Near-visible light generation of a quinone methide from 3-hydroxymethyl-2-anthrol

Article abstract of DOI:10.1021/jo500290y

Excitation of 2-hydroxy-3-(diphenylhydroxymethyl)anthracene (7) to S ₁ initiates photodehydration, giving the corresponding quinone methide (QM) that was detected by laser flash photolysis (LFP) in 2,2,2-trifluoroethanol (λ = 580 nm, τ = 690 ± 10 ns). The QM decays by protonation, giving a cation (λ = 520 nm, τ = 84 ± 3 μs), which subsequently reacts with nucleophiles. The rate constants in the reactions with nucleophiles were determined by LFP, whereas the adducts were isolated via preparative photolyses. The photogeneration of QMs in the anthrol series is important for potential use in biological systems since the chromophore absorbs at wavelengths > 400 nm. Antiproliferative investigations conducted with 2-anthrol derivative 7 on three human cancer cell lines showed higher activity for irradiated cells.

Full text of DOI:10.1021/jo500290y

Article
pubs.acs.org/joc
Near-Visible Light Generation of a Quinone Methide from
3‑Hydroxymethyl-2-anthrol
†
†
‡
‡
§
̌
Đani Skalamera, Kata Mlinaric-Majerski, Irena Martin-Kleiner, Marijeta Kralj, Peter Wan,
́
and Nikola Basaric*,†
́
†Department of Organic Chemistry and Biochemistry, Ruđer Bosk
̌
ovic
́
Institute, Bijenick
̌
a cesta 54, 10 000 Zagreb, Croatia
‡Department of Molecular Medicine, Ruđer Bosk
̌
ovic
́
Institute, Bijenick
̌
a cesta 54, 10 000 Zagreb, Croatia
§Department of Chemistry, University of Victoria, Box 3065 Stn CSC, Victoria BC V8W 3V6, Canada
S
* Supporting Information
ABSTRACT: Excitation of 2-hydroxy-3-(diphenylhydroxymethyl)-
anthracene (7) to S1 initiates photodehydration, giving the correspond-
ing quinone methide (QM) that was detected by laser flash photolysis
(LFP) in 2,2,2-trifluoroethanol (λ = 580 nm, τ = 690 10 ns). The QM
decays by protonation, giving a cation (λ = 520 nm, τ = 84 3 μs),
which subsequently reacts with nucleophiles. The rate constants in the
reactions with nucleophiles were determined by LFP, whereas the
adducts were isolated via preparative photolyses. The photogeneration of
QMs in the anthrol series is important for potential use in biological
systems since the chromophore absorbs at wavelengths > 400 nm.
Antiproliferative investigations conducted with 2-anthrol derivative 7 on
three human cancer cell lines showed higher activity for irradiated cells.
INTRODUCTION
■
Quinone methides (QMs) are common reactive intermediates
in chemistry and in the photochemistry of phenols, attracting much
attention recently owing to their biological activity.1 Although the
partial zwitterionic character of QMs makes them both electrophilic
and nucleophilic, their reactivity with nucleophiles is especially
important in biological systems. It has been demonstrated that
QMs react with amino acids2 and proteins3 and inhibit the action
of some enzymes.4 Moreover, QMs also react with nucleotides,5
inducing alkylation and the cross-linking of DNA.6 The ability of
QMs to cross-link DNA renders them as potential anticancer
therapeutics.7 Some antineoplastic agents such as mitomycin8 base
their antiproliferative action on the metabolic formation of QMs
that alkylate DNA. Moreover, some classes of anthracyclines such
as daunomycin, which base their action on DNA cross-linking, also
metabolically form QMs.9 However, later, it was shown that QMs
are not responsible reagents that cross-link DNA, but it probably
involves metabolic formation of formaldehyde.10
QMs can be formed under mild conditions in photochemical
reactions of suitably substituted phenols, such as photodehydrox-
ylation of hydroxybenzylphenols,11 and photoelimination of acetic
acid,12 amines,13 or ammonium salts.2b Photodehydration has also
been reported in the larger chromophoric systems, such as suitably
substituted phenylphenols14 and naphthols.15 Popik et al. studied
photodehydration of naphthol 1, which gave benzoxete
intermediate 2 that subsequently underwent ring-opening to
QM 3 (eq 1).16 The photogeneration of naphthalene QMs was
later applied to photocaging17 and for surface modification and
photolithography.18
We became interested in the photochemical formation of
sterically congested QMs that have potential biological
applicability.19 Photocytotoxicity was investigated on three
human cancer lines. Photoinduced antiproliferative activity was
also reported for naphthol,15b 1,1′-bi-2-naphthol (BINOL),20
and naphthalene diimide QM derivatives.21 For ultimate appli-
cation in vivo, it is essential to develop systems that can
photogenerate QMs when excited with light of longer wavelengths
(>350 nm). However, the photogeneration of QMs by photo-
dehydration reaction in 2-anthrols or larger chromophoric systems
has never been reported. Herein, we report the first example of
photochemical QM formation (via dehydration) in an anthrol
derivative 7. The photoreactivity was studied by preparative
irradiations, fluorescence measurements, and by laser flash
photolysis (LFP). Antiproliferative investigation was performed
on three human cancer cell lines with and without irradiation.
