Synthesis of novel mono and bis-indole conduritol derivatives and their α/β-glycosidase inhibitory effects

Article abstract of DOI:10.1016/j.bmcl.2012.10.038

Here we synthesized four novel indole conduritol derivatives 1-4 for the first time in the literature and probed their biological activities with the α and β-glucosidases. The compounds showed quite effective glucosidase inhibitory action. IC₅₀

Full text of DOI:10.1016/j.bmcl.2012.10.038

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7499–7503
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel mono and bis-indole conduritol derivatives and their
a/b-glycosidase inhibitory effects
Hüseyin Çavdar a, , Oktay Talaz b, Deniz Ekinci c
⇑
a Dumlupınar University, Education Faculty, 43100 Kutahya, Turkey
b Karamanog˘lu Mehmetbey University, Kamil Özdag˘ Science Faculty, Chemistry Department, 70100 Karaman, Turkey
c Ondokuz Mayıs University, Faculty of Agriculture, Department of Agricultural Biotechnology, 55139 Samsun, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we synthesized four novel indole conduritol derivatives 1–4 for the first time in the literature and
Received 31 August 2012
Revised 3 October 2012
Accepted 8 October 2012
Available online 23 October 2012
probed their biological activities with the
glucosidase inhibitory action. IC50 values of the compounds were compared with the known glucosidase
inhibitor acarbose and it was determined that newly synthesized indole conduritols had more powerful
a and b-glucosidases. The compounds showed quite effective
effect against b-glucosidase in addition to exhibiting moderate influence against a-glucosidase. Our mol-
ecules thus constitute an important starting point for the design and exploitation of novel glucosidase
inhibitors since glucosidase inhibitors have widespread applications in the treatment of diabetes, viral
infections, lysosomal storage diseases and cancers.
Keywords:
Conduritol
Indole
Glucosidase
Inhibitor
Ó 2012 Elsevier Ltd. All rights reserved.
The conduritol family compounds are cyclitol derivatives
possessing four contiguous hydroxyl groups on cyclohexene ring.
There are several possible stereoisomers; four couple of (+) and
(À) enantiomers (conduritols B, C, E and F) and two meso-forms
(conduritols A and D) (Fig. 1). Interest in conduritols and their ana-
logues has been heightened due to the synthetic challenge that
they represent and and presence of a variety of biological activities
such as antifeedant, antibiotics, antileukemics and growth-
regulation.1
Currently, as a vital motif in potent anticancer narciclasine4 and
antidiabetic conduritol A,5 facile and efficient synthetic approaches
have been developed to produce optically pure conduritols in large
quantity.6
a-Glucosidase inhibitors are a class of compounds that
inhibit the breakdown of oligo and disaccharides from dietary
complex carbohydrates and slowdown the absorption of absorb-
able monosaccharides available7a,b and reduce the postprandial
insulin and glucose peak. Delay in glucose absorption reduces post-
prandial hyperglycemia, which is associated with cardiovascular
Conduramines are an important member of the cyclitols com-
pounds. Conduramines are analog of conduritols in which one of
the hydroxyl group is replaced with amino group. Conduramines
have gained much attention due to their biologic activities towards
glycosidase and their usage in the synthesis of azosugars, amino
sugars, sphinoganies, lactams, narcisus alkaloids as a intermedi-
ates. There are several stereoisomers of monoamine containg con-
duritols (A–F) but only nine enantiomers have been synthesized to
date in literature (Fig. 2).2
Diamino contaning conduritols are derived from conduritols, in
which two of the hydroxyl groups are replaced with two amino
groups. There are four stereogenic centers of dimainoconduritols
in which different substituent groups allow it to exist in four differ-
ent structural isomers respectively 1,2-, 1,3-, 1,4- and 2,3-diamino-
conduritols (Fig. 3).3
mortality. Acarbose was the first member of the a-glucosidase
inhibitor family of therapeutic agents to be approved for the treat-
ment of type 2 diabetes.7
Indole moieties occur in many synthetic and natural products,
some of which are physiologically relevant or therapeutically used.
