Benzyl benzoates: New phlorizin analogs as mushroom tyrosinase inhibitors

Article abstract of DOI:10.1016/j.bmc.2010.12.051

In our research, 14 benzyl benzoates with hydroxyl(s) (3-16) were synthesized and their inhibitory activity on mushroom tyrosinase was tested. Results indicated that among these compounds, 4-hydroxybenzyl 3,5-dihydroxybenzoate (3), 4-hydroxybenzyl 2,4-dih

Full text of DOI:10.1016/j.bmc.2010.12.051

Bioorganic & Medicinal Chemistry 19 (2011) 1167–1171
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Benzyl benzoates: New phlorizin analogs as mushroom tyrosinase inhibitors
⇑
Yuntai Fang, Yaozong Chen, Guanfeng Feng, Lin Ma
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In our research, 14 benzyl benzoates with hydroxyl(s) (3–16) were synthesized and their inhibitory
activity on mushroom tyrosinase was tested. Results indicated that among these compounds, 4-hydroxy-
benzyl 3,5-dihydroxybenzoate (3), 4-hydroxybenzyl 2,4-dihydroxybenzoate (5), 4-hydroxybenzyl
2,4,6-dihydroxybenzoate (7), 3-hydroxybenzyl 3,5-dihydroxybenzoate (8), 3-hydroxybenzyl 2,4-
Received 9 November 2010
Revised 22 December 2010
Accepted 23 December 2010
Available online 30 December 2010
dihydroxybenzoate (10) exhibited inhibitory activity with their IC50 less than 10 lM. Further studies
showed these five compounds were competitive inhibitors of tyrosinase and their structure–activity rela-
tionships were investigated in this article.
Keywords:
Phlorizin analogs
Benzyl benzoates
Mushroom tyrosinase
Inhibition
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
studied by Wang et al. in 2002.9 The results suggested that phlorizin
might act as competitive inhibitor to tyrosinase which is more effec-
As the key enzyme of melanin biosynthesis,1 tyrosinase (EC
1.14.18.1; polyphenol oxidase) widely exists in plants and animals.
Tyrosinase is a copper-containing multifunctional oxidase that
catalyzes both the hydroxylation of monophenols to diphenols
and the oxidation of o-diphenols to o-quinones.2 Quinones are
highly reactive compounds, which can polymerize spontaneously
to form high molecular weight compounds or melanin or can react
with amino acids and proteins, thus enhance the brown color
produced.3 However, recently research demonstrated alternations
in melanin synthesis results in many skin effects like hyperpig-
mentation, melasma and lentigo.4 Moreover, tyrosinase may
involve in neuromelanin formation in human brain and contribute
to the neurodegeneration associated with Parkinson’s disease.5 In
addition, browning can lead to the darkening of fruits and plants,
which finally resulting in decrease on their market value.6
tive than arbutin and kojic acid. However, their studies were quite
rough and needed further research. Later its analogs, which mainly
distinguished by the alkyl chain between the two aryl rings, had
been prepared and studied including N-benzylbenzamides (the
C in the alkyl chain was replaced by a NH group),10 chalcones (C–C
single bond between -C and b-C were changed into C@C double
bond)11 and phenethyl gallates (the
-C in the alkyl chain was re-
a-
a
a
placed by an O atom, and the alkyl chain was lengthened with a
CH2 group)12 (Fig. 1). Both of these analogs showed exceptional
inhibitory to tyrosinase. On the other hand, those researches pointed
out that the inhibitory effect mainly depended on the position of the
hydroxyl moieties instead of their quantity.
Based on these results, it can be concluded that phlorizin and its
analogs may in a way inhibitory against tyrosinase. Hence, we
designed another phlorizin analogs 3–16 and carried out on their
inhibitory effect (inhibitory activity and inhibitory kinetics).
Should be noted that mushroom tyrosinase is used throughout
our studies. This research aimed at discovering and filtering effec-
tive compounds as tyrosinase inhibitors, which to offer potential
materials on food systems, cosmetic careers and other fields to
inhibit enzymatic browning.