RESULTS AND DISCUSSION
■
Synthesis of the new anthrol 7 was accomplished in 4 steps,
starting from the commercially available 2-aminoanthraqui-
none, which was converted to 2-hydroxyanthraquinone (4) via
a known procedure.22 Bromination of 4 afforded 3-bromo
Received: February 6, 2014
Published: April 23, 2014
© 2014 American Chemical Society
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Photochemical solvolysis of 7 was investigated by irradiations
in CH3OH−H2O (see the Supporting Information). Irradi-
ations gave cleanly one product (9, eq 2). Conversion to 9 after
Scheme 1
1 h of irradiation was higher in the presence of 20% H2O
(≈70%) than in neat CH3OH (≈50%). Such a finding has been
reported in systems wherein the phenolic OH is not H-bonded
to the benzylic alcohol19 and explained by a higher ability of
phenols to deprotonate in S1 to clusters of H2O than CH3OH.25
Photosolvolysis of trityl derivatives can, in principle, take
place via carbocations. To probe if 7 undergoes heterolytic
cleavage of OH to give carbocation 13 (Scheme 2), irradiation
of 7OMe was performed. However, in the condition where 7
gave 72% of 9, 7OMe remained unchanged. This finding
indicates that the free phenolic OH is required for the
formation of the solovolysis product. Furthermore, the finding
is in accord with the photosolvolysis mechanism involving QM
12 (vide infra).
derivative 5 (40%), and 1,3-dibromo derivative (38%), which
was separated from 5 by a column chromatography (Scheme 1).
Subsequent reduction of 5 gave 2-bromo-3-anthrol (6) in 80%
yield and a small amount of 2-anthrol (8) due to undesired
concomitant debromination. Lithiation with an excess of BuLi and
quenching with benzophenone furnished 7 in 40% yield.
Absorption spectra of 7 and 8 in CH3CN solution exhibit an
absorption band of lowest energy centered between 350 and
400 nm, 50 nm bathochromically shifted compared to that of
anthracene. The pKa of 2-anthrol (8) in CH3CN−H2O (1:9) in
S0 and S1 was determined by UV−vis and fluorescence titration,
respectively (pKa = 9.40 0.03; pKa* = 2.13 0.01; see the
Supporting Information). Since it is known that intramolecular
H-bonding with the benzyl alcohol increases acidity in
2-naphthol,16 the anticipated pKa values for 7 are expected to
be somewhat lower.
The photophysical properties of 7 and 8 were investigated
in CH3CN and CH3CN−H2O (1:1). Results are compiled
in Table 1. Fluorescence in aqueous solution is quenched
The scope of the photosolvolysis was further investigated by
performing irradiations in the presence of other nucleophiles.
Thus, azide adduct 10 and 2,2,2-trifluoroethanol (TFE) adduct
11 were isolated after irradiation of 7 in CH3CN−H2O and
CH3CN−TFE, respectively, in ≈35−40% yield. The structures
of the photoproducts 9, 10, and 11 were confirmed by NMR
analysis. Additionally, all photosolvolyses were achieved by use
of light > 350 nm (350 nm, 420 nm, and vis-lamps; see the
Supporting Information).
The efficiency of the photosolvolysis in CH3OH−H2O (4:1)
was determined by simultaneous use of three actinometers,
valerophenone, KI/KIO3, and ferrioxalate.26 Irradiation was
performed by use of monochromatic light at 254 nm, and the
composition of the irradiated solution of 7 was analyzed by
HPLC. All actinometers gave ΦR = 0.023 0.001 for reaction.
To probe for QM and other plausible long-lived inter-
mediates in the photochemistry of 7, LFP measurements were
performed. The samples were excited by use of a Nd:YAG laser
at 354 nm. The measurements were performed in CH3CN and
CH3CN−H2O (1:1), and the difference was anticipated due to
PT in the aqueous solution. In CH3CN solution (N2- and
O2-purged), a band centered at 700 nm can be seen (τ = 1.0
0.1 μs) that, in the aqueous solution, decays during the laser
pulse. The transient is tentatively assigned to the anthrol radical
cation, which, in the aqueous solution, decays by deprotona-
tion.27 In addition, in both solvents, more persistent transients
were detected absorbing at shorter wavelengths of 400−600 nm.
The decay is multiexponential, revealing several species. The major
contribution to the band more centered at shorter wavelengths
(400−500 nm) decays slower (τ ≈ 10−100 μs and τ ≈ 0.1−2 s)
and can also be seen in the transient spectra of 8 (see the
Table 1. Photophysical Properties of 7 and 8 in CH3CN and
CH3CN−H2O (1:1)
7
8
a
ΦF (CH3CN)
0.86 0.01
0.39 0.01
0.88 0.05
0.57 0.02
a
ΦF (CH3CN−H2O)
τ (CH3CN)/ns
b
17.8 0.1
25.3 0.1
b
τ (CH3CN−H2O)/ns
1.7 0.2 phenolate
8.1 0.2 phenolate
24.5 0.1 phenol
15.4 0.1 phenolate
25.3 0.1 phenol
a
Quantum yields of fluorescence measured by use of quinine sulfate in
0.05 M aqueous H2SO4 (ΦF = 0.53) as a reference.24 Fluorescence
lifetimes measured by time-correlated single-photon timing method.
b
compared to that in neat CH3CN. The quenching is due to
proton transfer (PT) to solvent. Furthermore, the ΦF for 7 in
both solvents is lower than that for 8. Since 8 cannot give QMs,
the lower ΦF of 7 may be due to the photochemical pathway
giving QM. Contrary to 2-methoxyanthracene,23 7 and 8 are
characterized by a single exponential decay of fluorescence in
CH3CN. Addition of H2O changes the decay. For 8, it becomes
double-exponential with a rise component (assigned to
phenolate) that contributes more at longer wavelengths. For
7, the best fit was obtained by a three-exponential function with
two rise components. Although a firm elucidation of the decay
kinetics cannot be made at this time, the finding is consistent
with a scheme that photodissociation of the anthrol OH of 7 in
S1 triggers elimination of OH− (overall loss of H2O) that leads
to the formation of QM.
