, one-disease” approach that continues to
dominate the pharmaceutical industry today and antici-
pates some benefit compared to the use of a monotarget
drug cocktail.[1]
One of the most interesting cases of multitarget com-
pounds is that of nitric oxide (NO)-donor phenol hybrids.[4]
This interest is strongly motivated by the key role NO plays
in a broad array of physiological processes,[5] encompassing
hormone secretion, neurotransmission and vasodilatation,
as well as by the well-known antioxidant properties of syn-
thetic and naturally occurring phenolic compounds
(ArOH).[6] Recently, Gasco and co-workers have shown a
series of phenols containing NO-donor hybrids as potential
candidates to tackle some forms of cardiovascular dis-
eases.[7] However, it should be stressed that NO can act as
a double-edged sword as far as its biological effects are con-
cerned, being either beneficial or detrimental depending on
the dose.[8] Considering than NO formation in vivo is pre-
[a] Dipartimento di Scienze Chimiche, Universitá di Catania,
Viale Andrea Doria, 95125 Catania, Italy
E-mail: ssortino@unict.it
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E. Vittorino, S. Sortino
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the regulated release of NO without affecting the radical
scavenging properties of the catecholic unit.
The radical scavenging properties of 1 were evaluated by
investigating its reactivity toward hydrogen abstraction by
tert-butoxyl radicals. The choice of these radicals as the oxi-
dizing agents is not casual. In fact, existing literature data
on their reactivity with catechol and other substituted phen-
ols[15] will allow us to compare the free radical scavenging
of 1 with that of the isolated antioxidant center.
The experiments were carried out in tert-butyl peroxide
as solvent and tert-butoxyl radicals were generated in situ
by fast laser flash photolysis (within the duration of the
laser pulse of ca. 6 ns) of di-tert-butyl peroxide [Equa-
tion (1)], using the third harmonic of a Nd-YAG laser (λexc
= 355 nm) as the excitation light source:
(1)
tert-Butoxyl radicals may decay by β-cleavage and reac-
tion with the solvent [Equation (2)].[16] However, in the
presence of hydrogen-atom donors, such as ArOH, the tert-
butoxyl radicals are capable of abstracting a hydrogen atom
from the phenolic OH groups, generating, therefore, a phen-
oxyl radical [(ArO·; Equation (3)].
Scheme 1. The molecular structure of 1 and its working principle.
Results and Discussion
Conjugate 1 was easily synthesized in two steps and its
absorption spectrum together with those of suitable model
compounds is reported in Figure 1. The absorption features
of 1 (Figure 1, a), reflect very well those of the equimolar
mixture of the single components (Figure 1, b and c), ac-
counting for negligible mutual interaction between the two
functional units in the ground state.
(2)
(3)
Laser flash photolysis with nanosecond time-resolution
is a powerful tool for obtaining spectroscopic and kinetic
features of phenoxyl radicals. Indeed, these species are gen-
erally characterized by lifetimes in the microsecond scale
and spectral absorptions in the UV/Vis region.[15]
Following irradiation of di-tert-butyl peroxide with
355 nm laser excitation in the presence of 1, we could read-
ily monitor the appearance of a transient with absorption
bands in the 380–420 nm region (Figure 2). According to
Figure 1. Absorption spectrum of a 10–4  aqueous solution of 1
(a) and model compounds 2 (b) and 3 (c).
Phenolic antioxidants are prototypic chain-breaking an-
tioxidants exerting their therapeutic action via the transfer
of a hydroxylic H atom to the chain carrying free radicals
at a rate faster than that of chain propagation.[13] The better
antioxidant activity of catecholic derivatives is largely due
to the stabilization of the aryloxyl radical (derived after hy-
drogen abstraction) due to the formation of intramolecular
hydrogen bonding with the adjacent hydroxy group,[14]
which is obviously absent in other phenols.
Figure 2. Transient absorption spectrum observed 10 µs after
355 nm laser excitation of a N2-saturated di-tert-butyl peroxide
solution containing compounds 1 (0.2 m). E355 ≈ 5 mJ/pulse.
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A Phenolic Antioxidant Releasing Nitric Oxide on Demand
the literature,[17] this transient species can be safely assigned tensively known from the literature[17a,19] and exemplified
to the semiquinone radical resulting from H abstraction in the inset of Figure 4 for 1, lead to orthoquinone species
from 1 (see inset Figure 2).
strongly absorbing at ca. 380 nm.