8a,b Melatonin, an important hormone containing the indole
moiety, is known to regulate biological rhythms, and to act as a
receptor-independent free-radical scavenger, being also a broad-
spectrum antioxidant.8 In recent investigations, antioxidant activ-
ity of synthetic indole derivatives and their possible mechanisms
of action have been widely studied. Many of these compounds have
been demonstrated to possess potent carbonic anhydrase inhibitor,
anticarcinogenic, and antibacterial activities.8
Glycosidase inhibition is important not only for the insightful
understanding of enzyme mechanism, but also for questing prom-
ising therapeutics in treatment of disorders such as diabetes9 and
metastatic cancer.10a The knowledge of the crystal structure of gly-
cosidase and its complexes with known inhibitors provides a rich
framework to design more potent inhibitors.10
⇑
Corresponding author. Tel.: +90 2742652031.
E-mail address: hcavdar43@hotmail.com (H. Çavdar).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.038

7500
H. Çavdar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7499–7503
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Conduritol A
Conduritol B
Conduritol C
Conduritol D
Conduritol E
Conduritol F
Figure 1. Structures of conduritols (A–F).
Indoline, one of the most common aromatic heterocyclic organ-
ic compounds, has a bicyclic structure, consisting of a six-mem-
bered benzene ring fused to 2C and 3C position of pyrrolidine
ring (Fig. 5). The compound is based on the indole structure, but
the 2–3 bond is saturated. By oxidation/dehydrogenation it can
be converted to indoles easily. Indoline constitutes an important
class of natural products and drug materials and also it is a key
molecule in the sytnthesis of indole derivatives.12a,b A lot of biolog-
ically active compounds have indoline moiety in their chemical
structures. For example, vincamine, a peripheral vasodilator that
increases blood flow to the brain, is a natural product and has ind-
oline skeleton.12c,d
OH
OH
OH
OH
OH
OH
OH
NH2
OH
NH2
OH
NH2
conduramine A-2
conduramine A-1
conduramine B-1
NH2
OH
OH
OH
OH
NH2
OH
OH
OH
OH
OH
NH2
conduramine C-1 conduramine C-2 conduramine D-1
OH
OH
NH2
Indoline plays an important role in the synthesis of N substi-
tuted indole derivatives. The NH group in its structure attacks
OH
OH
OH
OH
OH
OH
electrophilic compounds easily. Thus,
N substituted indoline
compounds can be obtained easily. Through oxidizing N substi-
tuted indoline compounds by several oxidants such as MnO2,
DDQ, chloroaniline and naphthoquinone, many N substituted in-
dole derivatives have been synthesized.12a,b
NH2
NH2
OH
conduramine F-4
conduramine F-1
conduramine E-1
Figure 2. Structures of conduramines have been synthesized to date.
Indole and conduritol molecules are present in an enormous
number of natural products and pharmaceuticals. Thus, we aimed
in this study to synthesize indole and conduritol containing com-
pounds. For this aim, we first synthesized anti-bisepoxide using
the reported procedure in the literature1,13 (Scheme 1).
Indoline (2 equiv) was reacted with anti-bisepoxide (1 equiv) in
the presence of CH2Cl2 and the aminoconduritol derivative (1) was
obtained.17 We were unable to oxidize this compound by MnO2 or
DDQ. Thus, we acetylated the hydroxyl group and then oxidized by
MnO2 and obtained (2) (Scheme 2).
NH2
OH
NH2
OH
NH2
NH2
OH
OH
NH2
OH
OH
OH
OH
NH2
NH2
NH2
Figure 3. Structures of diaminoconduritols.
After that, indoline (1 equiv) was reacted with anti-bisepoxide
(1 equiv) in order to synthesize mono indole conduritol derivative.
The product was treated with AcO2/pyridine to protect the hydroxyl
groups, and subsequently (3) was obtained. Finally, (1S,2S,3R,6R)-2-
hydroxy-6-(indolin-1-yl)cyclohex-4-ene-1,3-diyl diacetate was oxi-
dized by MnO2 at room temperature and (4) was synthesized
(Scheme 3). By means of this procedure, we combined two very
important groups indole and conduritol and synthesizes indole con-
duritol derivatives for the first time in the literature.
Considering above stated information, synthesis and discovery
of novel glycosidase inhibitors are of particular interest due to their
possible anti-diabetic capacities. Therefore, in this study, we ana-
lyzed the glycosidase inhibitory capacities of several molecules,
mostly indole conduritol derivatives, four of which have been newly
synthesized by our group (i.e. compounds 1–4, see Scheme 2 and 3).
