Synthesis and glycogen phosphorylase inhibitor activity of functionalized 1,4-benzodioxanes

Article abstract of DOI:10.1691/ph.2010.9706

A series of novel 1,4-benzodioxanes 11a-e and rac-12a-d carrying thiazolidine-2,4-dione moiety was synthesized and their glycogen phosphorylase inhibitor activity was also evaluated.

Full text of DOI:10.1691/ph.2010.9706

ORIGINAL ARTICLES
Department of Organic Chemistry1; Cell Biology and Signaling Research Group of the Hungarian Academy
of Sciences2, Department of Medical Chemistry; Research Center for Molecular Medicine3, Research Group for
Carbohydrates of Hungarian Academy of Sciences, Debrecen, Hungary
Synthesis and glycogen phosphorylase inhibitor activity of functionalized
1,4-benzodioxanes
Z. Czakó1, T. Docsa2, P. Gergely2, L. Juhász1, S. Antus1,3
Received July 15, 2009, accepted September 18, 2009
Zoltán Czakó, Department of Organic Chemistry, University of Debrecen, H-4010, P.O. Box 20 Debrecen, Hungary
czakoz@yahoo.com
Dedicated to Professor Károly Lempert on the occasion of his 85th birthday.
Pharmazie 65: 235–238 (2010)
doi: 10.1691/ph.2010.9706
A series of novel 1,4-benzodioxanes 11a-e and rac-12a-d carrying thiazolidine-2,4-dione moiety was
synthesized and their glycogen phosphorylase inhibitor activity was also evaluated.
1. Introduction
2. Investigations, results and discussion
Thiazolidine-2,4-diones 11a-e and 12a-d were prepared from
the corresponding 1,4-benzodioxane aldehydes 10a-e in one and
two steps respectively, as shown in Scheme 1. Condensation of
the neat aldehydes 10a-e with thiazolidine-2,4-dione and anhy-
drous sodium acetate at 110 ◦C for 10 min in a CEM-Discover
MW reactor afforded 11a-e 5-arylidene-2,4-thiazolidinediones
in excellent yield (88–92%), whose catalytic hydrogenation
in acetic acid at high pressure (12 atm) in the presence of
10% palladium/carbon resulted in the corresponding racemic
dihydro-(12a, b) and diastereomeric tetrahydro-(12c, d) deriva-
tives respectively. Since the latter compounds could not be
separated by either crystallization or chromatography, they were
characterized and tested as a 1:1 mixture of the diastereomers.
The 1,4-benzodioxane aldehydes 10a and 10e were pre-
pared as described in the literature (Kashima et al. 1987;
Vallejos et al. 2005). 5-Methoxyprotochatechualdehyde (13)
was alkylated with 1,2-dibromoethane in acetone in the
presence of potassium carbonate resulting in 3-methoxy-4,5-
ethylendioxybenzaldehyde (10b) in 81% yield as shown in
Scheme 2. The 6- and 7-formyl-2-benzylidene-1,4-benzodioxa-
nes (10c, d) of (Z)-geometry were prepared from 3- and 4-
propargylprotochatechualdehydes (14a, b) and iodobenzene
by Sonogashira coupling as published by Chowdhury et al.
(Chowdhury et al. 1998) in moderate yields (42% and 35%,
respectively) (Scheme 3).
Type II diabetes is caused by abnormal insulin secretion and/or
insulin resistance. Insufficient action of insulin in the liver
results in increased blood sugar levels. Although the molecu-
lar etiology of this disease remains unknown, several classes
of oral hypoglycaemic drugs [sulfonylureas, biguanides, thi-
azolidinediones (Cheng and Fantus 2005; Krentz and Balley
2005)] and ␣-glycosidase inhibitors [acarbose, miglitol (Laar
et al. 2003)] have been used as symptomatic treatments for
type II diabetes. The numerous side effects observed in a large
proportion of patients led to the investigation of the mecha-
nism of hepatic glucose output (Agius 2007) which can be
regulated by inhibition of glycogen phosphorylase (GP). Since
this is the rate-limiting enzyme in glycogen degradation, it
seemed reasonable to suppose that liver-specific GP inhibitors
could be a powerful tool for controlling glucose levels in
patients suffering from type II diabetes (Agius 2007; Morral
2003; Oikonomakos 2002; Oikonomakos and Somsák 2008;
Somsák et al. 2008). Since several GP inhibitors carry a hydan-
toin (1a, 2) or thiohydantoin (1b) moiety (Agasimundin et al.
