A photophysical and photochemical study of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic nonsteroidal antiinflammatory drug nabumetone

Article abstract of DOI:10.1562/0031-8655(2000)071<0173:APAPSO>2.0.CO;2

Nabumetone is a phototoxic nonsteroidal antiinflammatory drug used for the treatment of osteoarthritis. However, nabumetone is considered a prodrug with its metabolite 6-methoxy-2-naphthylacetic acid the active form. Photophysical and photochemical studies on this metabolite have been undertaken. It undergoes photodecarboxylation in aerated aqueous and organic solvents. In addition to the accepted photodegradation pathway for related molecules, a new mechanism that implies generation of the naphthalene radical cation from the excited singlet and addition of O₂ prior to the decarboxylation process has been demonstrated. Evidence for the involvement of the excited singlet state in this mechanism have been obtained by steady-state and time-resolved fluorescence experiments. The fluorescence quenching by O₂ and the shorter singlet lifetime in aerated solvents support this assignment. Laser flash photolysis also supports this mechanism by showing the noninvolvement of the triplet in the formation of the naphthalene radical cation. Finally, the well-known electron acceptor CCl₄ acts as an efficient singlet quencher, enhancing the route leading to the radical cation, preventing intersystem crossing to the triplet and thus resulting in a dramatic increase in the yield of 6-methoxy-2-naphthaldehyde, the major oxidative decarboxylation product; this constitutes unambiguous proof in favor of the new mechanistic proposals.

Full text of DOI:10.1562/0031-8655(2000)071<0173:APAPSO>2.0.CO;2

A Photophysical and Photochemical Study of 6-Methoxy-2-naphthylacetic Acid,
the Major Metabolite of the Phototoxic Nonsteroidal Antiinflammatory Drug
Nabumetone
Author(s): F. Boscá, N. Canudas, M. L. Marín, and M. A. Miranda
Source: Photochemistry and Photobiology, 71(2):173-177.
Published By: American Society for Photobiology
DOI: http://dx.doi.org/10.1562/0031-8655(2000)071<0173:APAPSO>2.0.CO;2
URL: http://www.bioone.org/doi/full/10.1562/0031-8655%282000%29071%3C0173%3AAPAPSO
%3E2.0.CO%3B2
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Photochemistry and Photobiology, 2000, 71(2): 173–177
A Photophysical and Photochemical Study of 6-Methoxy-2-naphthylacetic
Acid, the Major Metabolite of the Phototoxic Nonsteroidal
Antiinflammatory Drug Nabumetone
F. Bosca´1, N. Canudas2, M. L. Mar´ın1 and M. A. Miranda1*
1Departamento de Qu´ımica/Instituto de Tecnolog´ıa Qu´ımica UPV-CSIC, Universidad Polite´cnica de Valencia, Valencia,
Spain and
2Departamento de Qu´ımica, Universidad Simo´n Bol´ıvar, Caracas, Venezuela
Received 20 August 1999; accepted 18 November 1999
ABSTRACT
to the incidence of photosensitivity disorders that are higher
with NSAID than with other drugs (1–4).
Nabumetone is a phototoxic nonsteroidal antiinflamma-
tory drug used for the treatment of osteoarthritis. How-
ever, nabumetone is considered a prodrug with its me-
tabolite 6-methoxy-2-naphthylacetic acid the active form.
Photophysical and photochemical studies on this metabolite
have been undertaken. It undergoes photodecarboxyla-
tion in aerated aqueous and organic solvents. In addition
to the accepted photodegradation pathway for related
molecules, a new mechanism that implies generation of
the naphthalene radical cation from the excited singlet
and addition of O2 prior to the decarboxylation process
has been demonstrated. Evidence for the involvement of
the excited singlet state in this mechanism have been ob-
tained by steady-state and time-resolved fluorescence ex-
periments. The fluorescence quenching by O2 and the
shorter singlet lifetime in aerated solvents support this
assignment. Laser flash photolysis also supports this
mechanism by showing the noninvolvement of the triplet
in the formation of the naphthalene radical cation. Fi-
nally, the well-known electron acceptor CCl4 acts as an
efficient singlet quencher, enhancing the route leading to
the radical cation, preventing intersystem crossing to the
triplet and thus resulting in a dramatic increase in the
yield of 6-methoxy-2-naphthaldehyde, the major oxida-
tive decarboxylation product; this constitutes unambig-
uous proof in favor of the new mechanistic proposals.