Our groups recently investigated the interaction of
a and b-glu-
cosidase with acarbose and some secondary metabolites, such as
astragaloside IV, trojanoside H, astrasieversianin X and astragalo-
side VIII11 (Fig. 4). We tested acarbose as a positive control for
We report here the first study on the inhibitory effects of these
compounds on
positive control for
parison reasons.18 Data of Table 1 show the following regarding
inhibition of and b-glucosidase with these compounds with 4-
a
and b-glucosidase. Acarbose has been used as a
a
glucosidase in our experiments, and for com-
the
a-glucosidase inhibition. Compound 4 behaved as the stron-
gest
a
and b-glucosidase inhibitor with IC50 values of 11.6 and
a
23.1
lM, respectively (Table 1).
O
OAc
OAc
O
O
Br
Br
a,b,c
d
O
°
(a) 0 C Br2, CH2Cl2, 70% (b) NaBH4, H2O/Et2O, 84% (c) Ac2O, Pyridine 75% (d) KOH,
THF, 77%
Scheme 1. Reagents and conditions: (a) 0 °C Br2, CH2Cl2, 70%; (b) NaBH4, H2O/Et2O, 84%; (c) Ac2O, Pyridine 75%; (d) KOH, THF, 77%.

H. Çavdar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7499–7503
7501
O
N
N
N
OH
OH
OH
OH
MnO2
O
CH2Cl2
CH2Cl2
80%
N
H
N
1
1) Ac2O / Pyridine
2) MnO2 / CH2Cl2
74%
N
OAc
OAc
N
2
Scheme 2.
O
O
N
N
CH2Cl2
1)
MnO2
OAc
OH
OAc
CH2Cl2
85%
N
H
2) Ac2O / Pyridine 72%
OH
OAc
OAc
3
4
Scheme 3.
nitrophenyl
ranoside as substrate:
(i) Against glucosidase, compounds 1 and 2 behave as rather
weak inhibitors, with IC50 values of 18.1 and 19.3 M. A second
group of compounds 3 and 4 showed better inhibitory activity as
compared to the previously mentioned compounds, with IC50 val-
a
-
D
-glucopyranoside and 4-nitrophenyl b-
D
-glucopy-
OH
HO
HO
a
H3C
l
O
N
OH
H
HO
OH
OH
O
O
OH
ues of 11.6 and 12.4
groups in ortho-, para- and metha- to the OAc and OH moiety
strongly influences glucosidase inhibitory activity. Acarbose is
also a medium glucosidase inhibitor with this assay and sub-
strate against glucosidase (IC50 of 9.24 M).
lM (Table 1). Therefore, the nature of the
HO
OH
O
O
Acarbose
HO
a
OH
OH
a
a
l
Figure 4. Structure of acarbose.
(ii) A better inhibitory activity has been observed with the com-
pounds for the inhibition of b-glucosidase (Table 1). Compounds 1
and 2 were quite effective b-glucosidase inhibitors, with IC50 val-
Table 1
IC50 values (
l
M) of
a
and b glucosidases by compounds 1–4
ues of 67.7 and 52.8
more effective inhibitory activity with IC50 values of 24.3 and
23.1 M.
Especially, indoline containing cyclohexene derivatives influ-
ence the activity of glycosidases due to the presence of the differ-
ent functional groups (OH and OAc) present in their scaffold. Our
findings indicate thus another class of possible glycosidase inhibi-
tors of interest, in addition to the well-known conduritols in their
lM (Table 1). Compounds 3 and 4 exhibited
I
Inhibitor
IC50
a
glucosidase
IC50 b glucosidase
l
Acarbosea
9.24
103.12
67.7
52.8
24.3
23.1
1
2
3
4
18.1
19.3
12.4
11.6
a
From Ref. 11.

7502
H. Çavdar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7499–7503
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Me
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Figure 5. Structure of indoleine and vincamine.
molecules. Compounds 3 and 4 investigated here showed effective
and b glycosidase inhibitory activity, in the low micro molar
range. These findings point out that substituted –OAc and –OH
compounds may be used as leads for generating potent glycosidase
inhibitors.
It is apparent that conduritol derivatives have many important
roles. In addition, glycosidase inhibitors have gained great atten-
tion due to their impacts on cancer and diabetes. Thus, we synthe-
sized novel conduritol derivatives and measured their potencies at
glycosidase inhibition. In addition, we compared and discussed the
a
11. Koz, O.; Ekinci, D.; Senturk, M.; Perrone, A.; Piacente, S.; Caliskan, O. A.; Bedir, E.
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novel conduritols
a glycosidase inhibitory propensities with the
simple precursor and commercially available compound acarbose.
