Synthetic studies in butenonyl C-glycosides: Preparation of polyfunctional alkanonyl glycosides and their enzyme inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2009.03.136

A simple synthesis of phenyl butenoyl C-glycosides has been achieved by Aldol condensation of peracetylated glycosyl acetones with aromatic aldehydes followed by deacetylation with methanolic NaOMe. The selected butenoyl C-glycosides on conjugate addition

Full text of DOI:10.1016/j.bmcl.2009.03.136

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2699–2703
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthetic studies in butenonyl C-glycosides: Preparation of polyfunctional
alkanonyl glycosides and their enzyme inhibitory activity
Surendra Singh Bisht a, Seerat Fatima a, Akhilesh K. Tamrakar b, Neha Rahuja b, Natasha Jaiswal b,
Arvind K. Srivastava b, Rama P. Tripathi a,
*
a Divisions of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Biochemistry, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of phenyl butenoyl C-glycosides has been achieved by Aldol condensation of peracet-
ylated glycosyl acetones with aromatic aldehydes followed by deacetylation with methanolic NaOMe.
The selected butenoyl C-glycosides on conjugate addition of diethyl malonate resulted in polyfunctional
alkanonyl glycosides in good yields. The butenoyl C- and alkanoyl C-glycosides were evaluated for their
Received 20 November 2008
Revised 5 March 2009
Accepted 26 March 2009
Available online 29 March 2009
a-glucosidase, glucose-6-phosphatse and glycogen phosphorylase enzyme inhibitory activities in vitro.
Three of the synthesized (3, 5 and 9) showed potent enzyme inhibitory activities as compared to standard
drugs. Compounds 3, 5 and 9 were evaluated in vivo too displaying significant activity as compared to
standard drugs acarbose and metformin.
Keywords:
Alkenoyl glycosides
Alkanonyl glycosides
Ó 2009 Elsevier Ltd. All rights reserved.
a-Glucosidase
Glucose-6-phosphatase
Glycogen phosphorylase
Michael reaction
Metformin
Acarbose
Carbohydrates constitute one of the most abundant biomole-
cule in nature and are widely expressed as glycolipids and glyco-
proteins.1 The carbohydrate moiety as epitope in several
glycoconjugates are known to play central role in displaying vari-
ous biological responses such as immune response, inflammation,
metastasis, bacterial and viral infections among others.2 The glyco-
sidic cleavage and liberation of monosachharides from oli-
gosachharides in the body are controlled by different enzymes.
Glycosidases, glucose-6-phosphatase and glycogen phosphorylases
are extremely important in homeostatic regulation of blood glu-
cose levels and therefore of prime importance in diabetes and
many other diseases.3
Inhibitors of glucose-6-phosphatase and glycogen phosphory-
lase have also great potential as drug candidate via lowering of
blood glucose levels by inhibition of glycogen phosphorylase pro-
vides an alternative method to treat diabetes.10
Several C-glycosides of synthetic and natural product origins
are known as glycosidase inhibitors (Fig. 1).11 Many O-alkyl glyco-
sides have recently been reported to be associated with different
biological activities.12
C-Glycosides are being used as building blocks for the synthesis
several natural products and also as potential enzyme inhibitors.13
The biological activity in C-glycosides is due to the fact that the
conformational differences between the O- (or N-) glycosides and
the C-linked analogue are minimal.14 Moreover, C-glycosides are
more stable than O- or N-glycosides since the natural anomeric
center has been transformed from a hydrolytically labile O or N
acetal link to an ether. As a result, stereoselective synthesis of
C-glycosides has been a challenging task for organic chemists.15
We have been involved in design and development of antitubercu-
lar agents from simple sugar derivatives.16–19 Current reports that
diabetic patients are prone to tuberculosis have led us to explore
molecules having both antidiabetic and antitubercular activity.20,21
In this context we have synthesized C- phenylbutenoyl glycosides
and carried out their Michael addition reaction with diethylmalo-
nate to get polyfunctional C-alkanoyl glycosides. The synthetic
Therefore, inhibitors or elevators of these enzymes have many
potential medical applications.2–7 While inhibitors of glycosidases
in general have therapeutic values as anticancer, antiviral and anti-
bacterial, the inhibitors of intestinal
a-glycosidases in particular
have been used to treat diabetes through the lowering of blood glu-
cose levels. Several
a-glycosidase inhibitors are in the clinics for
the treatment of Type 2 diabetes8 and many other drugs in the
market.9
* Corresponding author. Tel.: +91 522 2612412; fax: +91 522 2623405.