Figure 3 shows a typical build-up trace (following laser
excitation) at 370 nm observed for the growth of the phen-
oxyl radicals from 1 in Equation (3). In order to determine
the absolute rate constants k3 we used low laser pulse en-
ergy (Ͻ6 mJ/pulse). Such a weak laser impulse ensures that
(i) the initial concentrations of tBuO· radicals is small and
(ii) the heating of the solution is negligible. Under these ex-
perimental conditions, the loss of tert-butoxyl radicals by
the reverse of Equation (1) is negligible and the observed
rate constant, kobs, for the growth of ArO· [Equation (3)],
is related to the concentration of ArOH via simple linear
Equation (4).
kobs = k2 + k3[ArOH]
(4)
Figure 4. Representative experimental trace showing the decay of
the phenoxyl radical observed after 355 nm laser excitation of a di-
tert-butyl peroxide solution of 1 and related second-order fitting.
E355 ≈ 5 mJ/pulse.
The mechanism leading to NO photorelease from the
photoactive unit of 1 has been described in our previous
works.[10a–10g] However, we consider it useful to recall it in
Scheme 2 for the sake of clarity.
Figure 3. Representative experimental trace showing the buildup of
phenoxyl radicals observed after 355 nm laser excitation of a di-
tert-butyl peroxide solution of 1 (0.2 m) and related first-order
fitting. E355 ≈ 5 mJ/pulse. The inset shows the plot of kobs as a func-
tion of the concentration of 1 according to Equation 4.
The inset of Figure 3 reports the plots kobs vs. [ArOH]
obtained by changing the concentration of 1 and by de-
termining the corresponding values of kobs for the growth
of ArO·.[18] Equation (4) appeared to be valid under all the
experimental conditions employed. The slopes of the
Scheme 2. The NO photodonor unit and its mechanism of NO re-
lease.
Briefly, due to the presence of the CF3 substituent the
straight lines afforded a k3 value of 1.4ϫ109 –1 s–1. This nitro group is placed almost perpendicularly to the aro-
value is basically similar to that reported for the same radi- matic plane. This out of plane geometry makes the p orbital
cals with catechol (1.9ϫ109 –1 s–1)[15] and provides strong of the oxygen atom have a constructive overlap with the
evidence that the radical scavenging properties of the anti- adjacent p orbital of the aromatic ring in the ground state.
oxidant center are preserved in conjugate 1.
Such a twisted conformation is crucial in triggering NO
For a complete characterization of the physicochemical photorelease, which takes place through a nitro to nitrite
properties of 1, we also monitored the fate of the phenoxyl photorearrangement followed by the rupture of the O–NO
radical over time. Figure 4 shows the decay profile of this bond, leading to the concomitant generation of NO and a
species at 380 nm. It is possible to note that the experimen- phenoxyl radical that, eventually, gives a phenol derivative
tal trace is best fitted by a second-order function and the as the only stable product. It is noteworthy that, analo-
transient absorption does not go to zero. These results are gously to some dimethylnitrobenzene derivatives, the pho-
in excellent agreement with the disproportionation pathway toactive center of 1 is unique in its mechanism of NO re-
commonly expected for semiquinone radicals, which, as ex- lease.
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E. Vittorino, S. Sortino
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The capability of 1 to generate NO under the exclusive view of the potential bioapplications of 1. In fact, one of
control of light excitation was demonstrated by using an the main problems associated with the NO donor is the
ultrasensitive electrode that detects directly and in real time formation of toxic side products. In the present case, the
this ephemeral radical species with n concentration resolu- phenol derivative generated after NO release is expected to
tion, by an amperometric technique. From the absorption be biocompatible, and moreover, in light of the presence of
spectra of Figure 1 one can promptly note that our design the hydroxy functions, it is also expected to exhibit radical
ensures that the visible light radiation used in the experi- scavenging properties. Studies in this concern are currently
ments (λexc = 420 nm) is selectively absorbed by the NO in progress in our laboratory.
photodonor unit. As shown in Figure 5, irradiation 1 re-
sults in the linear generation of NO, which promptly stops
when the light is turned off and restarts as the light is
turned on again, providing unambiguous evidence for the
exclusive light-controlled generation of NO.
Figure 6. Absorption spectral changes observed upon 0, 10, 20, and
40 min irradiation (λexc = 420 nm) of a water/MeOH (99:1) solution
of 1. The arrows indicate spectral evolution with time.