˝
1998; Osz et al. 1999), one can assume that related heterocy-
cles, such as glitazone-type molecules [citglitazone (3) (Shoda
et al. 1982), rosiglitazone (4) (Cantello et al. 1994), and
pioglitazone (5) (Ikeda et al. 1990), employed as oral hypo-
glycemics]andtheirdihydrobenzofuran(6), dihydrobenzopyran
(7) and 1,4-benzodioxane (8a) analogues (Clark et al. 1991;
de Nanteuil et al. 1995) may also possess a GP inhibitory
effect (Fig. 1). Indeed, we have found recently that 1,4-
benzodioxanes carrying a 5-arylidene-thiazolidine-2,4-dione
(8b, c) or N-␤-d-glucopyranosylcarbamoyl (9a-d) moiety pos-
sess a significant GP inhibitory effect (Czakó et al. 2009;
Juhász et al. 2007) (Fig. 1). Therefore, as a continuation
of our investigation into the synthesis of 1,4-benzodioxane
derivatives of potential hypoglycaemic agents, we prepared
novel analogues of 8b and 8c in order to obtain fur-
ther information about their structure-activity relationship
(SAR).
The 1,4-benzodioxanes 11a-e and 12a-d were tested against
unphosphorylated rabbit muscle GP (RMGPb) as described pre-
˝
viously (Juhász et al. 2007; Osz et al. 1999) and their inhibitory
activities are given in Table 1.
The IC50 value of 11a, possessing a 1,4-benzodioxane nucleus
of half-chair conformation (entry 1), has clearly indicated
that its inhibition action on RMGPb is significantly weaker
than those of rac-8b and -8c 1,4-benzodioxanes possess-
ing an aryl linker between their thiazolidine-2,4-dione and
1,4-benzodioxane moieties. It is also noteworthy that introduc-
tion of a methoxy or bromine group at C-8 of 11a (11b, 11e)
decreased the GP inhibitor activity (entries 2 and 5), while a
Pharmazie 65 (2010)
235

ORIGINAL ARTICLES
HO
OH
HO
O
H
O
H
N
HO
HO
HO
N
NH
O
O
HO
X
S
R
O
NH
N
H
O
1a, b
3-5
OH
O
O
2
R
1
X
O
S
K i(GP)
Me
Me
Ciglitazone (3)
a
3.1 μM
b
5.1 μM
Rosiglitazone (4)
N
N
Me
Pioglitazone (5)
N
O
O
3
R
3
NH
2
NH
S
R
S
O
2
O
1
O
6
1
O
7
6,7
R
2-Ph, c-hex, CH2-c-hex, 3-Ph, Bn
O
R1
O
HO
R2
R3
O
O
NH
O
HO
HO
NHCOR
S
HO
O
9a-d
8a-c
Ki(GP)
[μM]
IC50
9
a
R
8
a
b
c
R1
H
H
R2
H
Br
R3
H
Br
Br
Ki(GP)
-
12 μM
[μM]
O
252 7
120 7
128 5
630 35
300 15
320 15
125 12
O
O
OMe Br
30 μM
b
c
O
O
O
O
d
85 5 μM
O
Fig. 1: Structure of some hydantoin, tiohydantoin, thiazolidine-2,4-dione and N-acyl-␤-d-glucopyranosylamine derivatives
O
O
11
11
6
6
R1
R2
O
O
CHO
R1
O
R1
O
10
10
4
4
5
5
ii
i
NH
NH
3
S
S
7
7
3
2
R2 9 O
R2 9 O
1
1
2
8
8
O
O
R3
R3
R3
_
(+)
-12a-d
10a-e
11a-e
10, 11
R1
H
R2
R3
H
12
a
R1
H
R2
H
R3
a
b
c
d
e
H
H
H
H
OMe
H
b
c
H
H
OMe
H
H
(Z)-PhCH=
H
(Z)-PhCH=
H
Bn
H
H
Bn
H
H
H
Br
d
Scheme 1: (i) thiazolidine-2,4-dione, NaOAc, MW, 110 ◦C; (ii) AcOH, Pd(C)/H2, 12 atm
236
Pharmazie 65 (2010)

ORIGINAL ARTICLES
Table 1: GP inhibitor activities of functionalized 1,4-
CHO
CHO
benzodioxanes 11a-e and 12a-d
i
*
Compd.
