Synthesis and antiglycation potentials of bergenin derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.04.131

Bergenin (1), major bioactive compound isolated from methanolic extract of Mallotus philippinensis, displayed moderate AGE inhibition activity (IC ₅₀ = 186.73 μM). A series of derivatives of bergenin (3a-k) containing variety of aromatic acids

Full text of DOI:10.1016/j.bmcl.2011.04.131

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4928–4931
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiglycation potentials of bergenin derivatives
T. Vijaya Kumar a, Ashok K. Tiwari b, , A. Robinson a, K. Suresh Babu a, R. Sateesh Chandra Kumar a,
⇑
D. Anand Kumar b, A. Zehra b, J. Madhusudna Rao a,
⇑
a Natural Products Laboratory, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500607, India
b Pharmacology Division, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bergenin (1), major bioactive compound isolated from methanolic extract of Mallotus philippinensis, dis-
Received 14 March 2011
Revised 26 April 2011
Accepted 28 April 2011
Available online 5 May 2011
played moderate AGE inhibition activity (IC50 = 186.73 lM). A series of derivatives of bergenin (3a–k)
containing variety of aromatic acids were synthesized under mild conditions by modification of sugar
part. Selective esterification of hydroxyl groups on the sugar part enhanced antiglycation potential of
bergenin. Compounds 3j and 3k exhibited potent antiglycation activity with the IC50 values of 60.75
and 12.28 lM, respectively.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Bergenin
Antiglycation potentials
Esters derivatives
ABTSꢀ+ scavenging activity
Nonenzymatic protein or lipid glycation by reducing sugars
such as glucose or ribose is a complicated cascade of condensa-
tions, rearrangements, fragmentations, and oxidative modifica-
tions that lead to a plethora of compounds collectively called
advanced glycation end products (AGEs).1 This process is initiated
by the formation of Schiff bases between the sugar carbonyls and
the free amino groups of the proteins (Maillard Reaction), which
is followed by isomerization (Amadori Rearrangement), generating
a relatively stable aminoketose derivative. These derivatives un-
dergo further degradation giving rise to highly reactive dicarbon-
yls, such as glucosone, 3-deoxyglucosone, and glyoxal, all capable
of acting as protein cross linking agents and forming additional
Schiff bases. The ultimate effect of glycation is generation of high
molecular weight protein aggregates and other fluorescent entities,
referred to as AGEs. Some AGEs such as carboxymethyllysine (CML)
and pentosidine have become highly useful biomarkers of glycox-
idative damages.2 Accumulation of the reaction products of protein
glycation in living organisms leads to structural and functional
modifications of tissue proteins. Several studies have shown that
AGEs play significant role in acceleration of normal aging process
and age-related diseases, such as diabetes, atherosclerosis, end-
stage renal disease, and neurodegenerative disorders.3 It has been
hypothesized that AGEs play a causal role in the development of a
variety of diabetic complications. AGEs accumulate in plasma and
tissue proteins of patients with diabetes. Their accumulation corre-
lates with the severity of diabetic complications. With the rapid
development of therapy for diabetes, the mortality rate associated
with acute complications has decreased but that associated with
chronic complications of diabetes has increased. Inhibition of pro-
tein glycation is, therefore, one possible route of minimizing the
pathogenesis of secondary complications of diabetes.