Conclusions
We report the successful design of a novel, water soluble,
potential multitargeted compound merging radical scaveng-
ing properties with the ability to release NO under the input
Figure 5. NO released upon 420 nm light irradiation of a water/
MeOH (99:1) solution of 1 at 25 °C.
of visible light stimuli. The suitable choice of the two inde-
pendent units is, of course, crucial for the single properties
From the linear portions of the chronoamperogram, an to be retained in the new molecular conjugate, offering the
average rate for NO release of ca. 0.25 nMs–1 can be esti- possibility of joining, in a single compound, two functional
mated. Such a value is very close to that observed in the molecules without any loss of their effectiveness. We would
case of model compound 2 (ca. 0.30 nMs–1) under identical like to emphasize that, in contrast to nonphotoactivated
experimental conditions and indicates that the photoexcited compounds, the preservation of the properties of two inde-
NO photodonor in conjugate 1 is not involved in any sig- pendent units once merged into the same molecular skel-
nificant intramolecular interaction (i.e., photoinduced elec- eton is not obvious in the case of photoactivable molecular
tron transfer)[20] with the antioxidant unit, retaining its own systems. In most of these cases, the properties of the conju-
photochemical properties. That the mechanism for NO re- gate can be in fact considerably affected due to the occur-
lease reported in Scheme 2 applies also in the case of conju- rence of intramolecular photoinduced energy and/or elec-
gate 1 was also confirmed by additional photolysis experi- tron-transfer processes that preclude the final goal.
ments. Figure 6 reports the spectral changes observed after
The concept of balance between the independent units is
different intervals of irradiation of a solution of 1. The pho- central in the multitarget approach. In the case of the NO-
tolysis profile is virtually identical to that noted upon irra- donor–antioxidant hybrids known to date, for example, the
diation of the isolated NO photodonor unit (data not capacity of NO release is commonly adjusted by changing
shown), accounting for no changes in the nature of the the structure of the NO-donor moiety appropriately. In this
main photochemical reaction. The ESI-MS analysis of the concern, photoactivable conjugate 1 may represent a valid
crude reaction mixture carried out immediately after the alternative to these systems, as NO release can be immedi-
photolysis experiments further validates this point. In fact, ately activated, stopped, or accurately tuned depending on
a main peak with a [M + 1]+ value of 314.4 corresponding the light intensity. We finally believe that our proof-of-con-
to the phenol derivative reasonably expected after NO re- cept logical design can, in principle, be extended to a variety
lease was revealed, besides that of the remaining starting of ad-hoc chosen antioxidant and NO photodonor func-
compound. This represents an uncommon advantage in tional molecules, paving the way for the development of
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A Phenolic Antioxidant Releasing Nitric Oxide on Demand
Rayonet photochemical reactor equipped with 8 RPR lamps with
an emission in the 380–480 nm range with a maximum at 420 nm
in the presence of a 400 nm cut-off filter. The incident photon flux
on quartz cuvettes was ca. 1ϫ1015 quanta/sec.
novel classes of multitarget compounds for biomedical re-
search.
Laser Flash Photolysis: The samples were excited with the third
harmonic of a Nd-YAG Continuum Surelite II-10 laser system
(pulse width 6 ns FWHM, at λ = 355 nm) and the excited solutions
were analyzed at a right angle geometry by using a mini mLFP-111
apparatus developed by Luzchem Research. Briefly, the monitoring
beam was supplied by a ceramic xenon lamp and delivered through
quartz fiber optical cables. The laser pulse was probed by fiber that
synchronized the mLFP system with a Tektronix TDS 3032 digi-
tizer operating in the pretrigger mode. The signals from a compact
Hamamatsu photomultiplier were initially captured by the digitizer
and then transferred to a personal computer that controlled the
experiment with Luzchem software developed in the LabView 5.1
environment from National Instruments. The energy of the laser
pulse was measured at each laser shot by a SPHD25 Scientech py-
roelectric energy monitor. Oxygen was removed by vigorously bub-
bling the solutions with a constant flux of argon previously passed
through a water trap. The solution (in a flow cell of 1 cm path
length) was renewed after each laser shot. The sample temperature
was 295Ϯ2 K.
Experimental Section
Materials: All chemicals were purchased from Sigma–Aldrich and
used as received. Di-tert-butyl peroxide was purchased from Ald-
rich and was passed through alumina before use. All solvent used
(from Carlo Erba, Milan) were analytical grade. Model compound
2 was synthesized according to our previously reported pro-
cedure,[10f] whereas model compound 3 was purchased from
Sigma–Aldrich and used as received.
