Syntheses of hydroxy substituted 2-phenyl-naphthalenes as inhibitors of tyrosinase

Article abstract of DOI:10.1016/j.bmcl.2006.10.025

Oxyresveratrol and resveratrol, with hydroxy substituted trans-stilbene structure, exert potent inhibitory effects on cyclooxygenase, rat liver mitochondrial ATPase activity, and tyrosinase. As the isosteres of oxyresveratrol, a new family of hydroxyl sub

Full text of DOI:10.1016/j.bmcl.2006.10.025

Bioorganic & Medicinal Chemistry Letters 17 (2007) 461–464
Syntheses of hydroxy substituted 2-phenyl-naphthalenes
as inhibitors of tyrosinase
Suhee Song,a Hyojin Lee,a Youngeup Jin,a Young Mi Ha,b Sungjin Bae,b
Hae Young Chungb and Hongsuk Suha,*
aDepartment of Chemistry and Chemistry Institute for Functional Materials, Pusan National University,
Busan 609-735, Republic of Korea
bDepartment of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea
Received 25 July 2006; revised 2 October 2006; accepted 10 October 2006
Available online 12 October 2006
Abstract—Oxyresveratrol and resveratrol, with hydroxy substituted trans-stilbene structure, exert potent inhibitory effects on cyclo-
oxygenase, rat liver mitochondrial ATPase activity, and tyrosinase. As the isosteres of oxyresveratrol, a new family of hydroxyl
substituted phenyl-naphthalenes were synthesized to show excellent inhibition of mushroom tyrosinase. Compound 10, which is iso-
stere of resveratrol, showed IC50 value of 16.52 lM in mushroom tyrosinase activity. As compared to this, the reference compound,
resveratrol, showed IC50 value of 55.61 lM. Compound 4, which is isostere of oxyresveratrol, showed IC50 value of 0.49 lM.
Among the other three derivatives, compound 13 showed IC50 value of 0.034 lM.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxyresveratrol
(trans-2,30,4,50-tetrahydroxystilbene),
available from mulberry wood (Morus alba L.), has
the structure of hydroxy substituted stilbene. It has been
known that oxyresveratrol is transported to tissues at
high rates resulting in a bioavailability around 50%.1
Pharmacological studies have demonstrated that oxyres-
veratrol can be used as an active ingredient in dermatol-
ogy.2,3 It also has been revealed that the compound has
potent inhibitory effects on cyclooxygenase,4,5 rat liver
mitochondrial ATPase activity,6 and DOPA oxidase
activity.4 Tyrosinase catalyzes two distinct reactions of
the conversion of tyrosine to DOPA.7 Tyrosinase is
responsible for unwanted browning of fruits and vegeta-
bles, and coloring of skin, hair, and eyes in animals
including human beings.2 Many tyrosinase inhibitors
have been reported, including hydroquinone,8 vitamin
C,9 kojic acid,10 albutin,11 resveratrol,12 and
oxyresveratrol.4
For in vivo experiments for the melanin-related disor-
ders, it was necessary to synthesize oxyresveratrol in
large quantity. As shown in Scheme 1, for the synthesis
of oxyresveratrol, when Wittig reaction was done to
generate compound 2, the cis/trans mixture was ob-
tained. The wanted compound 2 with trans-olefin was
separated, by using column chromatography using silica
gel, for the synthesis of oxyresveratrol. The byproduct,
cis-isomer of compound 2,14b was treated with iodine
in chloroform to generate cis/trans mixture again to
recover more of the trans compound 2.14a But to our
surprise, the obtained major product was identified to
be 7-(3,5-dimethoxyphenyl)-1,3-dimethoxynaphthalene
In this report, we reveal hydroxy substituted 2-phenyl-
naphthalenes as new inhibitors of mushroom tyrosinase.
Keywords: Tyrosinase; Resveratrol; Oxyresveratrol; X-ray structure.