Due to the great market profits and enormous application pros-
pects, searching for effective and proper tyrosinase inhibitors is of
increasing importance. In recent decades, various tyrosinase inhib-
itors are extracted from natural resources or synthesized in lab,
while some are applied to the pharmaceutical and cosmetic fields.7
Overall, the majority of those inhibitors acted as competitive
inhibitors, which compete with the substrate L-DOPA or tyrosine.
Among the inhibitor families, flavonoids was thought to be the
2. Results and discussion
most effective inhibitors that already attained the IC50 and Ki value
lower than 1 l
M against mushroom tyrosinase.8
2.1. Effects of multisubstitute benzyl benzoate on the
diphenolase activity of mushroom tyrosinase
Phlorizin, defined as one of the flavonoids, was distributed in
some fruits and vegetables such as apples and pears. It had been
Among the compounds reported during these years, kojic acid
was widely used as a skin-whitening material, due to its high
inhibitory activity to tyrosinase.13 According to our research, nine
⇑
Corresponding author. Tel.: +86 20 8411 3690, +86 136 408 02515.
E-mail address: cesmal@mail.sysu.edu.cn (L. Ma).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.12.051

1168
Y. Fang et al. / Bioorg. Med. Chem. 19 (2011) 1167–1171
Figure 1. Phlorizin and its analogs. (a) Phlorizin; (b) chalcone, 2,20,4,40,6-pentahydroxychalcone as an example; (c) N-benzylbenzamides, N-(2,4-dihydroxybenzyl)-3,5-
dihydroxybenzamide as an example; (d) phenethyl gallates, 4-hydroxyphenethyl 3,4,5-trihydroxybenzoate as an example.
of the 14 synthetic compounds gave the IC50 value lower than kojic
acid, indicating these compounds were more effective tyrosinase
inhibitors when compared with kojic acid. As a result, these com-
pounds may be potential preservatives in cosmetic field or food
storage.
The two aromatic rings in benzyl benzoates are asymmetric,
therefore, different position of hydroxyl group(s) on ring A and B
may result in different inhibitory effect on tyrosinase. All the com-
pounds and kojic acid were tested for enzymatic inhibition. Results
are listed in Table 1.
The position of hydroxyl substituted on ring B remarkably af-
fected the inhibition, which in a way could be decisive to inhibitory
activity. Compounds 3–7 with p-phenol on ring
B revealed
significant tyrosinase inhibition in general while compound 5
among them exhibited the highest inhibitory activity by IC50 of
4.95 lM. Compounds 8–11, whose ring B was m-phenol, showed
slightly lower IC50 values. Compounds 12–16 ranked the last owing
to possessing an o-phenol on ring B. Especially, 5 exhibited
12-folds stronger than 14, which possesses identical 2,4-OH
moiety on ring A. The difference between compounds 3–11 and
compounds 12–16 was caused by the similarity between com-
Figure 2. Similarity between L-DOPA, compounds 5 and 10.
as L-DOPA, thus they exhibited high activity. The observations
emphasized that 4-substituted or 3-substituted phenol subunit
on B-ring was essential for the whole structure.
In contrast, the effects caused by different position of hydroxyl
groups attached on ring A were not as conspicuous as on ring B. In
general, ring A is likely to be a steric hindrance which prevented
pounds 3–16 and substrate L
-DOPA (Fig. 2). While R2 was 40-OH
or 30-OH, the position of hydroxyl on ring B was partially the same
Table 1
L
-DOPA to bind with the bicopper center. Hence blocked the way
Inhibition effect of benzyl benzoate derivatives on mushroom tyrosinase activities
DOPAchrome formed. When compared compounds 3–7 with each
other, the most effective one shown an IC50 value just five times to
the least one. The same phenomena were observed between
compounds 8–11. Interestingly, the gallyl subunit on ring A in
compounds 6 and 11 were no so effective when introduced to
tyrosinase, but the tendency was opposite to that subunit as on
ring B.