K
(␮M)
IC (␮M)
50
i
MeO
OH
MeO
O
OH
O
11a
11b
11c
11d
11e
12a
12b
12c
12d
233 11.0
243 11.0
25 3.0
100 8.5
283 12.2
200 9.5
257 11.8
217 10.4
217 10.4
700 6.5
730 6.0
75 4.2
300 5.0
850 8.2
600 5.8
770 7.6
650 6.0
650 6.0
13
10b
Scheme 2: (i) BrCH2CH2Br, K2CO3, acetone,ꢀ
R2
R1
OH
O
i
10c,d
14a, b
*
Calculated by the Cheng-Prusoff equation: K = IC /(1+[S]/K ) (Cheng and Prusoff 1973)
m
i
50
14
R1
R2
a
CHO
H
H
seems to be an important prerequisite for glycogen phosphory-
lase inhibitor activity.
b
CHO
Scheme 3: (i) PhI, (PPh3)2PdCl2, CuCl2, Et3N, 110 ◦C
3. Experimental
Analytical TLC was performed on Kieselgel 60 plates F254 (Merck). For
workup, the solutions were dried (MgSO4) and concentrated in vacuum.
1H and 13C NMR spectra were recorded on Bruker WP-200 and Bruker
WP-360 spectrometers. The chemical shifts are given in ␦ (ppm) and spin-
spin coupling constants (J) in Hz. Microanalyses were performed on a Carlo-
Erba Tpy 1106 analyser. Compounds listed below gave satisfactory C, H,
N analysis ( 0.4%). The reagents were purchased from Sigma-Aldrich.
The arylaldehydes 10a, 10e, 14a and 14b were prepared according to the
respective procedures reported in the literature (Kashima et al. 1987; Plourde
and Spaetzel 2002; Vallejos et al. 2005; Wei et al. 2006).
benzylidene group of (Z)-geometry at its C-10 or C-9 (11c,
11d) significantly increased it (entries 3 and 4). Interestingly,
the latter modification (11a → 11d) makes the inhibition one
order of magnitude stronger than that of 11c and it possess a
GP inhibitor activity comparable with those of rac-8c and -8c.
Finally, saturation of the exocyclie double bond of 11c and 11d
bycatalytichydrogenation(11c → 12c, 11d → 12d)alsocaused
a significant decrease of their activities.
In good agreement with our earlier results observed in the series
of N-(␤-d-glucopyranosyl)amides 9a-d (Czakó et al. 2009),
these data also underline the importance of the ␲-donor ability
3.1. General procedure for the preparation of 11a-e
A mixture of aldehyde 10a-e (0.5 mmol), thiazolidine-2,4-dione (2 mmol)
and anhydrous sodium acetate (0.2 mmol) was heated in a CEM-Discover
MW reactor at 110 ◦C for 10 min. Then water was added to the reaction
mixture and the solid product was filtered off, washed with chloroform and
dried to give 11a-e (Table 2).
of the aryl moiety of these compounds (11c, d > 12c, d > 11a,
∼
b, e 12a, b) and the presence of an aryl linker between the
=
thiazolidine-2,4-dione and 1,4-benzodioxane moieties of 8b and
8c (Ki(GP):12, 25, 30, 100 ␮M for 8b, 11c, 8c, 11d, resp.) which
Table 2: Physical and selected NMR data, and yields for functionalized 1,4-benzodioxanes 11a-e and 12a-d
1
13
Compd.