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Scheme 2
Figure 1. Transient absorption spectra of 7 in O2-purged 2,2,2-trifluoroethanol (TFE) (left), and growth and decay of the transient absorption at
520 nm (corresponding to cation 13) and 580 nm (corresponding to QM 12), respectively (right).
Supporting Information). The transients are not affected by the
presence of O2 and H2O. The shorter-lived species is tentatively
assigned to phenoxyl radical, according to the comparison with the
published spectra and decay kinetics.28 In addition, a transient
absorption was detected at 500−600 nm that decays multi-
exponentially that could be quenched by nucleophiles (and not by
O2). Therefore, this transient could tentatively be assigned to QMs
or other electrophilic species (see the Supporting Information).
However, because of complex decay kinetics and overlapping of
the transient absorption spectra with several other species, no firm
assignment to a QM can be made at this time.
A cleaner picture was obtained for LFP experiments carried
out in TFE. TFE is a polar non-nucleophilic solvent in which
electrophilic species such as QMs14,15,19 and carbocations29
exhibit longer lifetimes. LFP measurement for 7 in O2-purged
TFE gave rise to a strong transient absorption centered at 580
Table 2. Rate Constants for the Quenching of Cation 13
a
with Nucleophiles (kq or k13→9/s−1 M−1)
nucleophile
kq/s−1 M−1
CH3OH
H2O
9.8 × 103
1.6 × 103
2.1 × 108
NaN3
a
Measurements performed in air-saturated TFE.
first detected species in TFE by LFP is QM 12, which decays by
protonation, giving cation 13 (Scheme 2). Subsequent reaction
with nucleophiles furnishes adducts. Interestingly, ethanolamine
did not quench QM 12 in the tested concentration. The finding
was explained by the ethanolamine basicity (pKa = 9.5), which
prevented fast protonation of QM 12 to cation 13.
Cation 13 can also be formed in the CH3CN solution in a
thermal acid-catalyzed reaction and detected by UV−vis
spectroscopy. To the CH3CN solution was added H2SO4
(c = 0.25 M), resulting in an immediate color change to red.
The difference absorption spectrum has a maximum at 520 nm
(see the Supporting Information) with another band at longer
wavelengths (≈700 nm) and resembles the transient absorption
of 7 measured in TFE and 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) after decay of the short-lived species assigned to QM
12. The transient in CH3CN decays (τ = 0.63 0.02 min),
probably giving CH3CN adduct 14, resulting in a colorless
solution. However, within 45−60 min, a new species is formed
absorbing at 500−700 nm, resulting in a green color. The latter
is tentatively assigned to QM 12 formed in a thermal acid-
catalyzed reaction (Scheme 3).
nm that is formed within the laser pulse. It decayed (k12→13
=
1.4 × 106 s−1, τ = 690 10 ns), giving a new species absorbing
at 520 nm (Figure 1) that also decays (k13→9 = 1.4 × 104 s−1,
τ = 84
3 μs). Addition of ethanolamine, a ubiquitous
quencher of QMs,14,19 changed the appearance of the spectra.
However, the decay of the absorption at 580 nm was slower,
and faster at 520 nm, giving one band in the spectra. This
finding suggests that two species are in equilibrium that is
influenced by pH (ethanolamine is a base). Quenching with
nucleophiles was successful for species absorbing at 520 nm
(not affecting the faster decay at 580 nm). The quenching rate
constants are compiled in Table 2. According to the quenching
data and the position of the maximum in the absorption spectra
(comparison with the known spectra of trityl cation),30 the
long-lived transient was assigned to carbocation 13. Since the
short-lived transient is sensitive to acidity and in equilibrium with
the cation, it is tentatively assigned to QM 12. Consequently, the
Antiproliferative investigation was conducted with 7 on three
human cancer cell lines, HCT 116 (colon), MCF-7 (breast),
and H 460 (lung), with and without exposure to irradiation
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Scheme 3
(350 and 420 nm). In addition, the cells were irradiated in the
absence of compounds to check for the cytotoxic effect of
irradiations. The results are compiled in Table 3. Irradiation of
Photogeneration of QMs in the anthrol series that can be
initiated by near-visible light is of particular importance in
biological systems. Preliminary results of antiproliferative
investigations conducted for 7 on three human cancer cell
lines showed higher activity for the cells that were irradiated.
Consequently, we believe that anthrol derivatives have potential
as a new class of photochemotherapeutic reagents, or as
photolabeling markers for biological systems.
a
Table 3. IC50 Values (in μM) for 7
cell lines
HCT 116
21 0.3
MCF-7
H 460
not irradiated
20 0.5
19
1
3 × 5 min 350 nm
3 × 5 min 420 nm
2
2
0.4
0.4
4
2
3
3
2
1
0.1
0.2
EXPERIMENTAL SECTION
■
a
IC50: the concentration that causes 50% growth inhibition. Irradiation
1
Experimental Procedure, General. H and 13C NMR spectra
of the cells at 350 nm that were not treated with 7 induced up to a
maximum 25% inhibition of tumor cell growth, whereas irradiation of
untreated cells at 420 nm showed no effect. For the calculation of IC50,
see the Experimental Section.