E-mail address: rpt.cdri@gmail.com (R.P. Tripathi).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.136

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S. S. Bisht et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2699–2703
OH
OH
OH
HO
O
NH2
Ph
HO
HO
O
O
HO
HO
OH
NR2
HO
OH
Ph
OH
Figure 1. Glycosidase inhibitors.
method is ecofriendly and economical as readily available reagents
and chemicals are used and all the reactions are performed at
ambient temperature. The compounds were evaluated for a-gluco-
anomeric proton (H-10) appeared as a multiplet at around d 3.18–
3.15. The other four protons H-20, H-30, H-40 of the sugar ring and
one of the aglycon methylene protons (H-1a) appeared as multiplet
sidase, glucose-6-phosphatase and glycogen phosphorylase inhibi-
tory activity in vitro and antidiabetic activity of active compounds
was confirmed using in vivo animal models. The presence of other
potential functional groups in the molecule has potential for fur-
ther explorations in different disease areas.
at around d 3.11–2.93. The other aglycon methylene proton (H-1b)
appeared as dd at d 2.70 with J1b,1 = 8.6 Hz and J1a,1b = 16.2 Hz. 13
C
0
NMR spectrum of compound 2, a signal at d 198.9 accounted the car-
bonyl carbon while the signals for aromatic carbons were observed
at d 135.7, d 134.3. The two olefinic carbons appeared at d 141.4
and d 128.3. All the sugar ring carbons appeared at d 81.6, d 79.9, d
76.6, d 74.4 and 71.1 while the aglycon methylene carbon appeared
at d 44.3. Almost similar patterns were observed 1H NMR and 13C
NMR spectra of other compounds as well.
(E)-1-(20,30,40,60-Tetra-O-acetyl-b-
D-glucopyranosyl)-4-(aryl)-
but-3-en-2-ones (1a–i) were prepared by the aldol condensation of
respective aromatic aldehydes (substituted/unsubstituted) with 1-
(20,30,40,60-tetra-O-acetyl-b-
D
-glucopyranosyl)propan-2-one follow-
ing the earlier protocol.22–24 Deacetylation of all the acetyl group in
Michael reaction of the above (E)-1-(b-D
-glucopyranosyl)-4-(40-
the molecules resulted in respective (E)-1-(b-
D
-glucopyranosyl)-4-
chlorophenyl)but-3-en-2-one (2) with diethyl malonate in presence
of catalytic amount of sodium ethoxide/ethanol resulted in 6-(b-
(aryl)but-3-en-2-ones (2–10) in good yields.25 The structures of all
these compounds were accordance with their spectroscopic data.