*
Corresponding author. Tel.: +82 51 510 2203; fax: +82 51 516
7421; e-mail: hssuh@pusan.ac.kr
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.025

462
S. Song et al. / Bioorg. Med. Chem. Lett. 17 (2007) 461–464
Scheme 1. Reagents and conditions: (a) i—PPh3, C6H6, reflux; ii—
t-BuOK, EtOH; iii—3,5-dimethoxy-benzaldehyde; (b) I2, CHCl3; (c)
BBr3, CH2Cl2, reflux.
(3).14c Considerable efforts were directed toward identi-
fication of the structure of compound 3, utilizing HRMS
(Korea Basic Science Institute: Daegu) and experiments
with 500 MHz NMR including DEPT, COSY, HMQC,
and HMBC. In addition to this, the structure of single
crystal of compound 3 obtained from a CH2Cl2 solution
was confirmed by X-ray diffraction as shown in Figure
1. Crystal of compound 3 belongs to the triclinic system,
Scheme 2. Reagents and conditions: (a) i—2-bromo-6-methoxy-naph-
thalene, Mg, I2, THF; ii—Ni(dppp)Cl2, THF; iii—5; (b) BBr3, CH2Cl2,
reflux.
overnight at room temperature to generate 7-(3,5-
dimethoxyphenyl)-1,3-dimethoxynaphthalene (3) in
72% yield. 7-(3,5-Dimethoxyphenyl)-1,3-dimethoxy-
naphthalene (3) was treated with boron tribromide in
methylene chloride to obtain 7-(3,5-dihydroxyphenyl)-
1,3-naphthalenediol (4) in 27% yield.
˚
˚
space group P-1; a = 7.1600 (8) A, b = 10.9250 (12) A,
˚
c = 11.8562 (14) A, a = b = 105 °, c = 107 °, vol-
ume = 798.49 (16) A, Z = 2, Dcalcd = 1.349 Mg/m3,
˚
m = 0.093 mmꢀ1, F(000) = 344. The final value of
R[I > 2r(I)] was 0.0664, wR2 = 0.1436, GooF = 1.000.13
The synthetic route of compounds 10–13 is shown in
Scheme 2. 2-Bromo-6-methoxy-naphthalene was treated
with magnesium turnings, iodine, Ni(dppp)Cl2, and
1-bromo-3,5-dimethoxy-benzene to generate 2-(3,5-
dimethoxyphenyl)-6-methoxy-naphthalene, which was
converted to 5-(6-hydroxy-2-naphthyl)-1,3-benzenediol
(10)14i using boron tribromide. 5-(6-Hydroxy-2-naph-
thyl)-1,2,3-benzenetriol (11),14j 6-(3-hydroxyphenyl)-2-
naphthol (12),14k and 4-(6-hydroxy-2-naphthyl)-1,3-ben-
zenediol (13)14l were synthesized using the same method
using appropriate starting materials.
After demethylation of compound 3, the tetrahydroxy
substituted compound 414d was obtained to show excel-
lent inhibition of mushroom tyrosinase with IC50 value
of 0.49 lM (resveratrol: 55.61 lM). With the structure
of the new lead compound in hand, other hydroxy
substituted 2-phenyl-naphthalenes were synthesized by
using other simple method.
The synthetic routes of hydroxy substituted 2-phenyl-
naphthalenes are shown in Schemes 1 and 2. Commer-
cially available 1-bromomethyl-3,5-dimethoxybenzene
(1) was treated with triphenyl phosphine in N,N-dimeth-
ylformamide (DMF) at reflux to generate the phospho-
nium salt. The phosphonium salt was reacted with
potassium tert-butoxide in ethanol and 3,5-dimethoxy-
banzaldehyde to generate cis/trans mixture of 2,30,4,50-
tetramethoxy-trans-stilbene (2) in 74% yield. The solu-
tion of compound 2 in chloroform was treated with cat-
alytic amount of iodine (0.05 equiv) and stirred
Compound 3 contains extended conjugated systems
which can react as both diene and dienophile moieties.