In this context, nabumetone (NB) is an efficient NSAID
(Fig. 1) used for the treatment of osteoarthritis (5). Nabu-
metone is a relatively selective cyclooxygenase-2 inhibitor
(6,7) that shows less gastrointestinal side effects than other
NSAID (8,9). However, NB was reported to be potentially
phototoxic in human volunteers using an oral dosing proto-
col. Phototoxicity, consisting of wheal-and-flare reactions
following exposure to UV radiation, was demonstrated (10).
Nabumetone is considered a prodrug because it is metabo-
lized by the liver to 6-methoxy-2-naphthylacetic acid
(MNAA) that is actually the active form (Fig. 1).
Recently, a study on the transient intermediates generated
from the photoexcitation of NB appeared in the literature
(11). As the metabolite is the chemical entity able to reach
the skin, we found it of interest to study the photophysical
and photochemical properties of MNAA in order to under-
stand the phototoxic effects of NB. In the present paper, we
have dealt with two different aspects: (1) steady-state pho-
tolysis that provided insight into the photochemical proper-
ties and the photodegradation mechanisms of the metabolite
and (2) a photophysical study using conventional and time-
resolved techniques that provided information about the tran-
sient intermediates involved in the photodegradation path-
ways.
MATERIALS AND METHODS
Chemicals. Acetonitrile and methanol (HPLC grade) were pur-
chased from J. T. Baker (Holland). Benzophenone was from Prola-
bo. All other chemicals used were of reagent grade and used as
INTRODUCTION
Many drugs are known to induce phototoxic responses after
either systemic or topical application. The nonsteroidal an-
tiinflammatory drugs (NSAID)† deserve special mention due
received. 6-Methoxy-2-naphthylacetic acid was synthesized from 6
methoxy-2 -acetonaphthone (Aldrich) following a procedure de-
scribed in the literature for related compounds (12,13).
Synthesis of MNAA. 6 -Methoxy-2 -acetonaphthone (1 g, 5 mmol)
Ј-
Ј
Ј
Ј
was added to a solution of thallium (III) nitrate (2.2 g, 5 mmol, 1
eq) in 12 mL of MeOH containing 2.5 mL of 70% perchloric acid.
The mixture was stirred at room temperature for 6 h. The thallium
(I) nitrate was filtered, and the filtrate was poured onto water, ex-
*Author to whom correspondence should be addressed at: Depar-
tamento de Qu´ımica/Instituto de Tecnolog´ıa Qu´ımica UPV-CSIC,
Universidad Polite´cnica de Valencia, Avenida de los Naranjos s/n,
46022-Valencia, Spain. Fax: 349-6-387-7809;
tracted with ethyl acetate (3
ϫ 25 mL) and dried (Na2SO4). Evap-
e-mail: mmiranda@qim.upv.es
oration of the solvent under reduced pressure afforded the ester as
a solid that was submitted to hydrolysis without further purification.
The crude ester (1.15 g) was added to a solution of 30% aqueous
sodium hydroxide (7.5 mL) in methanol (25 mL) and heated under
reflux, with stirring, for 4 h. The reaction mixture was poured onto
†Abbreviations: GC, gas chromatography; MNAA, 6-methoxy-2-
naphthylacetic acid; MS, mass spectrometry; NB, nabumetone;
NSAID, nonsteroidal antiinflammatory drug; PBS, phosphate-
buffered saline; PMT, photomultiplier tube.
᭧
2000 American Society for Photobiology 0031-8655/00
$5.00
ϩ0.00
water, acidified and extracted with ethyl acetate (3 ϫ 25 mL). The
173

174 F. Bosca´ et al.
Figure 1. Chemical structures of NB and its major metabolite
MNAA.
combined organic extracts were washed with water and dried
(Na2SO4). Evaporation of the solvent under reduced pressure gave
the crude acid (0.9 g) that was purified by chromatography on silica
gel using hexane–ether (3:7) as eluent and then repurified by pre-
parative HPLC using methanol–water–acetic acid (60:39:1) as elu-
ent.
Figure 2. Emission spectra of MNAA in acetonitrile recorded after
excitation at 320 nm under different conditions.
Instrumentation. Gas chromatography/mass spectrometry (GC/
MS) analyses were achieved with a FISONS HRGC 8000 spectrom-
1
eter equipped with an HP-5 column (25 m
ϫ
0.32 mm). The H-
zone because this compound possesses a naphthalene chro-
mophore. In fact, when the spectrum was measured in ace-
tonitrile and PBS solutions it showed four bands with max-
ima at 220, 270, 320 and 330 nm.