Natural products and their active constituents have been re-
portedly used for the treatment of diabetes and diabetic complica-
tions.4 There are reports that some natural antioxidant compounds
like resveratrol (3,4,5-trihydroxystilbene) and curcumin, isolated
from plants possess AGE-inhibitory effects.5 Hence, natural antiox-
idants may be expected to be promising therapeutic modalities for
treatment of these diseases by scavenging free radicals being gen-
erated during oxidative stress. It has been proposed that strategies
involving antioxidants as AGE inhibitors may have future thera-
peutic potential.5
Mallotus philippinensis Muell-Arg (Family Euphorbiaceae) also
known as Kampillaka or Kamala in Ayurveda, has traditionally
been used in Ayurvedic preparations meant for removal of worms,
wound healing and also in diabetes.6 Kamala dye has been re-
ported some seventy years back to possess anthelmintic activity.7
Bergenin (1) is a C-glycoside of 4-O-methylgallic acids that has
been reported to occur naturally in M. philippinensis and also in
several other genera.8 It exhibits a wide array of biological activi-
ties like antioxidant,8,9 anti-HIV,10 antiarrhythmic,11 hepatoprotec-
tive,12 anti-inflammatory13 and anti-microbial.14 Mallotoxin
(rottlerin) isolated from M. philippinensis has been observed to
inhibit protein kinase C15 and prevent TNF
a-dependent NFkb
⇑
Corresponding authors. Tel.: +91 40 27193166; fax: +91 40 27160512 (J.M.R.).
activation in cancer cell lines MCF-7 and HT-29 transfected with
E-mail addresses:
tiwari@iict.res.in (A.KK. Tiwari),
janaswamy@iict.res.in
NFkb-driven plasmid pBIIx-LUC.16
(J. Madhusudna Rao).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.131

T. Vijaya Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4928–4931
4929
O
R
O
OH
OH
OH
OH
OH
O
O
OH
O
Acid, TPP, DEAD
THF, rt., 12 h.
MeO
HO
MeO
HO
OH
O
O
O
(3a-3h)
1
3a. R = Phenyl
3b. R = p-nitro Phenyl
3c. R = 4-methoxy-6-nitro phenyl
3d. R = 3,4-di methyl-6-nitro
3e. R = 3,4,5-trimethoxy phenyl
3f
. R = Styryl
3g
3h
. R = Furyl
. R = Pyridinyl
Scheme 1. Synthesis of bergenin esters 3a–h using Mitsunobu esterification protocol in dry THF.
R
O
O
O
OH
OH
OH
OH
OH
OH
OH
OH
O
O
OH
O
OBn
O
O
MeO
HO
MeO
HO
MeO
BnO
b) - c)
a)
OH
O
O
O
1
3i - 3k
2
3i. R =
Vanillyl
3j. R = 2,3-dihydroxy phenyl
3k.R = 3,4,5-trihydroxy phenyl
Scheme 2. Bergenin esters 3i–k; Reagents and conditions: (a) K2CO3, BnBr, DMF/acetone; (b) acid chloride, Py, DMAP (c) H2/Pd/C, MeOH/CH2Cl2.
Table 1
Activity profile of compounds synthesized from bergenin on ABTSꢀ+ free radical scavenging and various stages of Advanced Glycation End-product (AGEs) formation
Compound
ABTSꢀ+ radical scavenging
(IC50 M)
Inhibition of S-B23
(IC50 M)
Inhibition of FA24
(IC50 M)
Inhibition of DCs24,25
Inhibition of AGEs20,21
(IC50 M)
,
l
,
l
,
l
(IC50
,
lM)
l
MeOH extract
1
3a
3b
3c
3d
0.9
2
3.5
3.6
4.4
4
l
g/ml
112.03 1.14 (2.9
l
g/ml)
)
21.42 3.36
20.63 2.25 (163.6)
49.2 2.25
21.43 1.12
17.46 2.25
NA
ND
110.47 7.41 (11.21 lg/ml)
75.69 2.64 (186.73)
NA
NA
109.4 0.4 (5.4 ꢁ 10ꢂ4
102.66 0.43
ND
ND
ND
ND
ND
ND
89.83 0.0
NA
ND
43.90 12.69
3e
3f
3.2
3
ND
ND
42.06 5.61
NA
ND
ND
NA
NA
3g
3h
3i
3j
3.6
3.8
4.2
1.7
1.5
—
94.65 0.0
94.38 1.13
ND
97.86 1.51 (75.97)
95.96 1.13 (9.06)
—
32.54 3.37
NA
36.5 6.73
26.19 3.37(321.9)
22.22 2.24(183.71)
—
ND
97.90 1.72
ND
97.77 0.31(8.95)
102.22 0.57(8.8 ꢁ 10ꢂ8
—
NA
NA
NA
93.27 4.23 (60.75)
83.62 9.23 (12.28)
79.67 (88.87)
3k
)
Aminoguanidine
Values represents % inhibitory activity of extract at 100
lg/ml and for the compounds synthesized from bergenin at 200
lM. Values in the parentheses are lM values required
to impart 50% inhibitory activity (IC50). S-B; Schiff-base formation, FA; Fructosamines formation, DCs; Dicarbonyl compounds formation, AGEs; Advanced Glycation End-
products. ND; not detected, NA; not active. Aminoguanidine was taken as positive control and standard AGE inhibitor.