Our groups have reported several interactions of different func-
tional groups with different enzymes.14,15 However, this research
is starting point for us to design and discover novel glycosidase
inhibitors.
13. Altenbach, H.-J.; Stegelmeier, H.; Vogel, E. Tetrahedron Lett. 1978, 19, 3333.
14. (a) Ekinci, D.; Cavdar, H.; Talaz, O.; Senturk, M.; Supuran, C. T. Bioorg. Med.
Chem. 2010, 18, 3559; (b) Alp, C.; Ekinci, D.; Gultekin, M. S.; Senturk, M.; Sahin,
E.; Kufrevioglu, O. I. Bioorg. Med. Chem. 2010, 18, 4468; (c) Senturk, M.; Talaz,
O.; Ekinci, D.; Cavdar, H.; Kufrevioglu, O. I. Bioorg. Med. Chem. Lett. 2009, 19,
3661; (d) Ceyhun, S. B.; Senturk, M.; Yerlikaya, E.; Erdogan, O.; Kufrevioglu, O.
I.; Ekinci, D. Environ. Toxicol. Pharmacol. 2011, 32, 69; (e) Cakmak, R.; Durdagi,
S.; Ekinci, D.; Senturk, M.; Topal, G. Bioorg. Med. Chem. Lett. 2011, 21, 5398.
15. (a) Ekinci, D.; Senturk, M.; Beydemir, S.; Kufrevioglu, O. I.; Supuran, C. T. Chem.
Biol. Drug Des. 2010, 76, 552; (b) Durdagi, S.; Senturk, M.; Ekinci, D.; Balaydin,
H. T.; Goksu, S.; Kufrevioglu, O. I.; Innocenti, A.; Scozzafava, A.; Supuran, C. T.
Bioorg. Med. Chem. 2011, 19, 1381; (c) Cavdar, H.; Ekinci, D.; Talaz, O.;
Saracoglu, N.; Senturk, M.; Supuran, C. T. J. Enzyme Inhib. Med. Chem. 2012, 27,
148.
Consequently, conduritol derivatives used in this study affect
the activity of
ferent functional groups present in their aromatic scaffold. Our
findings here indicate thus another class of possible and b gluco-
a and b glucosidases due to the presence of the dif-
a
sidases of interest, in addition to the well-known acarbose and
conduritol F derivatives bearing bulky in their structures. Indeed,
new conduritol derivatives investigated here showed very effective
b glucosidases inhibitory activity compared to well known agents.
These findings point out that novel substituted conduritol deriva-
tives may be used as leads for generating potent glucosidases
inhibitors. Thus, this approach may also be useful in the design
and exploitation of novel drug candidates for diabetes, viral infec-
tions including HIV and influenza and cancer. However, these fea-
tures of the compounds are beyond the scope of this study and
merits further investigations.
16. Senturk, M.; Ekinci, D.; Goksu, S.; Supuran, C. T. J. Enzyme Inhib. Med. Chem.
2012, 27, 365.
17. Detailed synthetic procedures for the preparation of all derivatives 1–4 can be
found in: (1R,2R,3S,6S)-3,6-di(indolin-1-yl)cyclohex-4-ene-1,2-diol (1)
: To
solution of indoline (119 mg, 1.0 mmol) and anti-bisepoxide (56 mg,
0.5 mmol) in 20 mL CH2Cl2 was stirred at room temperature for 16 h . After
complete conversion as indicated by TLC, the solvent was removed by
evaporation and the residue was diluted with water and extracted with ethyl
acetate (2 Â 10 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was submitted to column
chromatography on silica gel (25 g) eluting with ethyl acetate/hexane (7%).
Elution gave (1R,2R,3S,6S)-3,6-di(indolin-1-yl)cyclohex-4-ene-1,2-diol (1) as a
sole product. Pale brown crystals from CH2Cl2/n-hexane (2:1), (140 mg, 80%,
mp 82–83 °C).
Supplementary data
1H NMR (400 MHz, CDCl3): d 7.10–7.05 (m, 4H), 6.71–6.67 (m,2H), 6.56 (d,
J = 8.1 Hz, 2H), 5.65 (br s, 2H), 4.26 (m, 2H), 4.06 (dd, J = 6.6 Hz, J = 2.2 Hz, 2H),
3.56–3.51 (m, 2H), 3.30 (dd, J = 18.5 Hz, J = 9.7 Hz, 2H), 2.04–3.03 (m, 4H).