The emission spectrum of MNAA in both solvents
showed a broad maximum at 351 nm; the excitation spec-
trum was essentially coincident with the absorption spec-
trum. From the intersection of the normalized excitation and
NMR spectra were measured by means of a Varian Gemini 300
MHz instrument. CDCl3 was used as a solvent and the signal cor-
responding to trimethylsilane was used as the internal reference. Ul-
traviolet spectra were recorded on a Shimadzu UV/visible scanning
spectrophotometer (2101PC) with a slit width of 5 nm. The HPLC
analyses were performed on an HPLC Varian Systems equipped
with a 9012Q pump and a photodiode array (Varian 9065). Samples
were injected onto an analytical Kromasil 100 C18 column (Tracer,
25
ϫ 0.4 cm, mean particle size 5 ␮m) using acetonitrile–water–
acetic acid (50:49:1) as the mobile phase; flow rate 0.5 mL/min.
Preparative HPLC purifications were performed on a Hitachi appa-
ratus equipped with an L-6250 intelligent pump and an L-400 fixed
wavelength UV detector at a wavelength of 320 nm. Samples were
emission spectra (336 nm) a singlet energy value of
ϳ355
Ϫ
Ϫ1
kJ mol 1 was estimated, identical to the E0–0
ϳ 355 kJ mol
reported for NB in acetonitrile (11).
The fluorescence quantum yields were 0.50 in acetonitrile
and 0.42 in PBS aqueous solution. The related NSAID na-
injected onto a Lichrosorb column (RP-18, 25
ticle size 7 m) using methanol–water–acetic acid (60:39:1) as the
ϫ 2.5 cm, mean par-
␮
mobile phase; flow rate: 10 mL/min.
proxen in acetonitrile (
(11,14). The excited singlet state of the metabolite was found
to be quenched by molecular oxygen. Thus, the of aer-
ated MNAA acetonitrile solutions was only 0.35; it still
dropped to 0.15 in oxygen-saturated solutions, a value sig-
nificantly lower than the 0.50 obtained under N2 (Fig. 2).
⌽
0.47) was used as a standard
Fluorescence measurements. Concentration was fixed by adjust-
ing the absorbance of the solutions at the arbitrary value of 0.4 at
the excitation wavelength (320 nm). The steady-state fluorescence
was obtained with an FS900 Edinburgh Analytical Instruments ap-
paratus, equipped with a 450 W xenon lamp. The time-resolved
fluorescence determinations were performed with an FL900 Edin-
burgh Analytical Instrument apparatus using a hydrogen lamp (0.7
ns pulse width) as the excitation source. The samples were placed
into quartz cells of 1 cm pathlength, and deoxygenation was made
by bubbling nitrogen.
flu
⌽
flu
Analogously, in PBS solutions the
⌽
flu
was 0.41 in aerated
solutions and 0.39 in oxygen-saturated solutions (note that
the apparently less effective quenching in PBS compared to
the acetonitrile is mainly due to the different concentration
of O2 in the two solvents).
The quenching constant of the singlet state by oxygen in
acetonitrile was calculated by means of time-resolved fluo-
Laser flash photolysis measurements. A pulsed Nd:YAG SL404G-
10 Spectron Laser Systems was used for the excitation at 266 or
355 nm. The single pulses were
was 10 mJ/pulse. A pulsed Lo255 Oriel xenon lamp was employed
ϳ10 ns duration and the energy
ϳ
as detecting light source. The laser flash photolysis apparatus con-
sisted of the pulsed laser, the Xe lamp, a 77200 Oriel monochro-
mator, an Oriel photomultiplier tube (PMT) system made up of a
77348 side-on PMT, 70680 PMT housing and a 70705 PMT power
supply. The oscilloscope was a TDS-640A Tektronix. The output
signal from the oscilloscope was transferred to a personal computer.
All the MNAA solutions studied had an absorbance of 0.5 at 266
nm and were degassed (when specified) by bubbling nitrogen.
rescence spectroscopy. The lifetime (␶) of the singlet state
was 13.6 ns under N2, 8.0 ns in aerated solutions and 2.9 ns
in oxygen-saturated solutions. From these data a value of
Ϫ
Ϫ
3.0
ϫ M
1010 1 s 1 was calculated for the quenching constant
by oxygen. Similarly, in PBS solutions the singlet lifetime
was 10.3 ns under N2, 10.1 ns in aerated solutions and 9.3
ns in oxygen-saturated solutions. From these data the cal-
Steady-state photolysis. Irradiations of the MNAA samples (1.5
3
ϫ
10Ϫ M, 5 mL/tube) were performed by using the pyrex-filtered
light from an OSRAM-HLQ 125 W medium-pressure Hg lamp lo-
cated inside an immersion well photoreactor (Applied Photophysics
model 3230). Parallel experiments were performed in acetonitrile
and phosphate-buffered saline (PBS) aqueous solutions under both
aerobic and anaerobic conditions. Eventually, different amounts of
CCl4 were added to the acetonitrile solutions. Photoreactions were
monitored by reversed-phase HPLC using the conditions mentioned
under instrumentation.