As bergenin has quite pronounced antioxidant activity8, we ob-
served that it also possess the potential of inhibiting protein glyca-
tion and acts as AGE inhibitor. In the present study, therefore,
eleven bergenin derivatives were prepared from the naturally
occurring bergenin and studied for their inhibition activity on var-
ious stages of AGEs formation. This is the first report on AGE inhib-
itory activity exhibited by bergenin and its synthetic analogues and
may open new avenues for the development of therapeutics tar-
geted against protein glycation in hyperglycemic condition.
Bergenin (1) was readily obtained in 11% yield from MeOH ex-
tract of the stem bark of M. philippinensis.17 The synthesis of ester
analogues 3a–h of bergenin at C-11 position were accomplished by

4930
T. Vijaya Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4928–4931
coupling various aromatic acids with bergenin (Scheme 1)18 by
employing Mitsunobu protocol in dry THF.19 For the synthesis of
analogues 3i–k, bergenin was converted to dibenzyl bergenin with
benzyl bromide under basic conditions to give two. Dibenzyl
bergenin was coupled with appropriate acid chloride (1.5 equiv)
and DMAP (0.2 equiv) in pyridine followed by hydrogenation with
Pd/C (Scheme 2) to give desired ester derivative (3i–k).20 The
structures of the resulting esters were confirmed by 1H NMR and
mass analysis.21 It is important to mention that in all cases esteri-
fication occurred solely at primary hydroxyl group even at the
large excess of the reagent and under more severe conditions.
Biological significance of bergenin derivatives (3a–k) was estab-
lished by screening for their activity potentials for free radical
ABTSꢀ+ scavenging22 and on various steps of protein-glycation pro-
cesses.23–25 Table 1 represents the IC50 values of the compounds.
All the compounds including extract displayed potent ABTSꢀ+ scav-
enging activity. AGE formation could be subdivided into three
stages. In the first stage Schiff-bases are formed followed by Ama-
dori rearrangement products and the third stage may be seen as
dicarbonyls formation, and cross linking with proteins leading to
the formation fluorescent AGEs formation. Inhibitors of these
stages, therefore, can delay the formation of AGEs. The methanol
extract of M. philippinensis in our study displayed potent inhibition
activity for AGEs formation; however, inhibitory potential in dicar-
bonyl compounds formation could not be detected. Compounds 1,
3j and 3k displayed potent inhibitory activities at all the three
stages. Esterification at primary hydroxyl group reduced the activ-
ity of bergenin. In a study on rutin and its metabolites, it was found
that compounds containing vicinyl dihydroxyl groups’ inhibited
AGE formation more effectively than the non-vicinyl hydroxyl
group-containing metabolites.26 Resveratrol (3,4,5-trihydroxystil-
bene), a natural phytoesterogen found in grapes has been shown
to inhibit AGE-induced proliferation and collagen synthesis activity
in vascular smooth muscle.27 Studies have revealed curcumin, a
diferuloylmethane isolated from Curcuma longa to be potent inhib-
itor of AGE formation and cross-linking of collagen in diabetic
rats.28 Similarly in our present study also, it was observed that
the compounds having vicinal hydroxyl groups 3j and 3k bearing
hydroxyl groups at 20,30 and 30,40,50 positions, respectively, showed
better activity than the other compounds. The mechanism of their
action may be inferred from the report that aromatic AGE inhibitor
compounds probably exert their inhibitory actions, either by che-
lating transition metals ions in the oxidative mechanisms of AGE
formation and/or interfering with the reactions of reactive dicar-
bonyl intermediates of AGE formation, or both.5 Compound 3k dis-
played seven times more potent inhibiting AGEs formation in our
study.