were recorded at 300 or 600 MHz at rt using TMS as a reference, and
chemical shifts were reported in parts per million (ppm). Melting
points were determined using a Mikroheiztisch apparatus and were not
corrected. IR spectra were recorded on a spectrophotometer in KBr,
and the characteristic peak values were given in cm−1. HRMS were
obtained on a MALDI TOF/TOF instrument. For the sample analysis,
an HPLC was used with a C18 (1.8 μm, 4.6 × 50 mm) column. HPLC
runs were conducted at rt (∼25 °C), and chromatograms were recorded
using a UV detector at 254 nm. Other HPLC data are given in the
Supporting Information, since the parameters vary. For the chromato-
graphic separations, silica gel (0.05−0.2 mm) was used. Irradiation
experiments were performed in a reactor equipped with 16 lamps with
the output at 350 nm or a reactor equipped with 8 lamps. During the
irradiations, the irradiated solutions were continuously purged with Ar
and cooled by a tap water finger condenser. Solvents for irradiations
were of HPLC purity. Chemicals were purchased from the usual
commercial sources and were used as received. 2-Hydroxyanthraquinone
(4) was prepared from commercially available 2-aminoanthraquinone
according to the known procedure.22 Solvents for chromatographic
separations were used as they are delivered from the supplier (p.a.
grade) or purified by distillation (CH2Cl2). Diethyl ether used for the
reaction with BuLi was previously refluxed over Na and freshly distilled.
3-Bromo-2-hydroxyanthraquinone (5). The reaction was
carried out in a two-neck round-bottom flask (250 mL) equipped
with a condenser and a dropping funnel. 2-Hydroxyanthraquinone (4,
4.54 g, 20.2 mmol) was dissolved in glacial acetic acid (50 mL) by
heating using an oil bath. Bromine (5 mL, 97.2 mmol) in glacial acetic
acid (50 mL) was added to the refluxing reaction mixture over 4 h, and
the refluxing was continued overnight (16 h). The progress of the
reaction was monitored by HPLC (see the Supporting Information).
The next day, the reaction mixture was allowed to cool to rt and
poured on water (300 mL). A saturated solution of Na2SO3 was added
to destroy the excess of bromine. The yellow precipitate was filtered
off, washed with water until neutral (tested with universal indicator
paper), and dried in a desiccator over KOH overnight. The crude
product contained 3-bromo-2-hydroxyanthraquinone (5) and 1,3-
dibromohydroxyanthraquinone in a 1:1 ratio. These two compounds
were separated using column chromatography (SiO2, CH2Cl2/EtOAc/
HOAc 760:40:1 to 720:80:1) to obtain 1,3-dibromo-2-hydroxy-
anthraquinone 5 (2.93 g, 7.68 mmol, 38% yield) and 3-bromo-2-
hydroxyanthraquinone (2.45 g, 8.08 mmol, 40% yield) as yellow solid
substances.
the cells at 350 nm that were not treated with 7 induced up to a
maximum 25% of inhibition of tumor cell growth, whereas
420 nm did not cause any significant inhibition of tumor cell
growth. On the other hand, exposure of the cells treated with 7
to irradiation induced a higher cytotoxic effect than cells that
were kept in the dark. Consequently, higher photocytotoxicity
of the compound allows for potential biological applications.
However, for the actual photochemotherapeutic applications
(except for maybe some forms of skin cancer), the compounds
should bear chromophores absorbing at >600 nm. Photo-
chemically induced higher cytotoxicity of 7 suggests that
the enhanced antiproliferative activity is due to the photo-
generation of QMs. Although the exact mechanism of the
enhanced antiproliferative activity was not determined, it is
presumed that it is due to the reactivity of 12 or 13 with
DNA,5,6 as well as some particular proteins (e.g., enzymes).2−4
Since the LFP experiments did not indicate formation of the
triplet excited state, singlet oxygen probably did not induce
antiproliferative activity. The investigation of biological action
of different anthrol derivatives is currently under way and will
be published separately.
CONCLUSION
■
The presented results show that dehydration of 2-anthrol
derivative 7 to QM 12 can be initiated in a photochemical
reaction and probably involves deprotonation of the phenol
OH as the first step, followed by expulsion of the alcohol OH−.
However, we could not time-resolve the formation of QM 12
(it is formed within the laser pulse). Therefore, we cannot rule
out mechanisms that involve (i) excited-state intramolecular
proton transfer (ESIPT) from the phenol OH to the benzyl
alcohol that is coupled with dehydration or (ii) formation of a
benzoxete intermediate that has a lifetime of <50 ns and
subsequently ring-opens to form the QM.
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1
1,3-Dibromo-2-hydroxyanthraquinone. H NMR (300 MHz,
DMSO-d6) δ/ppm 8.34 (s, 1H), 8.18−8.10 (m, 2H), 7.93−7.87 (m,
2H); IR (KBr) νmax/cm−1 3412 (O-H), 3105 (C-H), 3070 (C-H),
1672 (CO).
and K2CO3 (50 mg, 362 μmol) was added. The resulting suspension
was heated at reflux, resulting in a change of the color from pale yellow
to yellow. MeI (50 μL, 803 μmol) was then added, and the reaction
mixture was stirred for 5 h at rt (the color returns to pale yellow).