Ϫ
1
culated quenching constant by oxygen was 7.6
ϫ
109 M
Ϫ
1
s .
Laser flash photolysis. Figure 3 shows the transient ab-
sorption spectra obtained after laser flash excitation at 266
nm of deaerated (A) and aerated (B) solutions of the NB
metabolite in acetonitrile. The signal at 440 nm (Fig. 3A)
with a lifetime of 4.3
comparison with the literature (15). Another transient with
two maxima at 380 and 610 nm and a lifetime of 3.7 s was
␮s was assigned to the triplet state by
RESULTS AND DISCUSSION
Photophysical properties
␮
assigned to the naphthalene radical cation on the basis of
the reported data for related molecules (16). Finally, a lon-
Fluorescence. The absorption spectrum of MNAA was ex-
pected to extend into the biologically relevant UVA–UVB

Photochemistry and Photobiology, 2000, 71(2) 175
Scheme 1. Photodegradation products of MNAA under aerobic con-
ditions.
Ϫ
lutions (1.5
ϫ
10 3 M) led to the alcohol 2 and the aldehyde
3 as major photoproducts (Scheme 1), being the conversion
lower than 10% after 15 min. The same photoproducts were
obtained when the irradiation was performed in aerated ace-
tonitrile, although the extent of photodegradation was even
lower in this solvent. Thus, the photoreactivity of the car-
boxylate form (predominating species in PBS) appears to be
much higher than that of the free acid. No significant reac-
tion was observed when deaerated solutions of MNAA were
irradiated in any of the two solvents.
Reaction mechanism. The enhancement of photodegrada-
tion observed in the presence of oxygen had been previously
described for related molecules. Thus, in the case of na-
proxen the photodecarboxylation quantum yield was found
to be 0.001 under deaerated conditions and 0.012 in aerobic
medium (14). This could be explained by means of a new
reaction mechanism that would operate in addition to the
direct decarboxylation route established for related NSAID
(18,19). The new mechanism could imply deprotonation of
the naphthalene radical cation leading to a nondecarboxy-
lated benzylic radical intermediate that would be trapped by
O2. Subsequent loss of CO2 would result in the correspond-
ing oxidative fragmentation compound 3 (Scheme 2).
In order to confirm this hypothesis two different series of
experiments were undertaken following the rationale indi-
cated below.
Figure 3. (A) Transient absorption spectra of a nitrogen-saturated
acetonitrile solution of MNAA measured 1 s, 8 s and 20 s after
the pulse (266 nm). (B) Transient absorption spectra of an aerated
␮
␮
␮
acetonitrile solution of MNAA measured 1
the pulse (266 nm).
␮s, 3 ␮s and 7 ␮s after
ger-lived species (25 ␮s) with a maximum at 340 nm could
be associated with the formation of a benzylic radical; how-
ever, no further experiments were done to confirm unequiv-
ocally the nature of this band. Under oxygen-saturated con-
ditions (Fig. 3B) the signal with maxima at 380 and 610 nm
Chemical evidence for reaction via radical cation. First,
methyl esters cannot undergo direct photodecarboxylation in
organic solvents as the corresponding acids do. Thus, if
methyl 6-methoxy-2-naphthylacetate were irradiated instead
of the acid itself the direct mechanism would not be able to
was the only remaining absorption after 1 ␮s.
When the laser flash photolysis of MNAA was performed
in PBS solutions the same transient species were observed.
The band at 440 nm assigned to the triplet state showed a
longer lifetime (24
signal with the maxima at 380 and 610 nm had a lifetime
(3.7 s) similar to that found in acetonitrile. Again the band
at 340 nm (51 s) was observed as was the band correspond-
␮s) in this aqueous solvent. However, the
operate. As a matter of fact, irradiation of the ester (1.5
ϫ
Ϫ3
10 M) in aerated acetonitrile resulted in the formation of
the expected aldehyde as the sole compound ( 2% after 15
␮
ϳ
␮
min). Therefore, formation of the aldehyde under the irra-
diation conditions indicates that the naphthalene radical cat-
ion has evolved to the benzylic radical prior to decarboxyl-
ing to the solvated electron at 710 nm. In this solvent, the
same quenching behavior as above was observed in the pres-
1
ence of O2. As a result of the triplet state quenching, O2 is
probably formed, as described for related compounds (na-
proxen and NB) with a similar
⌽ of ϳ0.2 (11,17).