Yield
%
m.p.
Molecular Form.
Selected H-NMR data
Selected C-NMR data
◦
C
11a
11b
11c
88
91
89
>250
192–198
207–212
C12H9NO4S
C13H11NO5S
C19H13NO4S
7.67 (1H, s, H-6)
7.63 (1H, s, H-6)
4.18 (1H, s, PhCH=); 7.52 (1H, s, H-6)
119.53 C-5; 130.23 C-6
121.03 C-5; 131.99 C-6
107.43 PhCH = ; 122.61 C-5; 142.67
C-10; 146.27 C-6
11d
90
216–221
C19H13NO4S
5.88 (1H, s, PhCH=); 7.60 (1H, s, H-6)
107.79 PhCH=; 124.61 C-5; 143.56
C-9; 144.29 C-6
11e
12a
92
88
>250
158–161
C12H8BrNO4S
C12H11NO4S
7.24 (1H, s, H-6)
121.98 C-5; 128.18 C-6
35.37 C-6; 52.20 C-5
2.86 (1H, dd, J = 10.0 and J = 14.4,
H-6A); 3.27 (1H, dd, J = 4.0 and
J = 14.4, H-6B); 4.73 (1H, dd, J = 4.0
and J = 10.0, H-5)
12b
79
129–131
C13H13NO5S
2.87 (1H, dd, J = 9.8 and J = 14.2,
H-6A); 3.27 (1H, dd, J = 4.2 and
J = 14.0, H-6B); 4.76 (1H, dd, J = 4.0
and J = 9.8, H-5)
37.46 C-6; 53.65 C-5
12c
12d
35
39
217–226
231–239
C19H17NO4S
C19H17NO4S
2.78–2.94 (3H, m, H-6A and PhCH2-);
3.17–3.29 (1H, m, H-6B); 3.83–3.92
(1H, m, H-10); 4.58–4.61 (1H, m, H-5)
2.80 (1H, dd, J = 10.1 and J = 14.0,
H-6A); 2.95–2.97 (2H, m, PhCH2-);
3.31 (1H, dd, J = 3.6 and J = 14.0,
H-6B); 3.89–3.94 (1H, m, H-9); 4.49
(1H, dd, J = 3.9 and J = 10.1, H-5)
36.34 PhCH2-; 37.38 C-6; 54.77 C-5;
73.21 C-10
36.38 PhCH2-; 37.99 C-6; 55.96 C-5;
73.18 C-9
Pharmazie 65 (2010)
237

ORIGINAL ARTICLES
3.2. General procedure for the preparation of rac-12a-d
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Palladium-catalyzed heteroannulation leading to heterocyclic structures
with two heteroatoms: A highly convenient and facile method for a totally
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(1991) Novel thiazolidinedione derivatives as potent hypoglycemic and
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of N-(␤-D-glucopyranosyl)amides possessing 1,4–benzodioxane moiety.
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Effects of pioglitazone on glucose and lipid metabolism in normal and
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The arylidene derivatives (11a-d) (0.5 mmol) were hydrogenated in acetic
acid (25 mL) in the presence of 10% Pd(C) (200 mg) at 12 atm pressure until
thepressurewasstabilized. Thecatalystwasfilteredoffoncellite, thesolvent
was evaporated, and the residue was purified by column chromatography
(CC) on silica gel using a mixture of hexane and ethyl-acetate (1:1) as
eluent (Table 2).
