Synthesis of new UV-B light absorbents: (Acetylphenyl)glycosides with antioxidant activities

Article abstract of DOI:10.1016/j.bmcl.2008.05.006

m-Acetylphenyl-β-d-glucopyranosides and m-acetylphenyl-α/β-d-mannopyranosides were synthesized by the Koenigs-Knorr, Mitsunobu, and Helferich reactions as key glycosylation reactions, respectively. Their spectroscopic properties and antioxidative activities were characterized as potential ultraviolet B-ray absorbents.

Full text of DOI:10.1016/j.bmcl.2008.05.006

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3582–3584
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of new UV-B light absorbents: (Acetylphenyl)glycosides
with antioxidant activities
b
b
Takashi Otani a, Tetsu Tsubogo a, Naoki Furukawa a, Takao Saito a, , Katsumi Uchida , Kanako Iwama ,
*
Yuki Kanai b, Hirofumi Yajima b,
*
a Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
b Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
m-Acetylphenyl-b-D-glucopyranosides and m-acetylphenyl-a/b-D-mannopyranosides were synthesized
Received 3 January 2008
Revised 17 April 2008
Accepted 1 May 2008
Available online 6 May 2008
by the Koenigs–Knorr, Mitsunobu, and Helferich reactions as key glycosylation reactions, respectively.
Their spectroscopic properties and antioxidative activities were characterized as potential ultraviolet
B-ray absorbents.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
UV-B light absorbents
Antioxidant activities
Synthesis
Glycosides
Ultraviolet (UV) light in the sunlight is an environmental hu-
man carcinogen. UV light in sunlight is divided into three regions,
viz. UV-A (320–400 nm), UV-B (280–320 nm), and UV-C (200–
280 nm). The stratospheric ozone layer effectively blocks UV-C
light from reaching the earth’s surface. Both UV-A and UV-B light
reach the earth’s surface in sufficient amounts to give rise to seri-
ous biological consequences to the skin and eyes. Although UV-A
light is the predominant component of terrestrial UV radiation
and believed to be rather weak in the carcinogenesis, excessive
exposure to UV-A light causes aging and wrinkling of the skin.1
On the other hand, UV-B light is known to be absorbed into the
skin, producing erythema, burns, and eventually skin cancer as a
consequence of DNA damage.
generated through the aglycon, and that the active oxygen formed
is diminished by the in situ presence of the glycon of the glucoside,
acting as an antiphotooxidant. With regard to the antioxidant func-
tions of sugars, West et al. presented the radical scavenger pro-
cesses for hydroxyl radical (ꢀOH).7 In the sugar species, it has
been reported that the antioxidant activity increases in the order
glucose < mannose ꢁ fructose.8
The objective of this study was to develop a new UV-B light
absorbent by modification of the glycoside 3. In taking account of
the foregoing context, including the order of the sugar species for
antioxidant activity, we synthesized m-acetylphenyl-b-D-manno-
pyranosides (5: AP-b-Man) composed of an acetylphenyl group
as an aglycon and mannose as a glycon. The removal of the elec-
tron-releasing amino group (–NH2) from 2-amino-3-hydroxyace-
tophenone (AHA) of the aglycon in AAP-b-Glu (3) is predicted to
give rise to a blue shift of the characteristic absorption band from
the UV-A range to the UV-B range. For comparison, m-acetylphe-
The eye lenses of diurnal primates contain glucosides that act as
UV filters. Glucosides 1–4 were isolated and their structures iden-
tified.2–5 (3-Acetyl-2-aminophenyl)-b-
D-glucopyranoside (3: AAP-
b-
D-Glu) is known to be the precursor of yellow pigments, whose
intensity increases with age.4,6 Therefore, AAP-b-Glu (3) containing
an acetylaminophenyl group as an aglycon is expected to serve as a
UV-A absorbent in sunscreen for cosmetics. It should be noted that
an aromatic amino group of a liberated aglycon has been suspected
of being venomous. Satoh et al.6 showed that AAP-b-Glu (3) would
be involved in photodynamic processes at work in the aging hu-
man lens. Moreover, they suggested that photooxidation pro-
ceeded with an increase in accumulation of active oxygen
nyl-b-
D
-glucopyranosides (6: AP-b-Glu) and m-acetylphenyl-
a-D-
mannopyranoside (7: AP-
a-Man) were also synthesized. The
spectroscopic properties such as the UV–vis absorption and fluo-
rescence spectra were probed for the glycosides 5–7. Moreover,
their antioxidant activities were evaluated by monitoring the
increments of the absorbances at 550 nm responsible for the
photogeneration of superoxide anion radical (Oꢀ2ꢂ) using the cyto-
chrome-c reduction assay9 (see the Supplementary Data for de-
tails). The effects of the sugar species and anomer on the
physicochemical properties of the glycosides will be discussed
below.