Compounds
R1
R2
IC50 (lM)
When some of phlorizin analogs were taken into comparison,
some rules could be generalized. Firstly, inhibitory activity was
mainly determined by ring B. What’s more 20,40-hydroxyl moiety
was essential on ring B for binding with the active site of
tyrosinase. Among these two positions 40-OH was found to be more
important to 20-OH. As can be shown in our studies, 40-OH on ring B
resulted in higher inhibition in enzymatic oxidation. Nevertheless,
while the 40-OH was replaced by 20-OH, inhibitory activity was
unexpectedly decreased. From IC50 values it could infer that com-
bination between 40-OH and the bicopper center was stronger
compared with 20-OH.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Kojic acid
3,5-OH
2,5-OH
2,4-OH
3,4,5-OH
2,4,6-OH
3,5-OH
2,5-OH
2,4-OH
3,4,5-OH
3,5-OH
2,5-OH
2,4-OH
3,4,5-OH
2,4,6-OH
40-OH
40-OH
40-OH
40-OH
40-OH
30-OH
30-OH
30-OH
30-OH
20-OH
20-OH
20-OH
20-OH
20-OH
5.84 0.96
12.29 0.20
4.95 0.38
25.73 0.56
8.00 0.41
6.11 0.71
24.39 0.27
6.23 0.85
11.47 0.69
19.89 0.27
>100
66.23 0.25
>100
19.94 0.18
20.99 0.12
Secondly, as described above, ring A was just a role of steric
hindrance. Nonetheless, the position of hydroxyl groups on ring
A somehow affected the activity of the whole compound. Among

Y. Fang et al. / Bioorg. Med. Chem. 19 (2011) 1167–1171
1169
Table 2
Comparison between some best-performance inhibitions of phlorizin analogs
Constants
Phloridzin14
Hydroxychalcone11
N-Benzylbenzamide10
Phenethyl gallate12
Benzyl benzoate
R1
R2
2,4-OH-6-OGlu
40-OH
110
Competitive
64.3
2,4,6-OH
20,40-OH
1
Competitive
3.1
3,5-OH
20,40-OH
2.2
Competitive
1.3
3,4,5-OH
40-OH
4.93
2,4-OH
40-OH
4.69
Competitive
1.11
IC50
Inhibitory type
Ki ( M)
(
l
M)
a
—
a
l
—
a
No data afforded from the article.
the phlorizin analogs (Table 2), 2,4,6-OH or 2,4-OH were demon-
strated to be the most effective combinations, while gallyl subunit
or 3,5-OH were also proved to be efficient. However, proper size of
ring A was essential. Judging from Table 2, once hydroxyl was
Moreover, the alkyl chain between two aromatic rings should
be another factor, in which affected by length and different atoms.
We estimated that electronic effect should be considered and fur-
ther studies should be carried out on those interesting phenomena.
transformed into –O(b-
to be much weaker than other compounds. As –O(b-
D
-glucose), inhibitory activity was expected
-glucose) was
D
2.2. Inhibitory types of multisubstitute benzyl benzoate on
mushroom tyrosinase
extremely bulky, which resulted in difficulty in entering and bind-
ing with the active center, the IC50 value of phloridzin fell to
110
lM.
Kinetic behavior of the oxidation of L-DOPA catalyzed by
tyrosinase of compounds 3, 5, 7, 8 and 10, which shown excep-
tional tyrosinase inhibition, were further studied by method
steady-state kinetic analysis. Inhibition data were then analyzed
by a Lineweaver–Burk plot shown in Figure 3 (compounds 5 and
10 as an example). The plots of 1/V versus 1/[S] were characterized
by a family of straight lines with different slopes, which presented
different fixed substrate concentrations. All these lines were inter-
sected each other at vertical axis, indicating that the inhibitory
type of 5 was competitive manner with
L-DOPA as a substrate.
While its Ki reached 1.11 M, this data strongly suggested 5 to
l
be an effective inhibitor by binding to active site of the enzyme.
After identical research was carried out on 3, 7, 8 and 10, same con-
clusions were drawn that the four compounds were competitive
inhibitors.
3. Conclusion
In summary, series of multihydroxyl benzyl benzoates were
synthesized and tested. Judging from the results, position of hydro-
xyl moiety on ring B remarkably influenced their inhibition of
tyrosinase. Compounds 3, 5, 7, 8, 10 were observed to get an IC50
less than 10 lM, while compound 5 was five times more potent
than the positive control, kojic acid. These compounds may have
potential application on food preservation or cosmetic careers.