With hydroxy substituted stilbene, Diels–Alder reac-
tions followed by the fragmentation of the hydroxy
substituted benzene have been reported before, which
generated di-phenyl substituted naphthalene.15 The
compound which was obtained in our case contains
the mono-phenyl substituted naphthalene system, which
is isostere of the oxyresveratrol. Fragmentation of two
1,3-dimethoxybenzenes generated mono-phenyl substi-
tuted naphthalene system, which was caused by substi-
tution pattern of the methoxy groups on the benzene
as compared to the reported case.
While compounds 11 and 13 are new, compounds 4,16
10,17,18 and 1219 have been illustrated before. But there
has been no report about the inhibition of tyrosinase
activity Table 1.
Compound 10, which is isostere of resveratrol, showed
IC50 value of 16.52 lM in mushroom tyrosinase activi-
ty.20 As compared to this, the reference compound, res-
veratrol,12 showed IC50 value of 55.61 lM. Compound
4, which is isostere of oxyresveratrol, showed IC50 value
Figure 1. X-ray structure of 3.

S. Song et al. / Bioorg. Med. Chem. Lett. 17 (2007) 461–464
463
Table 1. Inhibition effects of hydroquinone, kojic acid, resveratrol,
and compounds 4 and 10–13 on mushroom tyrosinase activity
14. (a) trans-2: white solid: mp 56 °C; Rf 0.22 (SiO2, 17%
1
EtOAc–Hex); H NMR (300 MHz, benzene-d6) d 3.29 (s,
a
3H), 3.35 (s, 6H), 3.38 (s, 3H), 6.40 (d, 1H, J = 2.2 Hz),
6.43 (dd, 1H, J = 2.5, 8.3 Hz), 6.53 (t, 1H, J = 2.2 Hz),
6.88 (d, 2H, J = 2.2 Hz), 7.15 (d, 1H, J = 16.1 Hz), 7.50 (d,
1H, J = 8.3 Hz), 7.82 (d, 1H, J = 16.2 Hz); 13C NMR
(75 MHz, benzene-d6) d 55.5, 55.6, 55.7, 98.7, 99.6, 104.6,
105.2, 119.5, 124.1, 127.2, 127.6, 140.6, 158.3, 160.8, 161.1;
HRMS (EI), m/z 300.1359 (calculated for C18H20O4
300.1362).; (b) cis-2: colorless oil; Rf 0.27 (SiO2, 17%
Compound
HS #
IC50 (lM)
Hydroquinone
Kojic acid
33.48( 1.70)
38.24( 1.47)
55.61( 2.77)
0.49( 0.47)
16.52( 0.65)
2.95( 1.26)
6.40( 0.30)
0.034( 0.01)
Resveratrol
4
HS-1713
HS-1784
HS-1791
HS-1792
HS-1793
10
11
12
13
1
EtOAc–Hex); H NMR (300 MHz, benzene-d6) d 3.26 (s,
6H), 3.28 (s, 3H), 3.30 (s, 3H), 6.11 (dd, 1H, J = 2.2,
8.2 Hz), 6.41 (d, 1H, J = 2.2 Hz), 6.48 (t, 1H, J = 2.2 Hz),
6.56 (d, 1H, J = 12.1 Hz), 6.72 (d, 2H, J = 2.2 Hz), 6.96 (d,