The reaction mixture was then filtered, and the filtrate was evaporated
on a rotary evaporator. The residue product was purified on a short
column of silica gel (10 × 1 cm) using CH2Cl2 as eluent to give pure
2-methoxy-3-(diphenylhydroxymethyl)anthracene (7OMe, 11 mg,
3-Bromo-2-hydroxyanthraquinone (5).31 Yellow solid, mp
235−245 °C; 1H NMR (300 MHz, DMSO-d6) δ/ppm 11.97 (s,
1H), 8.22 (s, 1H), 8.17−8.11 (m, 2H), 7.95−7.86 (m, 2H), 7.64 (s,
1H); 13C NMR (150 MHz, DMSO-d6) δ/ppm 182.0 (s), 180.3 (s),
159.6 (s), 134.5 (d), 134.2 (d), 134.0 (s), 132.9 (s), 132.8 (s), 132.1
(d), 126.6 (d, 2C), 125.8 (s), 116.6 (s), 112.8 (d); IR (KBr)
νmax/cm−1 3350 (O-H), 1668 (CO), 1570 (CO), 1274 (C-H),
1
31 μmol, 64% yield) in the form of a pale yellow solid. H NMR
(600 MHz, CDCl3) δ/ppm 8.25 (s, 1H), 8.12 (s, 1H), 7.92 (d, J =
8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.44−7.40 (m, 2H), 7.34−7.28
(m, 11H), 7.11 (s, 1H), 5.19 (s, 1H), 3.79 (s, 3H); 13C NMR (150
MHz, CDCl3) δ/ppm 155.9 (s), 146.3 (s), 136.8 (s), 132.3 (s), 131.8
(s), 130.7 (s), 130.1 (d), 128.1 (d), 128.0 (d), 127.8 (d), 127.7 (d),
127.5 (d), 127.3 (s), 127.0 (d), 125.6 (d), 124.6 (d), 123.5 (d), 105.7
(d), 82.1 (s), 55.6 (q); IR (KBr) νmax/cm−1 3448 (O-H), 2920 (C-H),
+
719 (C-H); HRMS (MALDI) calculated for C14H7BrKO3 340.9210,
found 340.9204.
3-Bromo-2-hydroxyanthracene (6). NaBH4 (454 mg, 12 mmol)
was dissolved in 1 M Na2CO3 (aq) (30 mL), i-propanol (5 mL) was
added (foaming suppressor), and the mixture was heated until the boil-
ing point was achieved. 3-Bromo-2-hydroxyanthraquinone (5, 910 mg,
3 mmol) was added in three portions. The reaction mixture was refluxed
for 15 min (longer reflux time usually produced more debromination
product, 2-hydroxyanthracene). The reaction was quenched by careful
addition of ice-cooled water (30 mL), followed by the addition of 3 M
HCl until acidic reaction was achieved (tested by universal indicator
paper). The product was collected by filtration, washed with water (until
neutral reaction of the filtrate was achieved), and dried in an evacuated
desiccator (10 mbar) over KOH overnight. The crude product was
purified on a column of silica gel using dichloromethane as eluent to give
pure product 6 (656 mg, 2.4 mmol, 80% yield over two steps) as a
yellow powder: mp 225−232 °C; 1H NMR (300 MHz, CDCl3) δ/ppm
8.27 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.93 (t, J = 7.2 Hz, 2H), 7.50
(s, 1H), 7.48−7.38 (m, 2H), 5.64 (s, 1H); 13C NMR (300 MHz,
DMSO-d6) δ/ppm 150.9 (s), 132.0 (d), 131.7 (s), 131.5 (s), 129.7 (s),
128.0 (d), 127.7 (s), 127.4 (d), 125.7 (d), 125.1 (d), 124.6 (d), 123.1
(d), 114.7 (s), 107.8 (d); IR (KBr) νmax/cm−1 3512 (O-H), 3049 (C-H);
HRMS (MALDI) calculated for C14H9BrO+ 271.9831, found 271.9829.
2-Hydroxy-3-(diphenylhydroxymethyl)anthracene (7). The
reaction was carried out in a two-neck round-bottom flask (50 mL)
under a N2 inert atmosphere, equipped with a N2 balloon and a
septum. The flask was charged with 3-bromo-2-hydroxyanthracene
(6, 286 mg, 1.00 mmol) and dry Et2O (10 mL) and cooled in an ice−
methanol bath (−15 to −10 °C). BuLi (2.5 M in hexanes, 1.2 mL,
3.00 mmol) was added dropwise over 15 min, changing the color to
brown. The reaction mixture was then emerged from the ice bath and
stirred for 15 min at rt, whereby all the solid compound was dissolved,
giving a clear brown solution. The reaction mixture was then again
cooled to −10 °C, and benzophenone (900 mg, 4.94 mmol) in dry
Et2O (4 mL) was added. Stirring was continued 1 h at −10 °C. Then,
the reaction mixture was allowed to reach rt, and the stirring was
continued overnight. The reaction was quenched by careful addition of
water (15 mL) and transferred to the separation funnel. A solution of
1 M NaOH (20 mL) and water (100 mL) was added, and the aqueous
layer was extracted with hexane (2 × 20 mL) in order to remove
unreacted benzophenone and the product of the reaction of
benzophenone with BuLi. The aqueous layer was then acidified with
10% acetic acid and extracted with Et2O (3 × 25 mL). The ether
extracts were combined and dried over anhydrous MgSO4. After
filtration and removal of the solvent, the crude product was purified on
a column of silica gel using dichloromethane as eluent to give pure 7
(763 mg, 2.03 mmol, 40% yield) in the form of a yellow-orange solid.
+
2851 (C-H), 1458 (C-H); HRMS (MALDI) calculated for C28H22O2
390.1614, found 390.1624.
Irradiation Experiments. Preparative Photomethanolysis. In a
quartz vessel was placed a CH3OH−H2O (4:1) solution of compound
7 (100 mL, c ∼ 4 × 10−4 M), and it was irradiated in a Rayonet reactor
using 16 lamps at 350 nm. Prior to, and during the irradiation,
the solution was continuously purged with a stream of Ar and cooled
by a coldfinger condenser. After 90 min of irradiation, the solvent
was removed on a rotary evaporator and the residue was dried (water
was removed as azeotrope with toluene). The photoproduct was
purified on a column of silica gel (4 × 1 cm) using CH2Cl2 as eluent to
obtain pure 9 (13 mg, 33 μmol, 84% yield) in the form of a pale yellow
1
film on the walls of the flask. H NMR (600 MHz, CDCl3) δ/ppm
8.68 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H,),
7.86 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.46−7.42 (m, 4H), 7.41−7.31
(m, 8H), 3.35 (s, 3H); 13C NMR (150 MHz, CDCl3) δ/ppm 153.9
(s), 140.6 (s), 132.6 (s), 132.4 (s), 132.1 (s), 130.5 (d), 129.0 (d),
128.1 (d), 128.0 (d), 127.9 (d), 127.5 (d), 126.9 (s), 126.7 (d), 125.5
(d), 124.2 (d), 123.0 (d), 110.1 (d), 53.1 (q); IR (KBr) νmax/cm−1
3421 (O-H), 3055 (C-H), 2970 (C-H), 2924 (C-H), 2953 (C-H),
1448 (C-H); HRMS (MALDI) calculated for C27H20O+ 360.1509,
found 360.1506.