4. General experimental
Tyrosinase was purchased from Sigma–Aldrich Chemical Co.
(St. Louis, MO). 3,4-Dihydroxyphenylalanine
(L-DOPA) and
hydroxyphenylmethanols, 3,5-dihydroxybenzoic acid, 2,5-dihy-
droxybenzoic acid and 2,4,6-trihydroxybenzoic acid were pur-
chased from Alfa Aesar. Other reagents were purchased from
commercial suppliers and were dried and purified when necessary.
Water used was re-distilled and ion-free.
All UV–vis absorbance were measured on
a SHIMADZU
UV-2501PC spectrometer without correction. Melting points were
determined on a SGW X-4 melting point apparatus and were
uncorrected. IR spectra were recorded as KBr flakes on a Thermo
Nicolet 330FT-IR spectrometer. 1H NMR spectra were recorded
with a Varian Mercury-Plus 300 instrument (1H, 300 MHz) in
DMSO-d6.
Figure 3. (a) Lineweaver–Burk plot of mushroom tyrosinase inhibition by com-
pound 5. Enzyme activity was measured at 475 nm in the presence of 1
compound 5 while the substrate. -DOPA, varied from 30 to 80 M. (b) Lineweaver–
Burk plot of mushroom tyrosinase inhibition by compound 10. Enzyme activity was
measured at 475 nm in the presence of 0.5 M compound 10 while the substrate.
DOPA, varied from 30 to 80 M.
l
M
4.1. Chemistry
L
l
Benzyl benzoates were synthesized according to the routes
in Scheme 1. Hydroxyphenylmethanol 1 was mixed with
l
L-
l

1170
Y. Fang et al. / Bioorg. Med. Chem. 19 (2011) 1167–1171
Scheme 1. Reagents and conditions: (i) NaHSO4, microwave irradiation, 93–98%.
multihydroxybenzoic acids 2 in the presence of catalyst (NaHSO4)
to get multisubstitute benzyl benzoates 3–16. Microwave-assisted
organic synthesis (MAOS) was carried out in consideration of green
chemistry.15,16 The reaction was found to proceed smoothly under
microwave irradiation within 1–6 min. The mixture was treated
with cold water and filtered. The residue was recrystallized with
ethyl acetate to afford compounds 3–16.
4.3.1. 4-Hydroxybenzyl 3,5-dihydroxybenzoate (3)
Irradiation time: 6 min, yield 85%. Yellowish brown powders;
mp: 127–131 °C. IR(KBr):
m
(cmꢀ1) 3396(
m
O–H), 1702(
m
s
C@O), 1608,
1509, 1475, 1436, 1201(dC–O), 1180(
m
as), 820, 775(
). 1H NMR
(DMSO-d6): d 9.04(s, 1H), 9.00(s, 1H), 8.97(s, 1H), 7.00–6.49(m,
7H), 3.66(s, 2H).
To afford a better yield, some factors were investigated. Basi-
cally, microwave power was 450 W and NaHSO4 was 0.2 g, which
took the studies of Bian et al. as reference.16 The ratio of benzoic
acid to hydroxyphenylmethanol was the main factor for the yields
of this reaction. In the investigation, when the ratio decreased from
2:1 to 1:1, only slight fall occurred on the yield (Table 3). In terms
of economization, we lowered the ratio to 1:1.
Irradiation time was another important factor that varied from
each compound. As the time prolonged, the yield increased.
Whereas, too long time would lead to the carbonization of the mix-
ture (Table 3).
4.3.2. 4-Hydroxybenzyl 2,5-dihydroxybenzoate (4)
Irradiation time: 5 min, yield 87%. Yellow powders; mp:
132–137 °C. IR(KBr):
1474, 1441, 1227(
m
(cmꢀ1) 3331(
m
O–H), 1665(
m
C@O), 1609, 1508,
m
as), 1197(dC–O), 826, 792, 724(
s
). 1H NMR
(DMSO-d6): d 9.13(s, 1H), 9.05(s, 1H), 9.00(s, 1H), 7.13(d, 1H,
J = 3.1 Hz), 6.94(dd, 1H, J = 3.1 Hz), 6.76(d, 1H, J = 8.8 Hz), 6.62(d,
2H), 6.59(d, 2H), 3.66(s, 2H).