13C NMR (100 MHz, CDCl3): d 151.10, 130.80, 129.41, 127.51, 125.01, 118.65,
108.14, 72.20, 59.95, 48.30, 28.53. IR (KBr, cmÀ1): 3367, 3042, 3019, 2925,
2845, 1605, 1486, 1457, 1254, 1085, 1023. Anal. Calcd for C22H24N2O2: C,
75.83; H, 6.94; N, 8.04 Found: C, 75.82; H, 6.95; N, 8.06;
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.038.
References and notes
(1R,2R,3S,6S)-3,6-di(1H-indole-1-yl)cyclohex-4-ene-1,2-diyl diacetate (2)
: The
pure product (1) (200 mg, 0.57 mmol) was acetylated in pyridine (1.00 g) and
Ac2O (0.50 g) at 1 day. Then, the mixture was cooled to 0 °C and poured into a
cold solution (1%, 100 mL) of HCl. The mixture was extracted with CH2Cl2
(3 Â 50 mL). The combined organic layer was washed with NaHCO3 (5%,
100 mL) and water (100 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. Then, the crude product in
CH2Cl2 (10 mL) was added activated MnO2 (496 mg, 10 mmol).The mixture
was stirred at rt for24 h. After filtration, the mixture was evaporated under
vacuo. The residue was submitted to column chromatography on silica gel
(20 g) eluting with ethyl acetate/hexane (10%). Elution gave (1R,2R,3S,6S)-3,6-
di(1H-indole-1-yl)cyclohex-4-ene-1,2-diyl diacetate (2) as a sole product. White
crystals from CH2Cl2/n-hexane (2:1), (181 mg, 74%, mp 103–104 °C).
1H NMR (400 MHz, CDCl3): d 7.64 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H),
7.26–7.22 (m, 2H), 7.16–7.10 (m, 4H), 6.61 (d, J = 3.3 Hz, 2H), 6.13 (br s, 2H),
5.66 (dd, J = 6.4 Hz, J = 2.4 Hz, 2H), 5.47–5.46 (m, 2H), 1.62 (s, 6H).
13C NMR (100 MHz, CDCl3): d 169.31, 136.82, 129.64, 129.07, 125.16, 122.15,
121.60, 120.21, 109.67, 103.72, 73.07, 57.36, 20.40.
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IR (KBr, cmÀ1): 2924, 2854, 1744, 1611, 1514, 1460, 1372, 1311, 1222, 1052,
1014, 964, 904. . Anal. Calcd for C26H24N2O4: C, 72.88; H, 5.65; N, 6.54 Found: C,
72.87; H, 5.66; N, 6.52;
(1S,2S,3R,6R)-2-hydroxy-6-(indolin-1-yl)cyclohex-4-ene-1,3-diyl diacetate (3): To
4. Kornienko, A.; Evidente, A. Chem. Rev. 1982, 2008, 108.

H. Çavdar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7499–7503
7503
a stirred solution of indoline (179 mg, 1.5 mmol) in 10 mL CH2Cl2 was added
anti-bisepoxide (165 mg, 1.5 mmol) at room temperature. After the mixture
was stirred for 18 h. The solvent was concentrated under reduced pressure.
Then, the crude product was acetylated in pyridine (1.50 g) and Ac2O (0.60 g)
at 1 day. Then, the mixture was cooled to 0 °C and poured into a cold solution
(1%, 100 mL) of HCl. The mixture was extracted with CH2Cl2 (3 Â 50 mL). The
combined organic layers were washed with NaHCO3 (5%, 100 mL) and water
(100 mL), and then dried over Na2SO4. and concentrated in vacuo. The residue
was submitted to column chromatography on silica gel (25 g) eluting with
ethyl acetate/hexane (15%). Elution gave (1S,2S,3R,6R)-2-hydroxy-6-(indolin-1-
yl)cyclohex-4-ene-1,3-diyl diacetate (3) as a sole product. White crystals from
CH2Cl2/n-hexane (2:1), (358 mg, 72%, mp 112–113 °C)
1,3-diyl diacetate (4) as a sole product. Cream crystals from CH2Cl2/n-hexane
(2:1), (253 mg, 85%, mp 190–191 °C)
1H NMR (400 MHz, CDCl3): d 7.63 (d, J = 8.2 Hz 1H), 7.57 (d, J = 8.2 Hz 1H), 7.27–
7.23 (m, 1H), 7.16–7.12 (m,2H), 6.56 (d, J = 4.3 Hz 1H), 6.08 (br s, 2H), 5.73–5.71
(m, 1H), 5.38 (dd, J = 7.5 Hz, J = 3.1 Hz, 1H), 5.27 (d, J = 7.5 Hz 1H), 4.41 (dd,
J = 4.6 Hz, J = 3.1 Hz, 1H), 2.18 (s, 3H), 1.90 (s, 3H).