Irradiation in the Presence of NaN3. In a quartz vessel was placed
CH3CN solution (70 mL) of compound 7 (15 mg, 40 μmol), and a
solution of NaN3 (1 g, 15 mmol) in water (30 mL) was added. Upon
addition of NaN3, the solution changed color to yellow, probably
due to deprotonation of the anthrol OH (caused by hydrolysis of
the azide). The solution was irradiated in a reactor using 12 lamps at
350 nm for 2 h. Prior to, and during the irradiation, the solution was
continuously purged with a stream of Ar and cooled using a coldfinger
condenser. After the irradiation, the reaction mixture was poured on
water (150 mL) and extracted with diethyl ether (3 × 20 mL). The
organic extracts were combined and washed with water (2 × 100 mL).
The organic phase was separated and dried over anhydrous MgSO4
and filtered, and the solvent was removed on a rotary evaporator. The
crude product was chromatographed on a short column of silica gel
(10 × 1 cm) using CH2Cl2 as an eluent to obtain pure product 10
(6 mg, 15 μmol, 38% yield) in the form of a thin yellowish film on the
1
walls of the flask. H NMR (600 MHz, CDCl3) δ/ppm 8.23 (s, 1H),
8.18 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.44−
7.41 (m, 8H), 7.39 (s, 1H), 7.30 (m, 4H), 6.92 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ/ppm 152.4 (s), 140.9 (s), 132.54 (s), 132.46
(s), 131.4 (s), 130.9 (d), 130.4 (s), 128.6 (d), 128.4 (d), 128.3 (d),
128.2 (d), 128.1 (d), 127.6 (d), 127.1 (d), 126.8 (s), 125.6 (d), 124.5
(d) 123.2 (d), 111.3 (d), 29.6 (s); IR (KBr) νmax/cm−1 3421 (O-H),
3057 (C-H), 2924 (C-H), 2853 (C-H), 2104 (NN); HRMS
(MALDI) calculated for C27H20O+ 360.1509, found 360.1523.
Irradiation in the Presence of 2,2,2-Trifluoroethanol (TFE). In a
quartz vessel was placed a CH3CN solution (90 mL) of compound
7 (13 mg, 35 μmol), and 2,2,2-trifluoroethanol (10 mL) was added.
The solution was irradiated in a reactor using 12 lamps at 350 nm for
30 min. Prior to, and during the irradiation, the solution was
continuously purged with a stream of Ar and cooled using a coldfinger
condenser. After the irradiation, the solvent was evaporated on a rotary
1
mp 199−200 °C; H NMR (300 MHz, DMSO-d6) δ/ppm 10.22 (s,
1H), 8.28 (s, 1H), 8.26 (s, 1H), 7.95 (t, J = 7.0 Hz, 2H), 7.44−7.24
(m, 14 H), 6.70 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ/ppm
153.5, 145.9, 145.7, 136.5, 132.1, 131.8, 129.8, 128.6, 128.1, 128.0,
127.7, 127.6, 127.3, 127.1, 126.7, 126.6, 126.4, 126.2, 125.6, 124.2,
122.3, 108.5, 81.6, 74.2, 54.9; IR (KBr) νmax/cm−1 3367 (O-H), 3051
(C-H), 3024 (C-H), 1447 (C-H); HRMS (MALDI) calculated for
C27H19O+ 359.1430, found 359.1433.
2-Methoxy-3-(diphenylhydroxymethyl)anthracene (7OMe).
The reaction was carried out in a two-neck round-bottom flask (25 mL)
under a N2 atmosphere. 2-Hydroxy-3-(diphenylhydroxymethyl)-
anthracene (7, 18 mg, 48 μmol) was dissolved in acetone (8 mL),
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Article
evaporator. The crude product was chromatographed on a short
column of silica gel (10 × 1 cm) using CH2Cl2 as an eluent to obtain
the pure product 11 (6 mg, 13 μmol, 37% yield) in the form of a thin
Fluorescence decays were obtained on an instrument equipped with
a light-emitting diode (excitation wavelength = 375 nm), using a time-
correlated single-photon counting technique in 1023 channels.
Histograms of the instrument response functions (using LUDOX
scatterer), and sample decays, were recorded at 410, 420, 450, and
550 nm until they reached 2 × 103 counts in the peak channel. The
half-width of the instrument response function was ≈0.2 ns. The time
increment per channel was 0.02441 ns. Obtained histograms were
fitted as sums of exponential using a Gaussian-weighted nonlinear
least-squares fitting based on Marquardt−Levenberg minimization
implemented in the software package of the instrument. The fitting
parameters (decay times and pre-exponential factors) were determined
by minimizing the global reduced chi-squared, χ2. An additional
graphical method was used to judge the quality of the fit that included
plots of surfaces (“carpets”) of the weighted residuals versus channel
number.