⌬
According to the literature, the naphthalene radical-cation
in related molecules could arise from the excited singlet state
(11). We tried to confirm whether this could also be true for
MNAA by performing the laser flash photolysis experiment
in the presence of benzophenone. Thus, selective excitation
of benzophenone at 355 nm sensitized the formation of the
triplet state of MNAA as the sole transient. Its decay was
complete without formation of any other signal, confirming
that the triplet state is not involved in the formation of the
naphthalene radical cation.
Photochemistry
Products study. 6-Methoxy-2-naphthylacetic acid was found
Scheme 2. Indirect mechanism postulated for the photodegradation
to be photolabile. Its irradiation in aerated PBS aqueous so-
of MNAA in the presence of O2, CCl4 or other electron acceptors.

176 F. Bosca´ et al.
Figure 5. Fluorescence spectra of MNAA in acetonitrile upon ad-
dition of 0, 13, 26, 65, 258 and 517 mM CCl4.
of CCl4 to acetonitrile solutions of MNAA under anaerobic
conditions. When the reciprocal emission intensities were
plotted against the concentration of CCl4, a linear relation-
ship was observed; the calculated Stern–Volmer constant
Ϫ
1
was 148.2 M . Taking into account the fluorescence lifetime
of MNAA in acetonitrile (see above), the estimated value of
Ϫ
1
the fluorescence quenching rate constant was 1.1
s .
ϫ M
1010
Ϫ
1
The effect of the added CCl4 was also examined by means
of laser flash photolysis. The most striking observation was
a clear decrease in the amplitude of the transient signal as-
sociated with the triplet at 440 nm, concomitantly with a
corresponding increase in the bands at 380 and 610 nm as-
signed to the radical cation. Figure 6 shows the ratio radical
cation versus triplet as a function of the CCl4 concentration.
The transient lifetimes were not affected by CCl4.
Overall, the photophysical properties in the presence of
CCl4 are consistent with quenching of the MNAA singlet by
CCl4 leading to the radical cation that competes favorably
with intersystem crossing to the triplet.
Figure 4. The HPLC elution profile recorded at 254 nm from an
aerated (1 mM) solution of MNAA in acetonitrile after 2 min of
irradiation. Upper trace, in the absence of CCl4; lower trace, with
added CCl4 (65 mM). 2-Methoxynaphthalene (1 mM) was used as
standard for integration.
CONCLUSIONS
6-Methoxy-2-naphthylacetic acid, the major metabolite of
the phototoxic NSAID NB, has been found to be photoac-
tive. Its photodegradation is enhanced in the presence of ox-
ygen via a new photodegradation mechanism that involves
ation. Trapping of this radical by O2, subsequent formation
of a peroxylactone and final loss of carbon dioxide explains
formation of the aldehyde.
Second, carbon tetrachloride is known to act as an elec-
tron acceptor. Therefore, if the irradiation were performed
in the presence of CCl4, a significant enhancement of the
photodegradation proccess through formation of the radical
cation and irreversible evolution to the photoproducts would
be expected. As anticipated, irradiation of MNAA (1.5
ϫ
Ϫ3
10 M) in aerated acetonitrile containing 65 mM CCl4 re-
sulted in a dramatic enhancement ( 10 times) of the pho-
ϳ
todegradation, giving the aldehyde 3 as the only photoprod-
uct (Fig. 4).
Photophysics of MNAA in the presence of CCl4. The in-
teresting results obtained upon addition of CCl4 prompted us
to study the photophysical properties of MNAA in the pres-
ence of CCl4. Figure 5 shows the dramatic fluorescence
quenching that occurs upon addition of increasing amounts
Figure 6. Plot of the ratio radical cation/triplet (measured by the
relative intensities of the bands at 380 and 440 nm, respectively, in
the transient absorption spectra) against the concentration of CCl4.

Photochemistry and Photobiology, 2000, 71(2) 177
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does. Thus, a Type I photosensitization mechanism (in ad-
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taken into account to explain the photobiological properties
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Acknowledgements This work has been sponsored by the European
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