The IR spectra of compounds 2–10 exhibited absorption bands at
around 3400 cmꢀ1 and 1650 cmꢀ1 indicating the presence of hydro-
D
-glucopyranosyl)-2-carbethoxy-3-((R,S)-400-chlorophenyl)-5-oxo-
ethylhexanoate (11) as diastereoisomeric mixtures in good yields
(Scheme 1).26 The diastereoisomeric mixtures were inseparable by
column chromatography. The structure of the above glycoside 11
was established on the basis of its spectroscopic data. The ESMS of
compound 11 displayed 519.5 (M+18)+ peak corresponding to its
molecular weight. In the 1H NMR spectrum of compound 11, the sig-
nals corresponding to olefinic protons at d 7.58 and d 6.96 (in com-
pound 2) were not observed while one methine proton (H-2) of the
aglycone moiety was observed as multiplet merged with carbethoxy
(OCH2) protons as at around d 4.00–3.93. The other methine proton
H-3 appeared as multiplet at around d 3.68–3.52 and two methylene
protons (H-4) were observed along with two glycone methine pro-
tons as multiplet at around d 3.18–2.94. In the 13C NMR spectrum
of 11, two carbonyl carbons of carbethoxy appeared at d 168.8, and
d 168.2, while the ketonic carbon was observed at d 208.5 and C-2,
xyl groups of the sugar and a, b-unsaturated ketone group, respec-
tively. ESMS of all the compounds displayed M+H+ peaks
corresponding to their molecular weight. In the 1H NMR spectrum
of compound 2, olefinic protons appeared as two distinct doublets
at d 7.58 and d 6.96 (J = 16.2 Hz), indicating a trans geometry of dou-
ble bond. The aromatic protons of the phenyl ring were observed as
doublets each integrating two protons at d 7.75 and d 7.48 with J va-
lue 8.3 Hz. The exchangeable protons pertaining to the hydroxyl
groups appeared as two doublets, one singlet and one triplet at d
5.07 (J = 5.5 Hz), d 4.90 (J = 4.2 Hz), d 4.88, and d 4.36 (J = 5.3 Hz),
respectively. The splitting of hydroxyl protons is due to adjacent
CH or CH2 protons. H-50 and H-6a0 of sugar moiety appeared as mul-
tiplet at around d 3.65–3.57 and one proton H-6b0 at d 3.37 while the
OAc
OH
Ar
Ar
Ref. 22, 23, 24
O
O
NaOMe
HO
HO
AcO
D-Glucose
AcO
OAc
MeOH,rt,
2-3h
OH
O
O
(1a-1i)
(2-10)
2- Ar = 4-chlorophenyl, 74 %
3- Ar = 2-naphthyl, 60 %
4- Ar = 4-methoxyphenyl, 65 %
5- Ar = phenyl, 62 %
O
OEt
1
OH
6'
OEt
Ar
3
4'
HO
HO
6- Ar = 3-pyridyl, 77 %
Diethyl malonate
2
5'
2'
O
6
7- Ar = 4-hydroxyphenyl, 70 %
O
5
NaOEt/ EtOH,
rt, 15 min
4
8
9
- Ar = 3-nitrophenyl, 73 %
OH
- Ar = 3,4-dimethoxyphenyl, 71 %
3'
1'
O
10
- Ar = 3,4,5-Trimethoxyphenyl, 85 %
R:S isomers 1:1
(11-15)
11
14
12
13
- Ar = 4-chlorophenyl, 65 %; - Ar = 2-naphthy, 62 % ; - Ar = phenyl, 63 %
15
- Ar = 3-pyridyl 66 % ; - Ar = 3,4-dimethoxyphenyl, 72 %
Scheme 1. Synthesis of (E)-1-(b-D-glucopyranosyl)-4-(aryl)but-3-en-2-ones and 6-(b-D-glucopyranosyl)-2-carbethoxy-3-((R,S)aryl)-5-oxo-ethylhexanoate (2–15).

S. S. Bisht et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2699–2703
2701
C-3 appeared at d 57.4, d 39.7, respectively. The signals correspond-
ing tothe three methylenecarbons (C-4, C-6 and C-60) were observed
at d 62.3, d 61.8 and d 61.4.
Similar Michael addition of diethyl malonate with the deacety-
lated alkenoyl glycosides (3, 5, 6, 9) led to the formation of respective
en-2-one (19) in good yields (Scheme 3). The compounds synthe-
sized were evaluated against the -glucosidase purified from rat
intestine and Glucose-6-phosphatase and glycogen phosphorylase
purified rat liver following earlier protocols.27–30 Table 1 shows the
percent inhibitory activity of screened compounds against different
enzymes. As evident from the table 1 the above compounds inhib-
a
6-(b-D-glucopyranosyl)-2-carbethoxy-3-((R,S)aryl)-5-oxo-ethyl-
hexanoate (12, 13, 14, 15), respectively as diastereoisomeric mix-
tures in moderate to good yields. The compounds were isolated by
column chromatography and characterized on the basis of their
spectroscopic data. The 1H NMR and 13C NMR spectral data, the
chemicalshiftsand splittingpatternof differentprotonsandcarbons
of these compounds were similar to those described for the above
compound 11.