1
yellowish film on the walls of the flask. H NMR (600 MHz, CDCl3)
δ/ppm 8.22 (2s, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz,
1H), 7.72 (s, 1H), 7.49−7.45 (m, 4H), 7.43−7.35 (m, 9H), 3.77 (q,
3JH,F = 8.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ/ppm 152.9 (s),
139.7 (s), 132.64 (s), 132.58 (s), 132.4 (s), 130.9 (d), 130.4 (s), 128.6
(d), 128.5 (d), 128.3 (d), 128.1 (d), 127.6 (d), 127.0 (d), 126.9 (s),
1
125.8 (d), 125.5 (q, JC,F = 251 Hz), 124.5 (d), 123.2 (d), 111.0 (d),
3
62.7 (q, JC,H = 34 Hz), 29.6 (s); IR (KBr) νmax/cm−1 3435 (O−H),
3059 (C−H), 2924 (C−H), 2953 (C−H), 1281 (C−F), 1165 (C−F);
HRMS (MALDI) calculated for C27H20O+ 360.1509, found 360.1504.
Quantum Yield of the Photomethanolysis Reaction. Quantum
yield of the photomethanolysis reaction was determined by use of
three actinometers simultaneously: valerophenone,24 ferrioxalate,25
and KI/KIO3.32 A solution of ferrioxalate actinometer was handled in
the dark. The measurement was performed in five quartz cells with the
same dimensions (square, for UV−vis measurement, ca. 3 mL), which
were, during the irradiations, wrapped in black paper, except from the
front side to ensure the controlled absorption of the light from one
side only (no absorption of the radiation reflected from the walls of
the reactor). The solution of compound 7 in CH3OH−H2O (4:1) and
the solution of valerophenone in CH3CN−H2O (4:1) were freshly
prepared, and their concentrations were adjusted to have absorbances
of 0.4−0.8 at 254 nm. After adjustment of the concentrations and
measurement of the corresponding UV−vis spectra, 2.5 mL of the
solution was transferred to the quartz cell and the solutions were
purged with a stream of N2 (20 min each), and then sealed with a
cap. A freshly prepared solution of potassium trioxalatoferrate(III)
(0.012 M K3[Fe(C2O4)3] × 3H2O in 0.05 M H2SO4) (2.5 mL) and
the solution containing potassium iodate (0.1 M) and potassium
iodide (0.6 M) in borate buffer (pH = 9.25) (2.5 mL) were placed in
the third and the forth quartz cells, respectively. Potassium
trioxalatoferrate(III) (2.5 mL) was placed in the fifth cell, which was
not irradiated (blank sample). Before the irradiation, A352 for the
solution of KI/KIO3 was measured. The cells were placed in a holder,
which ensured equal distance of all samples from the lamp, and
irradiated at the same time in the reactor with 1 lamp at 254 nm for
30 s. Before and after the irradiation, the samples were taken from the
cells by use of a syringe and analyzed by HPLC to determine
conversion of 7 to 9 and valerophenone to acetophenone. The
conversion did not exceed 30% to avoid change of the absorbance, or
filtering of the light by the product. A352 of KI/KIO3 actionometer
Determination of pKa and pKa* for 2-Anthrol (8). UV−vis
Titration. A stock solution of the compound 8 was prepared by
dissolving 8 (0.50 mg) in CH3CN (500 μL). A 195 μL aliquot of
the stock solution was diluted to 200 mL with CH3CN−H2O (1:9)
to adjust the concentration of the compound to 5.0 × 10−6
M
(for titration I). For titration II, 8 (7.93 mg) was dissolved in 200 mL of
CH3CN/H2O (2:8). A 150.0 mL portion of each solution was titrated
with a diluted solution of NaOH (until pH 12.7 was reached). The pH
was measured by a pH meter, and UV−vis spectra were recorded on
an instrument. The measurement was performed at 25 °C. The resulting
UV−vis spectra were processed by multivariate nonlinear regression
analysis using the Specfit program.
Fluorescence Titration. A stock solution of the compound 8 was
prepared by dissolving 8 (1 mg) in CH3CN (1000 μL). A 855 μL aliquot
of the stock solution was diluted to 200 mL with CH3CN−H2O (1:9)
to adjust the concentration of the compound to 2.2 × 10−5 M.
A 150.0 mL portion of the solution was basified with a diluted solution
of NaOH (until pH 12.3 was reached) and titrated with a diluted
solution of H2SO4 (until pH 0.5 was reached). The pH was measured
by a pH meter, and fluorescence spectra were recorded on an instru-
ment (slits 2 × 2.5 nm). The measurement was performed at 25 °C.
The resulting fluorescence spectra were processed by multivariate
nonlinear regression analysis using the Specfit program.
Laser Flash Photolysis (LFP). All LFP studies were conducted at
the University of Victoria LFP facility employing a YAG laser, with a
pulse width of 10 ns and an excitation wavelength of 355 nm. Static
cells (0.7 cm) were used, and solutions were purged with nitrogen or
oxygen for 20 min prior to measurements. Absorbances at 355 nm
were ∼0.4.
−
solution was measured to determine the concentration of I3 using
ε352 = 27 600 M−1 cm−1.32 To both solutions of ferrioxalate actinometer
(irradiated and blank) was added a solution of phenantroline (0.5 mL,
0.1% phenanthroline in buffer containing 1.65 M NaOAc and 0.5 M
H2SO4), and A510 was measured. The concentration of FeII was
determined using ε510 = 11 100 M−1 cm−1.25 From the conversion
(valerophenone) and concentration of the photoproducts (in ferrioxalate
and KI/KIO3), irradiance was calculated. The similar values were obtained
for all three actinometers. These values and the value of conversion 7 → 9
were used to calculate the quantum yield of photomethanolysis for
compound 7. The mean value of three measurements was reported.