4.3.3. 4-Hydroxybenzyl 2,4-dihydroxybenzoate (5)
Irradiation time: 5 min, yield 84%. Yellow powders; mp:
148–150 °C. IR(KBr):
m
(cmꢀ1) 3374(
m
O–H), 1635(
mC@O), 1511, 1443,
1232( as), 880, 845, 821(
m
s
). 1H NMR (DMSO-d6): d 10.33(s, 1H),
4.2. Assay of the diphenolase activity
9.04(s, 2H), 7.60(d, 1H, J = 8.7 Hz), 7.00–6.46(m, 4H, 6.32(dd, 1H,
J = 2.3 Hz), 6.24(d, 1H, J = 2.3 Hz), 3.66(s, 2H).
All the synthesized compounds were screened for diphenolase
inhibitory activity of tyrosinase, using L-DOPA as substrate. The
inhibitors were dissolved in DMSO and prepared at concentrations
of 10 mmol/L. Firstly, 20 units of mushroom tyrosinase (2000
4.3.4. 4-Hydroxybenzyl gallate (6)
Irradiation time: 5 min, yield 76%. Yellow powders; mp:
141–144 °C. IR(KBr):
m
(cmꢀ1) 3370(
m
O–H), 1702(
mC@O), 1611, 1510,
U/mL), 10
l
L of DMSO and 900
l
L of phosphate buffer (pH 6.8) were
-DOPA
1472, 1438, 1243( as), 820, 771(
m
s
). 1H NMR (DMSO-d6): d 9.17(s,
mixed and pre-incubated for 20 min at 30 °C. Then, the
L
(2 mg/mL) was added into this blending and the reaction was
monitored for 1 min by measuring the change in absorbance at
475 nm, due to the yield of the DOPAchrome.
In subsequent experiments, DMSO was replaced by equivalent
inhibitors, whose concentration would be decreased from
1H), 9.06(s, 2H), 8.80(s, 1H), 7.00–6.50(m, 6H), 3.66(s, 2H).
4.3.5. 4-Hydroxybenzyl 2,4,6-dihydroxybenzoate (7)
Irradiation time: 5 min, yield 79%; Orange powders; mp:
153–157 °C. IR(KBr):
m
(cmꢀ1) 3472(
m
O–H), 1649(
mC@O), 1509, 1473,
100 lM until the inhibition was less than 50%. The extent of inhi-
1197(dC–O), 1164( as), 830, 739(
m
s
). 1H NMR (DMSO-d6): d 8.96(s,
bition by the addition of the sample was expressed as the percent-
age necessary for 50% inhibition (IC50). As a control, the IC50 of kojic
acid was also measured.
4H), 5.64(s, 2H), 7.01–6.40(m, 4H), 3.62(s, 2H).
4.3.6. 3-Hydroxybenzyl 3,5-dihydroxybenzoate (8)
Irradiation time: 1 min, yield 75%. Brown powders; mp: 153–
4.3. General procedure for the synthesis of compounds
155 °C. IR(KBr):
m
(cmꢀ1
)
3369(
s
mO–H), 1695(mC@O), 1590, 1492,
1454, 1154( as), 863, 774(
m
). 1H NMR (DMSO-d6): d 9.51(s, 1H),
Equivalent hydroxyphenylmethanol and multihydroxybenzoic
acid (1 mmol both) were mixed with NaHSO4 and grinded in mor-
tar. The mixture was then transferred to an evaporation pan and
put into the microwave oven. After irradiated for a few minutes
the solid was afford with high yield. It should be noted that all
yields below are isolated yield.
9.10(s, 2H), 6.78(d, 2H, J = 2.2 Hz), 6.39(t, 1H, J = 2.3 Hz), 7.15–
6.40(m, 4H), 3.67(s, 2H).