* Corresponding authors. Tel.: +81 3 52288254; fax: +81 3 52614631 (T. Saito).
E-mail addresses: tsaito@ch.kagu.tus.ac.jp, tsaito@rs.kagu.tus.ac.jp (T. Saito).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.006

T. Otani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3582–3584
3583
OH
OAc
OH
O
O
a), b)
c)
HO
AcO
AcO
O
HO
HO
HO
OH
O
OH
AcO
OH
R
Br
R =
NH2
12
13
O
R'
NH2
O
CO2H
O
HN
AcO
HO
CO2H
Me
d)
O
O
AcO
AcO
HO
HO
O
O
OAc
OH
1: R' = NH2
2: R' = H
3
4
14
6
Me
O
Me
O
The AP-b-Man 5 was synthesized by the Mitsunobu reaction10
Scheme 2. Reagents and conditions: (a) Ac2O, cat. HClO4; (b) P, Br2, H2O; (c) 10,
Ag2O, CaSO4, pyridine, I2 29%; (d) NaOMe, MeOH, H2O, 60%.
as a key reaction by a two-step procedure without resorting to
chromatographic purification (Scheme 1).11 First,
D
-mannose (8)
was converted to crystalline 2,3;4,6-di-O-cyclohexylidene-a-D-
OH
OH
O
OAc
O
mannopyranose (9) by reaction with 1-ethoxycyclohexene. The
protected mannose 9 was glycosylated with m-hydroxyacetophe-
none (10) under the Mitsunobu conditions to produce mannopy-
ranoside 11, which was hydrolyzed with acetic acid to give AP-b-
Man (5) in 56% yield.12
AcO
AcO
a)
O
HO
HO
OAc
AcO
OH
8
15
OR
The glucosides 6 were prepared by Koenigs–Knorr glycosylation
RO
RO
(Scheme 2).13
D
-Glucose (12) was converted to 2,3,4,6-tetra-O-
O
RO
O
b)
acetyl-a-D-glucopyranosyl bromide (13) in high yield, which was
then glycosylated with m-hydroxyacetophenone (10) by the Koe-
nigs–Knorr glycosylation to produce b-glycoside 14 (29%). Depro-
tection of the acetyl groups of 14 with sodium methoxide gave
AP-b-Glu (6) (60%).14
Me
16: R = Ac
7: R = H
c)
Scheme 3. Reagents and conditions: (a) Ac2O, pyridine; (b) 10, ZnCl2, AcOH/Ac2O
150 °C 41%; (c) MeONa, MeOH 30%.
The
a
-mannopyranoside 7 was prepared by the Helferich reac-
tion15 as a key reaction (Scheme 3).16 Treatment of
D-mannose (8)
with acetic anhydride in the presence of pyridine gave the penta-
in Table 1, including the antioxidation efficiencies (AO). It should
acetate 15 in high yield.17 The pentaacetate 15 was reacted with
be noted that the e360 value of the AAP-b-Glu (3) at 360 nm in
the UV-A region is ca. 3400 Mꢂ1 cmꢂ1 4
. Typical excitation (Ex)
10 upon heating in the presence of ZnCl2 to give
mannose 16 in 41% yield. Deprotection of 16 under basic condi-
tions produced AP-
-Man (7) in 30% yield.18
Figure 1 shows the UV–vis absorption spectra of HA (10), AP-b-
Man (5), AP-b-Glu (6), and AP- -Man (7), which were measured
a-glycosylated
and fluorescence spectra (Em) of AP-b-Man (5) in aqueous solution
are shown in Figure 2, where the emission wavelength for the for-
mer and excitation wavelength for the latter were kem = 400 nm
and kex = 320 nm, respectively. Likewise, the other glycosides, AP-
a
a
with a JASCO V-570 spectrophotometer. All the samples including
the aglycon HA (10) gave absorption spectra with three peaks at
around 210, 250, and 300 nm in the UV-B region. Compared with
the spectral feature of HA, the glycosides 5–7 exhibited blue shifts
for each of the peaks, accompanied by a slight hypochromic effect
for the band near 300 nm and bathochromic effects for the bands
near 210 and 250 nm. Each of the glycosides 5–7 has a moderate
b-Glu (6) and AP-a-Man (7) besides HA (10) exhibited similar Ex
and Em spectra to those of AP-b-Man (5). The Ex spectra showed
peaks at around 275 and 325 nm, whereas the Em spectra showed
a peak at around 400 nm, regardless of the sugar species and
anomer.