All equations for the calculation of quantum yields are given in the
Supporting Information.
Steady-State and Time-Resolved Fluorescence Measurements.
The steady-state measurements were performed using a luminescence
spectrometer. The samples were dissolved in CH3CN or CH3CN−
H2O (1:1), and the concentrations were adjusted to have absorbances
at the excitation wavelength (330, 350, or 370 nm) < 0.1. Solutions
were purged with nitrogen for 30 min prior to analysis. The measurements
were performed at 20 °C. Fluorescence quantum yields were determined
by comparison of the integral of the emission bands with the one of
quinine sulfate in 0.05 M aqueous H2SO4 (ΦF = 0.53). The measurements
were performed in triplicate, and the mean value was reported. Typically,
three absorption traces were recorded (and averaged) and three
fluorescence emission traces, exciting at three different wavelengths.
Three quantum yields were calculated, and the mean value was reported.
Antiproliferative Investigation. The experiments were carried
out on three human carcinoma cell lines, HCT 116, MCF-7, and H
460. Cells were cultured as monolayers and maintained in Dulbecco’s
modified Eagle medium (DMEM) supplemented with 10% fetal
bovine serum (FBS), 2 mM L-glutamine, 100 U/mL penicillin, and
100 μg/mL streptomycin in a humidified atmosphere with 5% CO2
at 37 °C.
The cells were inoculated in parallel on two 96-well microtiter
plates on day 0, at 1.5 × 104 cells/mL. Test agents were added in
10-fold dilutions (10−8 to 10−4 M) on the next day and incubated for a
further 72 h. Working dilutions were freshly prepared on the day of
testing. One of the plates was left in the dark, whereas the other was
irradiated in a reactor (6 lamps 350 or 420 nm, 5 min) for 4, 24, and
48 h after the addition of the compounds. After 72 h of incubation, the
cell growth rate was evaluated by performing the MTT assay33 (for the
irradiated and nonirradiated cells), which detects dehydrogenase
activity in viable cells. The absorbance (A) was measured on a
microplate reader at 570 nm. The absorbance is directly proportional
to the number of living, metabolically active cells. The percentage of
growth (PG) of the cell lines was calculated according to one or the
other of the following two expressions: If (mean Atest − mean Atzero) ≥ 0,
then PG = 100 × (mean Atest − mean Atzero)/(mean Actrl − mean Atzero).
If (mean Atest − mean Atzero) < 0, then PG = 100 × (mean Atest − mean
Atzero)/Atzero, where the mean Atzero is the average of absorbance
measurements before exposure of cells to the test compound, the mean
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Article
Atest is the average of absorbance measurements after the desired period of
time, and the mean Actrl is the average of absorbance measurements after
the desired period of time with no exposure of cells to the test compound.
In the experiments where the cells were irradiated, Actrl represents
irradiated control cells. After irradiation at 350 nm, 25% growth inhibition
compared to Actrl without irradiation was observed, whereas, after the
irradiation at 420 nm, no significant growth inhibition was observed.
The results are expressed as IC50, which is the concentration
necessary for 50% of inhibition. The IC50 values are calculated from
concentration−response curves using linear regression analysis by
fitting the test concentrations that give PG values above and below the
reference value (i.e., 50%). Each test was performed in quadruplicate
in at least two individual experiments.
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ASSOCIATED CONTENT
■
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* Supporting Information
6349−6356.
The contents of the Supporting Information include copies of
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5005−5008.
1
the H and 13C NMR spectra and UV−vis, fluorescence, and
LFP data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Soc. 2003, 125, 12961−12970. (b) Xu, M.; Lukeman, M.; Wan, P.
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AUTHOR INFORMATION
Corresponding Author
*Fax: + 385 1 4680 195. Tel: +385 1 4561 141. E-mail:
nbasaric@irb.hr.
(15) (a) Lukeman, M.; Veale, D.; Wan, P.; Munasinghe, V. R.;
Corrie, J. E. T. Can. J. Chem. 2004, 82, 240−253. (b) Verga, D.; Nadai,
M.; Doria, F.; Percivalle, C.; Di Antonio, M.; Palumbo, M.; Richter, S.
N.; Freccero, M. J. Am. Chem. Soc. 2010, 132, 14625−14637.
(16) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2009, 131,
11892−11899.
■
Notes
The authors declare no competing financial interest.
(17) Kulikov, A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73,
7611−7615.
(18) (a) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2011, 133,
15730−15736. (b) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2012,
134, 8408−8411.
ACKNOWLEDGMENTS
■
This work was supported by the Croatia Foundation for
Science (HRZZ grant no. 02.05/25), the Ministry of Science
Education and Sports of the Republic of Croatia (grant No.
098-0982933-2911), the Natural Sciences and Engineering
Research Council (NSERC) of Canada, and the University of
Victoria.
̌
(19) (a) Basaric,
Chem. 2010, 75, 102−116. (b) Basaric,
Mlinaric-Majerski, K.; Uzelac, L.; Kralj, M.; Wan, P. Photochem.
Photobiol. Sci. 2011, 10, 1910−1925. (c) Basaric, N.; Cindro, N.;
Bobinac, D.; Mlinaric-Majerski, K.; Uzelac, L.; Kralj, M.; Wan, P.
Photochem. Photobiol. Sci. 2012, 11, 381−396. (d) Veljkovic, J.; Uzelac,
L.; Molcanov, K.; Mlinaric-Majerski, K.; Kralj, M.; Wan, P.; Basaric, N.
J. Org. Chem. 2012, 77, 4596−4610.
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N.; Zabci
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c,
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I.; Mlinaric-
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Majerski, K.; Wan, P. J. Org.
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N.; Cindro, N.; Bobinac, D.;
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