13C NMR (100 MHz, CDCl3): d 170.11, 169.87, 136.60, 129.86, 129.17, 126.89,
125.84, 122.29, 121.36, 120.32, 110.12, 103.16, 71.60, 71.50, 54.63, 48.33, 21.16,
20.83.
IR (KBr, cmÀ1): 2924, 2862, 2330, 1755, 1608, 1510, 1457, 1367, 1309, 1232,
1051, 923.
Anal. Calcd for C18H19NO5: C, 65.64; H, 5.81; N, 4.25 Found: C, 65.66; H, 5.80; N,
4.26.
1H NMR (400 MHz, CDCl3): d 7.09–7.04 (m, 2H), 6.68–6.17 (m,2H), 5.91 (br s,
2H), 5.58 (t, J = 3.11 Hz 1H), 5.39 (dd, J = 8.3 Hz, J = 3.2 Hz, 1H), 4.51 (d,
J = 8.3 Hz 1H), 4.40 (t, J = 3.2 Hz, 1H), 3.51 (dd, J = 17.00 Hz, J = 8.8 Hz, 1H), 3.36
(dd, J = 17.00 Hz, J = 8.8 Hz, 1H), 2.98 (t, J = 8.8 Hz, 2H), 2.14 (s, 3H), 1.96 (s, 3H).
13C NMR (100 MHz, CDCl3): d 170.44, 170.02, 150.74, 132.63, 129.96, 127.50,
125.20, 124.90, 118.08, 107.41, 71.67, 67.72, 54.85, 50.34, 48.76, 28.51, 21.17,
21.07.
18. In vitro inhibition studies:
a-Glucosidase from Bacillus stearothermophilus (E.C.
3.2.1.20) was purchased from Sigma–Aldrich (CAS Number: 9001-42-7) and b-
glucosidase from almonds (E.C. 3.2.1.21) was purchased from Sigma–Aldrich
(CAS Number: 9001-22-3) for using in inhibition studies. Enzyme assay was
performed for four compounds 1–4 and acarbose. The reaction mixture
containing 1 mM PNPG (4-nitrophenyl
b-D-glucopyranoside), phosphate buffer (pH 6.8), and 10 lM
a
-
D
-glucopyranoside or 4-nitrophenyl
IR (KBr, cmÀ1): 2918, 2845, 1743, 1605, 1488, 1371, 1223, 1055, 1009, 959,
900.
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23 Found: C, 65.26; H, 6.37; N,
4.24.
(1S,2S,3R,6R)-2-hydroxy-6-(1H-indole-1-yl)cyclohex-4-ene-1,3-diyl diacetate (4):
To a stirred solution of (1S,2S,3R,6R)-2-hydroxy-6-(indolin-1-yl)cyclohex-4-ene-
1,3-diyl diacetate (3) (300 mg, 0.91 mmol) in 20 mL CH2Cl2 was added activated
MnO2(792 mg, 10 mmol).The mixture was stirred at rt for24 h. After filtration,
the mixture was evaporated under vacuo. The residue was submitted to
column chromatography on silica gel (30 g) eluting with ethyl acetate/hexane
(18%). Elution gave (1S,2S,3R,6R)-2-hydroxy-6-(1H-indole-1-yl)cyclohex-4-ene-
of the
corresponding isomers was incubated at 37 °C for 5 min then 0.075 unit of
enzyme was added and the resulting mixture was incubated at 37 °C for
30 min, then and reaction was stopped with 2 mL of 100 mM Na2CO3 and the
absorbance at 400 nm of the liberated p-nitrophenol was measured. All
compounds were tested in triplicate at each concentration used. Different
inhibitor concentrations were used. For
concentrations used were: 1, 3, 10, 15 and 25
a
-glucosidase, the inhibitor
l
M and for b-glucosidase, the
inhibitor concentrations used were: 10, 20, 30, 50, 70, 80, 90 and 100 lM.
Control cuvette activity in the absence of inhibitor was taken as 100%.16 For
each inhibitor an activity%ÀLog10[inhibitor] graph was drawn.