4. Marles, R. J.; Fransworth, N. R. Phytomed. 1995, 2, 137.
5. Rahbar, S.; Figarola, J. L. Arch. Biochem. Biophys. 2003, 419, 63.
6. Sharma, P. V. Classical Uses of Medicinal Plants, 1st ed.; Chaukhambha
Vishvabharati (Oriental Publisher and Distributors): Varanasi (India), 1996. p
81.
7. Rao, V. S.; Seshadri, T. R. Proc. Ind. Acad. Sci. -A 1947, 26, 178.
8. Arfan, M.; Amin, H.; Karamac, M.; Kosinska, A.; Wiczkowski, W.; Amarowicz, R.
Czech J. Food Sci. 2009, 27, 109.
9. Maduka, H. C. C.; Okoye, Z. S. C. Vasc. Pharmacol. 2002, 39, 21.
10. Piacente, S.; Pizza, C.; Detommasi, N. J. Nat. Prod. 1996, 59, 565.
11. Pu, H. L.; Huang, X.; Zhao, J. H.; Hong, A. Planta Med. 2002, 68, 372.
12. Kim, H. S.; Choi, H. S.; Oh, S.; Choi, J. J. Ethnopharmacol. 2000, 72, 469.
13. Swarnalakshmi, T.; Sethuraman, M. G.; Sulochana, N. Curr. Sci. 1984, 53, 917.
14. De Silva, S. L.; de Oliveira, V. G. Acta Amazonica 2009, 39, 177.
15. Gschwendt, M.; Muller, H.-J.; Kielbassa, K.; Zang, R.; Kittstein, W.; Rincke, G.;
Marks, F. Biochem. Biophys. Res. Commun. 1994, 199, 93.
16. Maioli, E.; Greci,L.; Soucek, K.; Hyzdalova, M.; pecorelli, A.; Fortino, V.;
Valacchi, G. J. Biomed Biotech. 2009, doi: 10.1155/2009/742936.
17. The dried powder of stem bark of Mallotus philippinensis (5 kg) was macerated
in methanol for three days at room temperature. The methanolic extract was
evaporated to dryness and the residue (200 g) was chromatographed on silica
gel (100–200 mesh) eluted successively with CHCl3, CHCl3/MeOH (9:1), CHCl3/
MeOH (4:1) to give four fractions. Fraction second was subjected to column
chromatography on silica gel and eluted with CHCl3/MeOH (12:1) to give
bergenin (18 g), which was identified on the basis of its NMR and mass spectral
data.
18. General procedure for the synthesis of 3a–h: To a stirred solution of 1 (300 mg
0.914 mmol), triphenyl phospine (359 mg 1.37 mmol 1.5 equiv) and benzoic
acid (167 mg, 1.37 mmol 1.5 equiv) in dry THF 10 ml was added
Diisopropylazodicarboxylate (0.3 ml 1.37 mmol 1.5equiv) drop wise to the
mixture at 0 °C, which was allowed to attain room temperature. After stirring
at room temperature for 24 h, the reaction was worked up by removal of the
solvent, and the residue was partitioned between EtOAc and saturated NaHCO3
(ca. 50 ml each). The organic phase was washed with brine, dried over Na2SO4
and evaporated. The residue was purified by chromatography on silica gel 100–
200, using CHCl3 to remove the Mitsunobu byproducts, and 24:1 (CHCl3/
MeOH) to recover desired product (3a–h, 25–30% yield).
19. Appendino, G.; Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C. Org. Lett. 2002,
4, 3839.