4.3.7. 3-Hydroxybenzyl 2,5-dihydroxybenzoate (9)
Irradiation time: 4 min, yield 78%. Light brown powders; mp:
167–169 °C. IR(KBr):
m
(cmꢀ1) 3316(
m
O–H), 1669(
mC@O), 1616, 1591,
). 1H NMR (DMSO-
Table 3
1446, 1238( as), 1197(dC–O), 860, 793, 754(
m
s
Effect of the ratio of hydroxyphenylmethanol–benzoic acid and irradiation time on
the reaction (compound 3 as example)
d6): d 10.61(s, 1H), 9.11(s, 2H), 7.13(d, 1H, J = 3.1 Hz), 6.94(dd, 1H,
J = 3.1 Hz), 6.76(d, 1H, J = 8.8 Hz), 6.64–6.31(m, 4H), 3.67(s, 2H).
Entry
Methanol/acid
(molar ratio)
Irradiation
time (min)
Isolated
yield (%)
4.3.8. 3-Hydroxybenzyl 2,4-dihydroxybenzoate (10)
1
2
3
4
6
7
2
1.5
1
1
1
5
5
5
4
6
7
88
86
85
75
Irradiation time: 4.5 min, yield 76%. Light brown powders; mp:
171–175 °C. IR(KBr):
m
(cmꢀ1
s
)
3374(
mO–H), 1631(mC@O), 1446,
1153( as), 878, 849, 774(
m
). 1H NMR (DMSO-d6): d 11.38(s, 1H),
87
10.33(s, 1H), 9.10(s, 1H), 7.60(d, 1H, J = 8.7 Hz), 6.32(dd, 1H,
J = 2.3 Hz), 6.24(d, 1H, J = 2.3 Hz), 7.07–6.36(m, 4H), 3.68(s, 2H).
1
73 (partly carbonized)

Y. Fang et al. / Bioorg. Med. Chem. 19 (2011) 1167–1171
1171
4.3.9. 3-Hydroxybenzyl gallate (11)
1196(dC–O), 1164(mas), 831, 798, 751(s d
). 1H NMR (DMSO-d6):
Irradiation time: 2 min, yield 73%. Light green powders; mp:
8.95(s, 4H), 7.04–6.47(m, 4H), 5.64(s, 2H), 3.65(s, 2H).
177–180 °C. IR(KBr):
m
(cmꢀ1) 3278(
m
O–H), 1700(
mC@O), 1617, 1543,
1450, 1252( as), 866, 767(
m
s
). 1H NMR (DMSO-d6): d 12.08(s, 1H),
Acknowledgements
9.14(s, 2H), 8.79(s, 1H), 6.89(s, 2H), 7.21–6.02(m, 4H), 3.67(s, 2H).
The project was funded by Grant 091055811 of the China Uni-
versity Students Research Fund.
4.3.10. 2-Hydroxybenzyl 3,5-dihydroxybenzoate (12)
Irradiation time: 2 min, yield 83%. Yellow powders; mp:
143–144 °C. IR(KBr):
m
s
(cmꢀ1) 3403(
m
O–H), 1696(
mC@O), 1609, 1503,
1455, 1249( as), 755(
m
). 1H NMR (DMSO-d6): d 9.52(s, 1H), 9.22(s,
Supplementary data
1H), 8.97(s, 1H), 6.78(d, 2H, J = 2.3 Hz), 6.39(t, 1H, J = 2.3 Hz),
7.02–6.41(m, 4H), 3.66(s, 2H).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2010.12.051. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
4.3.11. 2-Hydroxybenzyl 2,5-dihydroxybenzoate (13)
Irradiation time: 3 min, yield 85%. Light yellow powders; mp:
165–168 °C. IR(KBr):
m
(cmꢀ1) 3311(
m
O–H), 1668(
mC@O), 1618, 1501,
). 1H NMR (DMSO-d6): d 10.61(s,
References and notes
1447, 1236( as), 835, 793, 745(
m
s
1H), 9.50(s, 1H), 9.12(s, 1H), 7.13(d, 1H, J = 3.0 Hz), 6.94(dd, 1H,
J = 3.1 Hz), 6.76(d, 1H, J = 8.8 Hz), 6.75–6.54(m, 4H), 3.75(s, 2H).