ited or elevated
phosphorylase enzymes to a different extent at 100
tion. The -glucosidase inhibitory activity ranges from 2.3% to
70.7% at the experimental concentration of the compounds. A clo-
sure look into inhibitory activity reveals that among all the com-
pounds only compound 9 with 3,4-dimethoxyphenyl substituent
a
-glucosidase, glucose-6-phosphatase and glycogen
lM concentra-
a
exhibits good
a-glucosidase inhibitory activity at 100 lM (IC50,
In order to see the effect of other sugars on the
inhibitory activity, (E)-1-(20,30,40-tri-O-acetyl-b-
-xylopyranosyl)-
4-(400-chlorophenyl)but-3-en-2-one and (E)-1-(20,30,40-tri-O-acet-
yl-b- -xylopyranosyl)-4-(3,4-dimethoxyphenyl)but-3-en-2-one
were deacetylated with NaOMe/MeOH to give the respective glyco-
sides (E)-1–(b- -xylopyranosyl)-4-(4-chlorophenyl)but-3-en-2-one
(16) and (E)-1-(b- -xylopyranosyl)-4-(3,4-dimethoxyphenyl)but-3-
en-2-one (17) (Scheme 2) in moderate yields. The compounds were
isolated by column chromatography and characterized on the basis
of their spectroscopic data.
a
-glucosidase
51.5 M) as compared to standard drug acarbose. Among all the
compounds only two compounds 2 and 5 inhibited glucose 6-phos-
phatase enzyme significantly to the extent of 25.3% and 49.7%
(IC50 = 87.0 lM), respectively, while the standard drug sodium orh-
to-vandate inhibited to the extent of 39% only. Out of the above gly-
cosides synthesized compounds 2, 3, 4, 6, 13, 15, 17 and 18 showed
significant inhibitionof glycogen Compound3 with naphthylmoiety
in alkenonyl glycoside proved to be potent inhibitor of glycogen
l
D
D
D
D
phosphorylase with an IC50 value 98.0 lM. The above three most po-
tent compounds 3, 5 and 9, showing activity against three different
enzymes were further evaluated in vivo in validated animal models,
that is, Sucrose loaded rat model (SLM) and streptozotocin induced
diabetic rat model.31 Results are summarized in Table 2; Table 3.
Figure 2 shows the blood glucose profile of sucrose loaded rats
treated with test compounds. It is evident from the results that
compound 3 and 9 show significant improvement in glucose toler-
ance. The average activity profile of compounds 3, 5, 9 and the
standard drug metformin is shown in Table 2. The effect exerted
by compound 3 and 9 (25.0%, p < 0.05 and 26.7%, p < 0.05, respec-
tively) is comparable with the standard drug metformin (31.2%,
During biological evaluation the Michael adducts were not ac-
tive as compared to their olefinic counterparts, therefore we did
not carry out Michael reaction of diethyl malonate with the above
alkenoyl glycosides.
Finally, deacetylation of
a
disaccharide derived (E)-1-(20,30,
60,200,300,400,600-hepta-O-acetyl-b-cellobiosyl)-4-(2-napthyl)but-3-en-
2-one and (E)-1-(20,30,60,200,300,400,600-hepta-O-acetyl-b-cellobiosyl)-
4-phenylbut-3-en-2-one (under the above experimental condition
led to the formation respective (E)-1-(b-cellobiosyl)-4-(2-nap-
thyl)but-3-en-2-one (18) and (E)-1-(b-cellobiosyl)-4-phenylbut-3-
Ar
Ar
O
O
Ref. 22, 23, 24
NaOMe
AcO
AcO
HO
HO
D-Xylose
OAc
OH
MeOH, rt,
2-3 h
O
O
(1j,1k)
16- Ar = 4-chlorophenyl, 85 %
17- Ar = 3,4-dimethoxyphenyl, 82 %
Scheme 2. Synthesis of (E)-1-(b-
D-xylopyranosyl)-4-(aryl)but-3-en-2-one (16, 17).