20. General procedure for the synthesis of 3i–k: To a solution of benzyl protected
bergenin and dimethylamino pyridine (DMAP) in pyridine, was added
corresponding acid chloride in dry DCM drop wise at 0 °C. The reaction was
continued to stir for 12 h at room temperature. After completion (monitored by
TLC), reaction mixture was diluted with water and extracted with EtOAc
(10 ml). The organic layer was washed successively with 2N HCl, 5% NaHCO3
solution then dried over Na2SO4. Evaporation of the solvent gave a crude
product, which was chromatographed on silica gel (CHCl3 / MeOH, 24:1) to
afford monoester (380 mg, 30%). Further, monoester (280 mg, 0.3 mmol.) was
debenzylated-using Pd-C/H2 in ethanol (5 ml) and CH2Cl2 (5 ml). The reaction
mixture was filtered, concentrated, and the residue was purified by column
chromatography (CHCl3/MeOH = 9:1) to afford pure compounds 3i–k.
21. Spectral data for the new compounds: Compound 3a: white solid, mp 240 °C;
½
a 2D5
ꢃ
= +31 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528, 1462, 1317,
1102 cmꢂ1 1H NMR (DMSO-d6, 400 MHz): d 3.40–3.47 (1H, m, H-3), 3.67–3.73
;
(1H, m, H-2), 3.76 (3H, s, H-12), 3.90–3.95 (1H, m, H-4), 4.05 (1H, t, J = 9.6,
10.1 Hz, H-4a), 4.35 (dd, J = 11.8, 6.6 Hz, H-11a), 4.77–4.82 (1H, m, H-11b), 5.05
(1H, d, J = 10.57, H-10b), 7.0 (1H, s, H-7), 7.54–7.59 (2H, m), 7.67–7.72 (1H, m)
and 8.02 (2H, d, J =7.2 Hz); ESI–MS: m/z 433 (M+H)+; Compound 3b: white
solid, mp 235 °C, ½a D25
ꢃ
= +28 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610,
1528, 1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.40–3.47 (1H,
m, H-3), 3.67–3.73 (1H, m, H-2), 3.76 (3H, s, H-12), 3.90–3.95 (1H, m, H-4), 4.05
(1H, t, J = 9.6, 10.1 Hz, H-4a), 4.35 (dd, J = 11.8, 6.6 Hz, H-11a), 4.77–4.82 (1H,
m, H-11b), 5.05 (1H, d, J = 10.57, H-10b), 7.0 (1H, s, H-7), 8.20–8.26 (2H, m) and
8.34–8.37 (2H, m); ESI–MS: m/z 478.04 (M+H)+; Compound 3c: white solid, mp
A series of bergenin derivatives were synthesized with the aim
to increase AGEs inhibition activity exhibited by bergenin. Com-
pounds 3j, 3k showed potent inhibitory activities at all the three
stages and also better AGEs inhibitory activity than that of
bergenin.
239 °C, ½a 2D5
ꢃ
= +11 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528, 1462,
1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.66–3.72 (1H, m, H-3), 3.76
(3H, s, H-12), 3.84–3.89 (1H, m, H-2), 3.91 (3H, s), 4.05 (1H, t, J = 9.6, 10.1 Hz,
H-4a), 4.35 (1H, dd, J = 6.3, 12,08 Hz, H-11a), 4.70–4.75 (1H, m, H-11b), 5.01
(1H, d, J = 10.38, H-10b), 7.0 (s, H-7), 7.35 (1H, dd, J = 2.45, 8.68), 7.58 (1H, d,
J = 2.45), 7.94 (1H, d, J = 8.68); ESI–MS: m/z 508.1(M+H)+. Compound 3d: white
solid mp 219 °C; ½a D25
ꢃ
= +4 (c 0.5, MeOH); IR (KBr)
;
mmax 3383, 1724, 1610, 1528,
Acknowledgments
1462, 1317, 1102 cmꢂ1
1H NMR (DMSO-d6, 400 MHz). d 3.27–3.32 (1H, m, H-
3), 3.66–3.71 (1H, m, H-2), 3.72 (3H, s, H-12), 3.87–3.90 (1H, m, H-4), 3.91 (3H,
s), 3.95 (3H, s), 4.05 (1H, t, J = 9.6, 10.1 Hz, H-4a), 4.32 (dd, J = 7.5, 11.8 Hz, H-
11a), 4.75–4.79 (1H, m, H-11b), 5.02 (1H, d, J = 10.57, H-10b), 7.0 (1H, s, H-7),
7.34 (1H, s) and 7.66 (1H, s); ESI–MS: m/z 538.1(M+H)+. Compound 3e: white
The authors thank Dr. J.S. Yadav, Director, IICT for his constant
encouragement. T.V.K. thanks CSIR for the financial support. This
work was supported by grant NWP-0004 (CSIR) New Delhi, India.