1. Liu, S.-H.; Pan, I.-H.; Chu, I.-M. Biol. Pharm. Bull. 2007, 30, 1135.
2. Claus, H.; Decker, H. Syst. Appl. Microbiol. 2006, 29, 3.
3. Olivares, C.; Solano, F. Pigment Cell Melanoma Res. 2009, 22, 750.
4. Martín, G. M. C.; Ponce, Y. M.; Khan, M. T. H.; Ather, A.; Khan, K. M.; Torrens, F.;
Rotondo, R. Eur. J. Med. Chem. 2007, 42, 1370.
5. Nihei, K.; Yamagiwa, Y.; Kamikawa, T.; Kubo, I. Bioorg. Med. Chem. Lett. 2004, 14,
681.
6. Shin, N. H.; Ryu, S. Y.; Choi, E. J.; Kang, S. H.; Chang, I.-M.; Min, K. R.; Kim, Y.
Biochem. Biophys. Res. Commun. 1998, 243, 801.
4.3.12. 2-Hydroxybenzyl 2,4-dihydroxybenzoate (14)
Irradiation time: 3 min, yield 82%. Cream powders; mp:
144–149 °C. IR(KBr):
m
s
(cmꢀ1) 3271(
m
O–H), 1647(
m
C@O), 1502, 1447,
11.38(s, 1H),
1237( as), 786, 754(
m
). 1H NMR (DMSO-d6):
d
10.35(s, 1H), 9.23(s, 1H), 7.59(d, 1H, J = 8.7 Hz), 7.03–6.50(m, 4H),
6.32(dd, 1H, J = 2.3 Hz), 6.24(d, 1H, J = 2.3 Hz), 3.61(s, 2H).
7. Kima, Y.-J.; Uyama, H. Cell. Mol. Life Sci. 2005, 62, 1707.
8. Chang, T.-S. Int. J. Mol. Sci. 2009, 10, 2440.
9. Wang, J. X.; Zhou, Z.; Wang, J. G. Flavour Fragrance Cosmet. 2002, 2, 4 (Chinese).
10. Cho, S. J.; Roh, J. S.; Sun, W. S.; Kimd, S. H.; Park, K. D. Bioorg. Med. Chem. Lett.
2006, 16, 2682.
11. Jun, N.; Hong, G.; Jun, K. Bioorg. Med. Chem. 2007, 15, 2396.
12. Lee, C. W.; Son, E.-M.; Kim, H. S.; Xu, P.; Batmunkh, T.; Leeb, B.-J.; Koo, K. A.
Bioorg. Med. Chem. Lett. 2007, 17, 5462.
13. Noh, J.-M.; Kwak, S.-Y.; Kim, D.-H.; Lee, Y.-S. Biopolymers (Pept. Sci.) 2007, 88,
300.
14. Wang, Q.; Qiu, L.; Chen, X.-R.; Song, K.-K.; Shi, Y.; Chen, Q.-X. Bioorg. Med. Chem.
2007, 15, 1568.
4.3.13. 2-Hydroxybenzyl gallate (15)
Irradiation time: 2 min, yield 85%. White powders; mp:
150–152 °C. IR(KBr):
m
s
(cmꢀ1) 3289(
m
O–H), 1702(
mC@O), 1614, 1502,
1452, 1248( as), 757(
m
). 1H NMR (DMSO-d6): d 9.16(s, 1H), 8.97(s,
1H), 8.80(s, 1H), 8.31(s, 1H), 6.90(s, 2H), 6.82–6.49(m, 4H),
3.76(s, 2H).
15. Wang, R.; Lu, X.; Yu, X.; Shi, L.; Sun, Y. J. Mol. Catal. A: Chem. 2007, 266,
198.
16. Bian, Y. J.; Duan, X. T.; Zhang, S.; Tian, C.; Kong, J. Speciality Petrochemicals 2006,
23, 17 (Chinese).
4.3.14. 2-Hydroxybenzyl 2,4,6-dihydroxybenzoate (16)
Irradiation time: 3 min, yield 84%. Orange powders; mp:
132–137 °C. IR(KBr):
m ) 3471(mO–H), 1646(mC@O), 1458,
(cmꢀ1