OAc
OAc
Ar
O
Ref . 22, 23, 24
O
AcO
AcO
O
D-Cellobiose
AcO
OAc
OAc
O
(1l-1m)
OH
OH
Ar
O
NaOMe
O
HO
HO
(1l-1m)
O
HO
MeOH, rt,
2-3 h
OH
OH
O
18- Ar = 2-napthyl, 74 %; 19- Ar = phenyl, 65 %
Scheme 3. Synthesis of (E)-1-(b-D-cellobiosyl)-4-(aryl)but-3-en-2-one (18, 19).

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S. S. Bisht et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2699–2703
Table 1
a
-Glucosidase, glucose-6-phosphatase, and glycogen phosphorylase inhibitory activity of compounds (2–19)
Compounds
% Activity (100 lM)
a-Glucosidase inhibition
Glucose-6-phosphatase inhibition
Glycogen phosphorylas inhibition
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
ꢀ5.97
ꢀ16.9
ꢀ32.3
ꢀ10.4
ꢀ35.4
ꢀ30.7
ꢀ10.0
ꢀ70.7
ꢀ25.0
ꢀ10.0
ꢀ20.0
ꢀ45.0
ꢀ20.0
ꢀ2.3
ꢀ25.3
ꢀ7.7
ꢀ9.7
ꢀ49.7
ꢀ8.1
+4.2
+8.0
+15.0
+4.7
ꢀ36.2
ꢀ52.4
ꢀ37.2
+7.3
ꢀ28.9
ꢀ3.4
+15.6
ꢀ5.9
ꢀ19.6
ꢀ5.4
ꢀ6.0
+4.6
ꢀ14.7
ꢀ25.9
ꢀ11.7
ꢀ24.0
ꢀ19.6
ꢀ21.5
ꢀ8.3
ꢀ3.3
+37.6
ꢀ36.2
+4.7
ꢀ19.9
ꢀ3.9
ꢀ16.3
—
ꢀ8.3
ꢀ16.6
NIL
ꢀ24.6
ꢀ39.0
—
18
19
ꢀ30.8
Acarbose
Sodium-ortho-vandate
—
ꢀ39.0
—
Table 2
p < 0.05) whereas the compound 5 shows mild effect (19.5%) at the
same dose level of 100 mg/kg.
Antihyperglycaemic effect of in vitro of selected compounds and the standard drug-
metformin in sucrose loaded hyperglycaemic rats
Table 3 and Figure 3 represent the average antihyperglycaemic
activity profile of compound 3, 5, 9 and standard drug metformin
in the streptozotocin-induced diabetic rats post sucrose-load. It is
evident from the results that compounds 3 and 9 caused a signifi-
cant decline of 14.2% (p < 0.05) and 14.1% (p < 0.05) in the hyper-
glycaemia of the diabetic rats post sucrose-load after 5 hour
interval, respectively. The standard drug metformin at the same
dose level of 100 mg/kg showed a blood glucose lowering effect
of 26.9% (p < 0.01) after 5 h interval. Compound 5 has no effect
on blood glucose level of treated animals.
Compounds
Dose (mg/kg)
% Activity
9
3
5
100
100
100
100
26.7*
25.0*
19.5
Metformin
31.2*
*
p < 0.05.
Table 3
In conclusion, we have developed a method for the syntheses
of polyfunctionalised alkenyl and alkanonyl glycosides and eval-
uated their enzyme inhibitory activities against three enzymes
Antihyperglycaemic activity of in vitro compounds and standard drug Metformin in
sucrose-challenged STZ-induced diabetic rats
Compound
Dose (mg/kg)
% Antihyperglycaemic activity
24 h
a
-glucosidase, glucose-6-phosphatase and glycogen phosphory-
lase. Three compounds 3, 5 and 9 showed potent inhibition
against glycogen phosphorylase, glucose-6-phosphatase and
5 h
a-
3
5
9
100
100
100
100
14.2*
2.91
10.3
12.1
13.4
21.4*
glucosidase, respectively. The compounds 3 and 9 caused a sig-
nificant decline in the hyperglycaemia of the diabetic rats post
sucrose-load. The other compounds of the series hold potential
to be transformed into other molecules of great chemotherapeu-
tic importance.