Table 1 shows the AO values estimated by the following for-
mula (Eq. 1) from the cytochrome-c reduction assay9:
UV-B
absorbance
with
molar
extinction
coefficients
ꢀ
ꢁ
D
D
A550
Ao550
e300 ꢃ 2000 Mꢂ1 cmꢂ1 at 300 nm, regardless of the sugar species
and anomer. The e300 values of all the samples are summarized
AOð%Þ ¼ 1 ꢂ
ꢄ 100;
ð1Þ
where D DA550 refer to the increments in the absorbances at
Ao550 and
550 nm over the reaction time of 1 h for aglycon HA (10) and each
of the glycosides 5–7. All of the glycosides 5–7 show antioxidant
activities, in particular, the AO value of AP-b-Man (5) is the largest.
It should be noted that the synthesized glycoside 5 has also effi-
cient antioxidant activity for singlet oxygen generated in the photo
reaction (based on the squaleneperoxide assay, see the Supple-
mentary Data for details).
In conclusion, new UV-B absorbent glycosides 5–7 with efficient
antioxidant activity were synthesized. The results show that AP-b-
Man (5) is expected to serve as a potential UV-B absorbent in sun-
screen for cosmetics.19
OH
O
OH
O
O
b)
a)
O
O
HO
HO
O
OH
OH
8
9
O
O
Me
Me
O
OH
O
c)
HO
HO
O
O
O
O
O
O
HO
Supplementary data
11
5
Scheme 1. Reagents and conditions: (a) 1-ethoxycyclohexene, p-TsOH (cat.), DMF
44%; (b) m-hydroxyacetophenone (10), DEAD, TPP, toluene; (c) AcOH, H2O 56% in
two steps.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.05.006.

3584
T. Otani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3582–3584
40
30000
25000
20000
15000
10000
5000
0
2000
1500
1000
500
0
30
20
280
300
320
340
360
Wavelength (nm)
10
0
300
400
500
200
250
300
350
400
Wavelength (nm)
Wavelength (nm)
Figure 2. Excitation (solid line) and emission (dashed line) spectra of AP-b-Man (5).
30000
25000
20000
15000
10000
5000
0
2000
1500
1000
500
0
References and notes
1. Matsumura, Y.; Ananthaswamy, H. N. Toxicol. Appl. Pharmacol. 2004, 195, 298.
2. van Heyningen, R. Nature 1971, 230, 393.
3. (a) Inoue, A.; Satoh, K. Bioorg. Med. Chem. Lett. 1994, 4, 2303; (b) Truscott, R. J.
W.; Wood, A. M.; Carver, J. A.; Sheil, M. M.; Stutchbury, G. M.; Zhu, J.; Kilby, G.
W. FEBS Lett. 1994, 348, 173; (c) Chenault, H. K.; Yang, Jie; Taber, D. F.
Tetrahedron 2000, 56, 3673.
4. (a) Inoue, A.; Satoh, K. Bioorg. Med. Chem. Lett. 1993, 3, 345; (b) Das, S. K.; Saha,
U. K. Bioorg. Med. Chem. Lett. 1994, 4, 1219.
5. Shirao, E.; Ando, K.; Inoue, A.; Shirao, Y.; Balasubramanian, D. Exp. Eye Res.
2001, 73, 421.
6. Inoue, A.; Sasaki, D.; Satoh, K. Exp. Eye Res. 2004, 79, 833.
7. West, P. R.; Schnarr, G. W.; Sitwell, L. Tetrahedron Lett. 1977, 18, 3869.
8. Grankvist, K. Biochem. J. 1981, 200, 685.
9. Rajendran, M.; Inbaraj, J. J.; Gandhidasan, R.; Murugesan, R. J. Photochem.
Photobiol. A 2006, 182, 67.
280
300
320
340
360
Wavelength (nm)
200
250
300
350
400
Wavelength (nm)
10. Mitsunobu, O. Synthesis 1981, 1.
11. (a) Garegg, P. J.; Iversen, T. Carbohydr. Res. 1979, 70, C13; (b) Garegg, P. J.;
Iversen, T.; Norberg, T. Carbohydr. Res. 1979, 73, 313.
12. 5: colorless solid, mp 64.4–65.0 °C; 1H NMR (500 MHz, D2O, d): 7.72 (d,
J = 7.8 Hz, 1H, 40-H), 7.62 (s, 1H, 20-H), 7.51 (t, J = 8.0 Hz, 1H, 50-H), 7.37 (dd,
J = 2.6, 8.2 Hz, 1H, 60-H), 5.41 (s, 1H, 1-H), 4.23 (d, J = 3.3 Hz, 1H, 2-H), 3.92 (dd,
J = 2.2, 12.4 Hz, 1H, 6-H), 3.80–3.76 (m, 1H, 3-H), 3.75 (d, J = 6.6 Hz, 1H, 6-H),
3.69 (t, J = 9.8 Hz, 1H, 4-H), 3.62–3.57 (m, 1H, 5-H), 2.65 (s, 3H, CH3); 13C NMR
(150 MHz, D2O, d): 203.1 (C@O), 156.3 (C), 137.7 (C), 130.1 (CH), 123.2 (CH),
121.8 (CH), 115.3 (CH), 97.4 (CH), 76.4 (CH), 72.6 (CH), 70.4 (CH), 66.6 (CH),
60.1 (CH2), 26.2 (CH3); HRMS-FAB (m/z): [M+H]+ Calcd for C14H19O7, 299.1131;
found 299.1129.