4-(2-{[4-Nitro-3-(trifluoromethyl)phenyl]amino}ethyl)benzene-1,2-
diol (1): Compound 1 was synthesized by a two-step synthesis re-
ported in the following. Syntheses were carried out under a low
intensity level of visible light.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-nitro-3-(trifluoromethyl)aniline
(1a): 2-(3,4-Dimethoxyphenyl)ethanamine (500 mg, 2.76 mmol), 4-
chloro-1-nitro-2-(trifluoromethyl)benzene (622 mg, 2.76 mmol),
and sodium carbonate (230 mg, 2.76 mmol) were heated at reflux
in CH3CN (15 mL) under continuous stirring for 16 h. After cool-
ing down to ambient temperature the resulting suspension was fil-
tered. The organic solution was concentrated under reduced pres-
sure and purified by column chromatography (silica gel; CH2Cl2/
cyclohexane, 7:3) to give 1a (4.1 g, 76%). C17H17F3N2O4 (370.33):
calcd. C 55.13, H 4.63, N 7.56; found C 54.32, H 4.78, N 7.15. MS
(ESI): m/z (%) = 371.2 (100) [M + H]+. 1H NMR (500 MHz,
CDCl3): δ = 8.00 (d, J = 9.2 Hz, 1 H, ArH), 7.15 (d, J = 2.4 Hz, 1
H, ArH), 6.84 (d, J = 8.2 Hz, 1 H, ArH), 6.75 (dd, J = 8.2, 1.8 Hz,
NO Detection: NO release was measured with a World Precision
Instrument, ISO-NO meter, equipped with a data acquisition sys-
tem, and based on direct amperometric detection of NO with short
response time (Ͻ5 s) and sensitivity range 1 nM–20 µ. The analog
signal was digitalized with a four-channel recording system and
transferred to a PC. The sensor was accurately calibrated by mixing
standard solutions of NaNO2 with 0.1  H2SO4 and 0.1  KI ac-
cording to the Equation (5).
1
1 H, ArH), 6.71 (d, J = 1.8 Hz, 1 H, ArH), 6.64 (dd, = 9.2,
2.4 Hz, 1 H, ArH), 4.58 (br. s, 1 H, NH), 4.26 (t, J = 7.2 Hz, 2 H,
NHCH2), 3.88 (s, 6 H, OCH3), 2.91 (t, J = 7.2 Hz, 2 H, ArCH2)
ppm.
–
4H+ + 2I– + 2NO2 Ǟ 2H2O + 2NO + I2
(5)
NO photorelease experiments were performed in a thermostatted
quartz cell (1 cm path length, 3 mL capacity) by using the mono-
chromatic radiation of 420 nm of a fluorimeter Fluorolog-2 (mod.
F-111) as the light source. NO measurements were carried out with
the electrode positioned outside the light path in order to avoid
false NO signal due to photoelectric interference on the ISO-NO
electrode.
4-(2-{[4-Nitro-3-(trifluoromethyl)phenyl]amino}ethyl)benzene-1,2-
diol (1): Compound 1a (120 mg, 0.32 mmol) was dissolved in anhy-
drous CH2Cl2 (12 mL) and cooled to –78 °C. Afterwards, BBr3 (1 
in CH2Cl2, 2.1 mL) was added dropwise. The reaction mixture was
stirred for 2 h at this temperature and then overnight (16 h) at room
temperature. Upon completion, the reaction mixture was quenched
by adding water and extracted with CH2Cl2. The organic layer was
washed with water, dried with anhydrous Na2SO4 and concen-
trated. The residue was purified by flash column chromatography
(2–6% MeOH in CH2Cl2) to afford desired product 1 (80 mg,
73%). C15H13F3N2O4 (342.27): calcd. C 52.64, H 3.83, N 8.18;
found C 52.12, H 3.95, N 7.95. MS (ESI): m/z (%) = 343.3 (100)
Acknowledgments
We thank the Università di Catania (Progetti di Ateneo) for finan-
cial support.
1
[M + H]+. H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 9.2 Hz,
1 H, ArH), 7.53 (d, J = 2.4 Hz, 1 H, ArH), 6.98 (d, J = 1.9 Hz, 1
H, ArH), 6.85 (d, J = 7.8 Hz, 1 H, ArH), 6.83 (dd, J = 7.8, 1.9 Hz,
1 H, ArH), 6.64 (dd, J = 9.2, 2.4 Hz, 1 H, ArH), 5.83 (br. s, 1 H,
NH), 4.21 (t, J = 7.2 Hz, 2 H, NHCH2), 2.98 (t, J = 7.2 Hz, 2 H,
ArCH2) ppm.
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[8]
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Received: October 22, 2009
Published Online: December 4, 2009
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