14.1*
26.9**
Metformin
*
p < 0.05.
p < 0.01.
**
Control
700
200
150
100
50
Control
Compound 9
Compound 3
Compound 9
Compound 3
Compound 5
600
500
400
300
200
100
0
Compound 5
Metformin
0
-60
0
60 120 180 240 300 24h
Time (min)
0
30
60
90
120
Time (min)
Figure 2. Effect of in vitro active compounds and metformin on blood glucose level
of sucrose loaded rats at various time intervals. Values are mean S.E. of five rats in
each group.
Figure 3. Effect of in vitro active compounds and metformin on blood glucose level
of streptozotocin induced diabetic rats at various time intervals. Values are
mean S.E. of five rats in each group.

S. S. Bisht et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2699–2703
2703
20. Dixon, B. Lancet 2004, 7, 444.
21. Jeon, C. Y.; Murray, M. B. PLoS Medicine 2008, 7, 1092.
22. Rodrigues, F.; Canac, Y.; Lubineau, A. Chem. Commun. 2000, 2049.
Acknowledgments
This is CDRI communication No.7616. The authors thank CSIR
and UGC New Delhi for award of SRF and JRF to Surendra and Seer-
at, respectively. We sincerely acknowledge the financial assistance
from DRDO New Delhi.
23. Riemann, I.; Papadopoulos, M. A.; Knorst, M.; Fessner, W. D. Aust. J. Chem. 2002,
55, 147.
24. Bisht, S. S.; Pandey, J.; Sharma, A.; Tripathi, R. P. Carbohydr. Res. 2008, 343, 1399.
25. Typical procedure for the synthesis of (E)-1- (b-
chlorophenyl) but-3-en-2-one (2): To a stirring solution of (E)-1- (20,30,40,60-
tetra-O-acetyl-b- -glucopyranosyl) -4-(4-chlorophenyl)but-3-en-2-one (2.0 g,
D
-Glucopyranosyl)-4-(40-
D
3.89 mmol) (1a) in methanol at 25 °C, a solution of sodium methoxide (10 mL,
1.94 mmol) was added. The reaction mixture was stirred till the disappearance
of the starting material (TLC). Amberlite IR 120 (H+) resin was added to the
reaction mixture and stirred for further 10 min. The reaction mixture was
filtered and the filtrate was concentrated in vacuum to afford the deacetylated
product 2 as a colorless solid (1.0 g, yield 74%); mp 178–179 °C; Rf 0.5 (1:10,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.136.
MeOH:CHCl3); ½a D25
ꢂ
ꢀ9.59 (c 0.05, MeOH); ESMS m/z = 343 (M+H)+, IR (KBr)
mmax cmꢀ1: 3399 (OH stretching), 1630 (C@O); 1H NMR (300 MHz, DMSO) d
7.75 (d, J = 8.3 Hz, 2H, ArH), 7.58 (d, J = 16.2 Hz, 1H, H-4), 7.48 (d, J = 8.3 Hz, 2H,
ArH), 6.96 (d, J = 16.2 Hz, 1H, H-3), 5.07 (d, J = 5.5 Hz, 1H, OH), 4.90 (d,
J = 4.2 Hz, 1H, OH), 4.88 (s, 1H, OH), 4.36 (t, J = 5.3 Hz, 1H, OH), 3.65–3.57 (m,
2H, H-5, H-6b0), 3.37 (m, 1H, H-60a), 3.18–3.15 (m, 1H, H-10), 3.06 (m, 4H, H-20,
H-30, H-40, H-1a), 2.70 (dd, J10 b;1 = 8.6 Hz, J1a,1b = 16.2 Hz, H-1b, 1H). 13C NMR
(50 MHz, DMSO) d 198.9 (C@O), 135.7, 134.3 (Ar-C), 141.48 (C-4), 128.3 (C-3),
131.0, 129.8 (ArCH), 81.6, 79.9, 76.6, 74.4, 71.1 (CH), 62.0 (C-60), 44.3 (C-1).