1H, J = 12.4 Hz), 7.44 (d, 1H, J = 8.5 Hz); 13C NMR
(75 MHz, benzene-d6) d 55.3, 55.4, 55.6, 98.2, 99.6, 104.2,
106.7, 118.7, 125.8, 129.0, 130.9, 139.6, 158.3, 160.4,
160.5.; (c) Compound 3: white solid: mp 89 °C; Rf 0.27
(SiO2, 17% EtOAc–Hex); 1H NMR (300 MHz, benzene-
d6) d 3.35 (s, 6H), 3.37 (s, 3H), 3.51 (s, 3H), 6.54 (d, 1H,
J = 1.8 Hz), 6.63 (t, 1H, J = 2.2 Hz), 6.66 (d, 1H,
J = 2.2 Hz), 7.07 (d, 2H, J = 2.2 Hz), 7.69 (d, 1H,
J = 8.8 Hz), 7.80 (dd, 1H, J = 1.8, 8.4 Hz), 8.84 (d, 1H,
J = 1.5 Hz); 13C NMR (75 MHz, benzene-d6) d 55.2, 55.3,
55.4, 98.6, 98.9, 100.4, 106.3, 121.2, 123.0, 127.6, 127.8,
135.6, 137.0, 144.7, 157.7, 158.4, 162.3; HRMS (EI), m/z
324.1359 (calculated for C20H20O4 324.1362).; (d) Com-
pound 4: dark brown solid: mp 119 °C; Rf 0.22 (SiO2, 66%
a Values are means of three experiments, standard deviation is given in
parentheses.
of 0.49 lM. Among the other three derivatives, com-
pound 13 showed IC50 value of 0.034 lM.
Acknowledgment
This work was supported for two years by Pusan
National University Research Grant (H. Suh).
Supplementary data
1
EtOAc–Hex); H NMR (300 MHz, benzene-d6) d 6.76 (s,
1H), 6.92 (s, 1H), 7.00 (s, 1H), 7.11 (s, 2H), 7.60 (d, 1H,
J = 8.5 Hz), 7.74 (d, 1H, J = 8.5 Hz), 8.77 (s, 1H); 13C
NMR (75 MHz, benzene-d6) d 101.7, 101.9, 102.2, 106.8,
121.0, 121.7, 126.9, 127.8, 135.6, 136.8, 145.0, 155.9, 156.7,
159.6; HRMS (EI), m/z 268.0731 (calculated for C16H12O4
268.0736); (e) Compound 6: dark brown solid: mp 77 °C;
Rf 0.25 (SiO2, 20% EA–Hex); 1H NMR (300 MHz,
benzene-d6) d 3.39 (s, 6H), 3.40 (s, 3H), 6.64 (t, 1H,
J = 5.2 Hz), 6.96 (d, 1H, J = 2.5 Hz), 7.03 (d, 2H,
J = 2.2 Hz), 7.21 (dd, 1H, J = 2.5, 8.8 Hz), 7.55 (d, 1H,
J = 9.1 Hz), 7.66 (d, 1H, J = 8.5 Hz), 7.75 (dd, 1H, J = 1.9,
8.5 Hz), 7.99 (d, 1H, J = 1.6 Hz); 13C NMR (75 MHz,
benzene-d6) d 55.3, 55.3, 100.1, 106.2, 106.4, 119.9, 126.6,
126.8, 127.8, 130.1, 130.5, 134.9, 137.4, 144.3, 158.7, 162.2;
HRMS (EI), m/z 294.1257 (calculated for C19H18O3
294.1256); Compound (f) 7: dark brown solid: mp 74 °C;
Rf 0.20 (SiO2, 20% EA–Hex); 1H NMR (benzene-d6)
d(ppm) : 3.43 (s, 3H), 3.46 (s, 6H), 3.94 (s, 3H), 6.90 (s,
2H), 7.02 (d, 1H, J = 2.4 Hz), 7.25 (dd, 2H, J = 2.5,
9.1 Hz), 7.63 (d, 1H, J = 9.1 Hz), 7.76 (d, 1H, J = 2.2 Hz),