30000
25000
20000
15000
10000
5000
0
2000
1500
1000
500
0
280
300
320
340
360
13. Koenig, W.; Knorr, E. Ber 1901, 34, 957.
Wavelength (nm)
14. 6: Colorless solid, mp 172.0–173.1 °C; 1H NMR (600 MHz, D2O, d): 7.74 (d,
J = 7.7 Hz, 1H, 40-H), 7.66 (s, 1H, 20-H), 7.53 (t, J = 8.0 Hz, 1H, 50-H), 7.40 (dd,
J = 2.4, 9.1 Hz, 1H, 60-H), 5.18 (d, J = 7.1 Hz, 1H, 1-H), 3.94 (dd, J = 1.7, 12.4 Hz,
1H, 6-H), 3.74 (dd, J = 6.1, 12.4 Hz, 1H, 6-H), 3.62–3.56 (m, 1H, 5-H), 3.56–3.48
(m, 2H, 2-H and 3-H), 3.50 (t, J = 9.2 Hz, 1H, 4-H), 2.66 (s, 3H, CH3); 13C NMR
(150 MHz, D2O, d): 206.8 (C@O), 159.4 (C), 140.8 (C), 133.0 (CH), 126.3 (CH),
124.9 (CH), 118.5 (CH), 102.9 (CH), 79.0 (CH), 78.3 (CH), 75.6 (CH), 72.2 (CH),
63.3 (CH2), 29.1 (CH3); HRMS-FAB (m/z): [M+H]+ Calcd for C14H19O7, 299.1131;
found 299.1130.
200
250
300
350
400
Wavelength (nm)
15. Helferich, B.; Schmitz-Hillebrecht, E. Ber 1933, 378, 66.
16. (a) Conchie, J.; Levvy, G. A. Methods Carbohydr. Chem. 1963, 345; (b) Vervoort,
A.; De Bruyne, C. K. Carbohydr. Res. 1970, 12, 277.
Figure 1. Absorption spectra of glycosides (5, a; 6, b; 7, c) in solid line and aglycon
HA (10) in a dashed line. Insets: magnification of UV-B region of spectra.
17. Levene, P. A. J. Biol. Chem. 1924, 59, 141.
18. 7: colorless solid, mp 161.2–162.2 °C; 1H NMR (600 MHz, D2O, d): 7.72 (d,
J = 3.3 Hz, 1H, 40-H), 7.69 (s, 1H, 20-H), 7.51 (dd, J = 7.8, 8.2 Hz, 1H, 50-H), 7.43
(dd, J = 1.7, 8.2 Hz, 1H, 60-H), 5.67 (d, J = 1.7 Hz, 1H, 1-H), 4.20 (dd, J = 1.7,
3.7 Hz, 1H, 2-H), 4.06 (dd, J = 3.4, 9.2 Hz, 1H, 3-H), 3.82–3.68 (m, 4H, 4-H, 5-H,
and 6-H), 2.65 (s, 3H, CH3); 13C NMR (150 MHz, D2O, d): 203.3 (C@O), 155.5 (C),
137.9 (C), 130.1 (CH), 123.2 (CH), 122.5 (CH), 116.4 (CH), 98.1 (CH), 73.4 (CH),
70.3 (CH), 69.8 (CH), 66.5 (CH), 60.6 (CH2), 26.3 (CH3); HRMS-ESI (m/z):
[M+Na]+ Calcd for C14H18NaO7, 321.0945; found 321.0934.
Table 1
Molar extinction coefficients e300 at 300 nm and degree of antioxidant activity (AO)
for HA (10) and the glycosides 5–7
Compound
e300 (Mꢂ1 cmꢂ1
)
AO (%)
HA (10)
AP-b-Man (5)
AP-b-Glu (6)
1870
1946
1982
1976
0.0
71.5
51.7
66.9
19. Satoh, K.; Yajima, H.; Saito, T.; Uchida, K.; Otani, T.; Iwama, K.; Tsubogo, T.
(Tokyo University of Science, Japan). Jpn. Kokai Tokkyo Koho JP 2007230879 A
20070913, 2007.
AP-a-Man (7)