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26. Typical procedure for syntheses of 6-(b-
((R,S)400-phenyl)-5-oxo-ethylhexanoate (11): To a stirred solution of ((E)-1-(b-
-glucopyranosyl)-4-(40-chlorophenyl)but-3-en-2-one (2), (0.5 g, 1.46 mmol)
D-glucopyranosyl)-2-carbethoxy-3-
D
and diethyl malonate (0.22 mL, 1.46 mmol) in ethanol, a solution of sodium
ethoxide (3 mL, 0.48 mmol) was added at ambient temperature and stirring
was continued till the disappearance of the starting material on the TLC plates.
The reaction was neutralized by the addition of Amberlite IR 120 (H+) resin.
Stirred the reaction mixture further for 10 min., filtered the resin and the
filtrate was concentrated under vacuum. The product 11 was purified by
column chromatography using methanol/chloroform (2:10), elute as
a
colorless liquid (0.48 g, yield 65%); Rf 0.4 (1:10, MeOH:CHCl3); ½a D25
ꢀ6.96 (c
ꢂ
0.05, MeOH); ES–MS m/z = 519.5 (M+18)+, IR (neat) mmax cmꢀ1: 3389 (OH
stretching), 1726 (C@O); 1H NMR (300 MHz, CDCl3) d 7.25–7.19 (m, 4H, ArH),
5.30–4.50 (m, OH ꢃ 4), 4.21–4.12 (m, 2H, OCH2), 4.00–3.93 (m, 3H, H-60 and H-
2), 3.68–3.52 (m, 4H, CH, H-3 and OCH2), 3.41 (s, 2H, CH ꢃ 2), 3.18–2.94 (m,
4H, CH2, CH ꢃ 2), 2.78–2.70 (m, 1H, 6Ha), 2.56–2.49 (m, 1H, 6Hb), 1.26–1.21
(m, 3H, OCH2CH3), 1.05 (t, J = 7.11 Hz, 3H, OCH2CH3). 13C NMR (50 MHz, CDCl3)
d 208.5, 168.8, 168.2, 139.7, 133.1, 130.3, 128.9, 69.8, 75.5, 76.1, 77.4, 79.8,
57.4, 39.7, 14.3, 14.1.
´
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an overnight starvation. Animals showing blood glucose level between 60 and
80 mg/dl at 0 min were finally selected and divided into groups of five animals
in each. Rats of experimental group were administered the suspension of the
test sample orally prepared in 1.0% gum acacia (vehicle) at desired dose levels,
that is, 250 mg/kg body weight in case of plant extracts and 100 mg/kg in case
of standard antidiabetic drug, that is, metformin. Animals of control group
were given an equal amount of 1.0% gum acacia and termed as sham control.
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exactly after 30 min post administration of the test sample/ vehicle. Blood
glucose profile of each rat was again determined at 30, 60, 90 and 120 min post
administration of sucrose by glucostrips. Food but not water was withheld
from the cages during the course of experimentation.(b) Effects in
Streptozotocin induced diabetic rat model: Male albino rats of Sprague Dawley
strain were selected and made diabetic by intraperitoneal administration of
streptozotocin at a dose level of 45 mg/kg body weight (prepared in 100 mM
citrate buffer, pH 4.5) to overnight fasted rats. Blood glucose profile was again
checked after 48 h and animals showing blood glucose values between 180 and
270 mg/kg at ꢀ20 and 0 min (baseline) were included in the experiments and
termed diabetic. The diabetic animals were divided into groups were
administered suspension of the desired test sample prepared in 1% gum
acacia at desired dose levels (250 mg/kg) in case of plant extracts and 100 mg/
kg in case of metformin). Animals of control group were given an equal amount
of 1% gum acacia and termed as sham control. A sucrose load of 2.5 g/kg was
given to each animal orally exactly after 30 min post administration of the test
sample/vehicle. Blood glucose profile of animals of all groups was again
checked at 30, 60, 90, 120, 180, 240 and 300 min post administration of
sucrose. Food but not water withheld from the cages during the course of
experimentation.
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