solid mp 257 °C; ½a D25
ꢃ
= +51 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610,
1528, 1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.27–3.32 (1H,
References and notes
m, H-3), 3.64–3.7 (1H, m, H-2), 3.73 (3H, s), 3.76 (3H, s, H-12), 3.88 (6H, s)
3.92–3.97 (1H, m, H-4), 4.06 (1H, t, J = 9.6, 10.0 Hz, H-4a), 4.35 (dd, J = 11.8,
6.6 Hz, H-11a), 4.91–4.96 (1H, m, H-11b), 5.01(1H, d, J = 10.5 Hz, H-10b), 7.0 (s,
H-7), 7.30 (2H, s). ESI–MS: m/z 545(M+Na)+. Compound 3f: white solid mp
1. Ardestani, A.; Yazanparast, R. Food Chem. Toxicol. 2007, 45, 2402.
2. Khalifah, R. G.; Baynes, J. W.; Hudson, B. G. Biochem. Biophys. Res. Commun.
1999, 257, 251.
3. (a) Brownlee, M. Nature 2001, 414, 813; (b) Schmidt, A. M.; Yan, S. D.; Yan, S. F.;
Stern, D. M. Biochem. Biophys. Acta 2000, 1498, 99; (c) Takeuchi, T.; Stustumi, O.
T.; Ikezuki, Y.; Takai, Y.; Taketani, Y. Endocrinol. J. 2004, 51, 165.
222 °C; ½a 2D5
ꢃ
= +53 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528, 1462,
1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.27–3.32 (1H, m, H-3),
3.66–3.73 (1H, m, H-2), 3.76 (3H, s, H-12), 3.82–3.88 (1H, m, H-4), 4.05 (1H, t,
J = 9.6, 10.0 Hz, H-4a), 4.27 (dd, J = 12.2, 6.7 Hz, H-11a), 4.61–4.67 (1H, m, H-

T. Vijaya Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4928–4931
4931
11b), 5.04 (1H, d, J = 10.38, H-10b), 6.68 (1H, d, J = 16.05), 7.0 (1H, s, H-7), 7.35–
7.49 (3H, m) and 7.69–7.76 (3H, m); ESI–MS: m/z 459.1 (M+H)+. Compound 3g:
1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.4–3.47 (1H, m, H-3),
3.68–3.72 (1H, m, H-2), 3.76 (3H, s, H-12), 3.89–3.94 (1H, m, H-4), 4.05 (1H, t,
J = 8.9, 10.7 Hz, H-4a), 4.35 (dd, J = 12.5, 7.1 Hz, H-11a), 4.79–4.83 (1H, m, H-
11b), 5.06 (1H, d, J = 10.7, H-10b), 6.77 (1H, t, J = 7.16, 8.9 Hz), 7.0 (1H, s, H-7),
7.05 (1H, d, J = 7.16) and 7.30 (1H, d, J = 8.9); ESI–MS m/z 487 (M+Na)+.