8.01 (s, 1H); 13C NMR (75 MHz, benzene-d6) d 54.7, 55.8,
60.5, 105.4, 105.9, 119.6, 125.8, 126.4, 127.5, 127.6, 129.6,
129.9, 134.3, 137.2, 137.3, 154.3, 158.2; HRMS (EI), m/z
324.1359 (calculated for C20H20O4 324.1362); (g) Com-
pound 8: dark brown solid: mp 84 °C; Rf 0.28 (SiO2, 20%
EA–Hex); 1H NMR (300 MHz, benzene-d6) d 3.38 (s, 3H),
3.40 (s, 3H), 6.85 (d, 1H, J = 6.5 Hz), 6.95 (d, 1H,
J = 2.5 Hz), 7.19 (m, 2H), 7.28 (t, 1H, J = 6.8 Hz), 7.35
(s, 1H), 7.53 (d, 1H, J = 8.9 Hz), 7.65 (d, 1H, J = 8.5 Hz),
7.71 (d, 1H, J = 8.5 Hz), 7.94 (s, 1H); 13C NMR (75 MHz,
benzene-d6) d 55.1, 106.1, 113.3, 113.7, 119.9, 120.4, 120.5,
126.6, 126.8, 120.5, 120.5, 124.8, 127.2, 130.1, 143.6, 158.6,
161.1; HRMS (EI), m/z 264.1149 (calculated for C18H16O2
264.1150); (h) Compound 9: dark brown solid: mp 99 °C;
Rf 0.25 (SiO2, 20% EA–Hex); 1H NMR (300 MHz,
benzene-d6) d 3.26 (s, 3H), 3.40 (s, 3H), 3.41(s, 3H), 6.48
(dt, 1H, J = 2.5, 8.3 Hz), 6.58 (t, 1H, J = 3.3 Hz), 7.00 (s,
1H), 7.22 (dt, 1H, J = 8.9, 2.8 Hz), 7.37 (dd, 1H, J = 8.5,
3.6 Hz), 7.59 (dd, 1H, J = 9.0, 3.0 Hz), 7.72 (dd, 1H,
J = 8.5, 3.0 Hz), 7.89 (dt, 1H, J = 1.6, 8.5 Hz), 8.00 (s, 1H);
Supplementary data associated with compound 3
including 1H/13C NMR, DEPT, COSY, HMQC,
HMBC, and X-ray diffraction data. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2006.10.025.
References and notes
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13. Crystallographic data (excluding structure factors) for the
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Cambridge Crystallographic Data Centre as supplemen-
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data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].

464
S. Song et al. / Bioorg. Med. Chem. Lett. 17 (2007) 461–464
13C NMR (75 MHz, benzene-d6) d 55.1, 55.3, 55.4, 100.0,
d 6.72 (dd, 1H, J = 2.2, 8.5 Hz), 6.86 (d, 1H, J = 2.5 Hz),
7.23 (dd, 1H, J = 2.5, 8.8 Hz), 7.28 (d, 1H, J = 8.5 Hz),
7.37 (d, 1H, J = 2.5 Hz), 7.60 (d, 1H, J = 5.8 Hz), 7.62 (d,
1H, J = 5.5 Hz), 7.78 (dd, 1H, J = 1.6, 8.5 Hz), 7.98 (s,
1H); 13C NMR (75 MHz, benzene-d6) d 104.0, 108.4,
109.8, 119.1, 121.9, 126.7, 127.4, 129.3, 129.7, 130.4, 132.5,
134.6, 134.7, 155.8, 156.1, 158.5; HRMS (EI), m/z
252.0790 (calculated for C16H12O3 252.0786).
105.4, 106.3, 119.5, 124.8, 126,8, 128.7, 129.7, 130.0, 130.3,
132.3, 134.3, 135.0, 158.4, 158.6, 161.3; HRMS (EI), m/z
294.1255 (calculated for C19H18O3 294.1256); (i) Com-
pound 10: dark brown solid: mp 189 °C; Rf 0.22 (SiO2, 5%
1
MeOH–MC); H NMR (300 MHz, benzene-d6) d 6.85 (t,
1H, J = 2.2 Hz), 7.12 (d, 2H, J = 2.2 Hz), 7.30 (dd, 1H,
J = 2.5, 8.8 Hz), 7.40 (d, 1H, J = 2.5 Hz), 7.60 (s, 1H), 7.63
(s, 1H), 7.74 (dd, 1H, J = 1.6, 8.5 Hz), 8.04 (d, 1H,
J = 1.4 Hz); 13C NMR (75 MHz, benzene-d6) d 102.0,
106.6, 109.8, 119.1, 126.0, 126.3, 127.0, 129.3, 130.8, 135.0,
138.5, 144.8, 155.9, 159.9; HRMS (EI), m/z 252.0785
(calculated for C16H12O3 252.0786); (j) Compound 11:
dark brown solid: mp 215 °C; Rf 0.19 (SiO2, 10% MeOH–
15. Li, X. M.; Hung, K. S.; Lin, M.; Zhou, L. X. Tetrahedron
2003, 59, 4405.
16. Gerber, N. N. Phytochemistry 1986, 25, 1697.
17. Minutolo, F.; Sala, G.; Bagnacani, A.; Bertini, S.;
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Sacchi, N.; Macchia, M.; Ghiconi, R. J. Med. Chem. 2005,
48, 6783.
1
MC); H NMR (benzene-d6) d(ppm) : 7.13 (s, 2H), 7.28
(dd, 1H, J = 2.5, 8.8 Hz), 7.37 (d, 1H, J = 2.5 Hz), 7.62
(dd, 2H, J = 1.9, 8.8 Hz), 7.71 (dd, 1H, J = 1.9, 8.5 Hz),
7.98 (d, 1H, J = 1.6 Hz); 13C NMR (75 MHz, benzene-d6)
d 107.4, 109.8, 119.8, 125.7, 126.6, 127.8, 129.8, 130.5,
133.4, 134.2, 134.9, 136.9, 147.0, 155.8; HRMS (EI), m/z
268.0733 (calculated for C16H12O4 268.0736); (k) Com-
pound 12: dark brown solid: mp 174 °C; Rf 0.22 (SiO2, 3%
MeOH–MC); 1H NMR (300 MHz, benzene-d6) d 7.08 (dt,
1H, J = 7.1, 1.9 Hz), 7.24 (s, 1H), 7.26 (t, 1H, J = 8.4 Hz),
7.33 (dd, 1H, J = 2.5, 8.8 Hz), 7.41 (d, 1H, J = 2.5 Hz),
7.50 (d, 1H, J = 1.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 7.68 (dd,
1H, J = 1.6, 8.2 Hz), 7.98 (s, 1H); 13C NMR (75 MHz,
benzene-d6) d 109.8, 114.8, 115.0, 119.5, 126.4, 126.6,
127.5, 129.7, 130.6, 130.7, 135.3, 136.7, 143.8, 156.2, 158.5;
HRMS (EI), m/z 236.0834 (calculated for C16H12O2
236.0837); (l) 13: dark brown solid: mp 186 °C; Rf 0.22
(SiO2, 5% MeOH–MC); 1H NMR (300 MHz, benzene-d6)
18. Roberti, M.; Pizzirani, D.; Recanatini, M.; Simoni, D.;
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20. Tyrosinase enzymatic assay: briefly a 10 lL sample was
added to an assay mixture containing with 1 mM L-
tyrosine solution, 50 mM phosphate buffer, pH 6.5, and
20 lL of aqueous solution of mushroom tyrosinase
(1000 U) was added to a 96-well microplate (Nunc,
Denmark), in a total volume of 200 lL. The assay mixture
was incubated at 25 °C for 30 min After incubation, the
amount of dopachrome produced in the reaction mixture
was determined as the optical density at 492 nm (OD492) in
a microplate leader (Hewlett-Packard).