white solid mp 238 °C; ½a D25
ꢃ
= +27 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724,
1610, 1528, 1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.39–3.48
(1H, m, H-3), 3.65–3.73 (1H, m, H-2), 3.76 (3H, s, H-12), 3.82–3.89 (1H, m, H-4),
4.05 (1H, t, J = 9.6, 10.1 Hz, H-4a), 4.35 (dd, J = 11.8, 6.6 Hz, H-11a), 4.7–4.75
(1H, m, H-11b), 5.01(1H, d, J = 10.5, H-10b), 6.81(1H, s), 7.0 (1H, s, H-7), 7.85
(1H, s), 8.30 (1H, s); ESI–MS: m/z 423.01 (M+H)+ .Compound 3h: white solid
Compound 3k: white solid mp 269 °C; ½a D25
ꢃ
= +29 (c 0.5, MeOH); IR (KBr) mmax
;
3383, 1724, 1610, 1528, 1462, 1317, 1102 cmꢂ1
1H NMR (DMSO-d6, 400 MHz).
d 3.4–3.47 (1H, m, H-3), 3.67–3.71 (1H, m, H-2), 3.76 (3H, s, H-12), 3.83–3.88
(1H, m, H-4), 4.05 (1H, t, J = 9.82, 9.6 Hz H-4a), 4.35 (dd, J = 11.8, 5.2 Hz, H-11a),
4.62–4.67 (1H, m, H-11b), 5.01 (1H, d, J = 10.5, H-10b), 6.98 (2H, s) 7.0 (s, H-7).
mp 202 °C; ½a 2D5
ꢃ
= +26 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528,
1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.68–3.72 (1H, m, H-
3), 3.76–3.81 (1H, m, H-2), 3.76 (3H, s, H-12), 3.9–3.96 (1H, m, H-4), 4.05 (1H, t,
J = 9.6, H-4a), 4.35 (dd, J = 11.8, 6.6 Hz, H-11a), 4.7–4.75 (1H, m, H-11b), 5.06
(1H, d, J = 10.5, H-10b), 7.0 (1H, s, H-7), 7.61 (1H, dd, J = 4.7, 7.5 Hz), 8.3–8.36
(2H, m) and 8.85 (1H, s); ESI–MS: m/z 434.1(M+H)+. Compound 3i: white solid
ESI–MS: m/z 481.1(M+H)+
.
22. Walker, R. B.; Everette, J. D. J. Agric. Food. Chem. 2009, 57, 1156.
23. Matsuura, N.; Ardate, T.; Sasaki, C.; Kojima, H.; Ohara, M.; Hasegawa, J.;
Ubukata, M. J. Health Sci. 2002, 48, 520.
24. Ju-Wen, W.; Chiu-Lan, H.; Haiso-yan, W.; Hui-yin, C. Food Chem. 2009, 113, 78.
25. Sultana, N.; Choudhary, M. I.; Khan, A. J. Enzyme Inhib. Med. Chem. 2009, 24, 257.
26. Cerventes–Laurean, D.; Schramm, D. D.; Jacobson, E. L.; Halaweish, I.; Bruckner,
G. G.; Boissonneault, G. A. J. Nutr. Biochem. 2006, 17, 531.
27. Mizutani, K.; Ikeda, K.; Yamori, Y. Biochem. Biophys. Res. Commun. 2000, 274, 61.
28. Sajithlal, G. B.; Chithra, P.; Chandrakasan, G. Biochem. Pharmacol. 1998, 56,
1607.
mp 262 °C; ½a 2D5
ꢃ
= +58 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528,
1462, 1317, 1102 cmꢂ1
;
1H NMR (DMSO-d6, 400 MHz). d 3.38–3.42 (1H, m, H-
3), 3.66–3.72 (1H, m, H-2), 3.74 (3H, s, H-12), 3.86 (3H, s), 3.89–3.94 (1H, m, H-
4), 4.05 (1H, t, J = 9.8, 10.0, H-4a), 4.35 (dd, J = 11.8, 7.5 Hz, H-11a), 4.8–4.85
(1H, m, H-11b), 5.06 (1H, d, J = 10.5, H-10b), 7.0 (s, H-7), 6.89 (1H, d, J = 8.12),
and 7.48–7.54 (2H, m); ESI–MS: m/z 479.1 (M+H)+. Compound 3j: white solid
mp 264 °C; ½a 2D5
= +33 (c 0.5, MeOH); IR (KBr) mmax 3383, 1724, 1610, 1528,
ꢃ