3.3. 3-Benzylidene-6-formyl-1,4-benzodioxane (10c) and
2-benzylidene-6-formyl-1,4-benzodioxane (10d)
A mixture of iodobenzene (7.35 mmol), (Ph3P)2PdCl2 (0.34 mmol) and
CuI (0.63 mmol) in anhydrous Et3N was stirred under nitrogen at room
temperature for 30 min, and then propargylprotochatechualdehyde (14a or
14b) (10.2 mmol) in anhydrous Et3N (50 mL) and THF (15 mL) was added
dropwise. The reaction mixture was stirred at room temperature for 1 h and
then at 100 ◦C for 20 h. The precipitation was filtered off and the solvent
was evaporated. The residue was dissolved in ethyl acetate (150 mL) and
washed with water (3 × 100 mL). The organic phase was dried, evaporated
and then purified by CC on silica gel using a mixture of hexane and ethyl
acetate (4:1) as eluent.
Juhász L, Docsa T, Brunyászki A, Gergely P, Antus
S (2007)
Synthesis and glycogen phosphorylase inhibitor activity of 2,3-
dihydrobenzo[1,4]dioxin derivatives. Bioorg Med Chem 15: 4048–4056.
Kashima C, Tomotake A, Omote Y (1987) Photolysis of the ozonide derived
from 1,4-benzodioxins. Synthesis of labile o-benzoquinones. J Org Chem
52: 5616–5621.
10c: Yield 35%; m.p. 88–91 ◦C; 1H NMR: ␦ (ppm): 9.87 (1H, s, CHO),
7.72–7.26 (8H, m, Ar-H), 5.96 (1H, s, CH), 4.82 (2H, s, CH2).
10d: Yield 42%; m.p. 84–85 ◦C;1H NMR: ␦ (ppm): 9.83 (1H, s, CHO),
7.67–7.19 (8H, m, Ar-H), 5.65 (1H, s, CH), 4.61 (2H, s, CH2).
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3.4. 6-Formyl-8-methoxy-1,4-benzodioxane (10b)
Laar FA, Lucassen PL, Akkermans RP, Lisdonk EH, Rutten GE, Weel C
(2003) ␣-Glucosidase inhibitors for patients with type 2 diabetes. Dia-
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(1995) Euglycaemic and biological activities of novel thiazolidine-2,4-
dione derivatives. Arzneim Forsch 45: 1176–1181.
To a solution of 13 (7.14 mmol) in dry acetone (60 mL) anhydrous K2CO3
(24 mmol) was added and stirred for 10 min at room temperature. Then
1,2-dibromoethane (17.4 mmol) was added to the solution, and the reaction
mixture was refluxed with stirring and the progress of the reaction was
followed by TLC. After 3 days, K2CO3 was filtered off and the solvent
was evaporated. The residue was purified by CC, using hexane and ethyl-
acetate (3:1) as eluent to give 10b as white crystals (81% yield, m.p.: 69-
72 ◦C). 1H-NMR: ␦ (ppm): 9.79 (1H, s, CHO), 7.08 (2H, s, Ar-H), 4.43-4.39
(2H, m, CH2), 4.33-4.29 (2H, m, CH2), 3.95 (1H, s, OMe).
Oikonomakos NG (2002) Glycogen phosphorylase as a molecular target
for type 2 diabetes therapy. Curr Protein Pept Sci 3: 561–586.
Oikonomakos NG, Somsák L (2008) Recent advances in glycogen phos-
phorylase inhibitor design. Curr Opin Invest Drugs 9: 379–395.
Acknowledgement: The authors thank the National Science Foundation
(OTKA F-47025, OTKA T-049436 and NI-61336), Péter Pázmány Pro-
gramme (NKTH, RET 006/2004) for valuable financial support.
˝
Osz E, Somsák L, Szilágyi L, Kovács L, Docsa T, Tóth B, Gergely P
(1999) Efficient inhibition of muscle and liver glycogen phosphorylases
by a new glucopyranosylidene-spiro-thiohydantoin. Bioorg Med Chem
Lett 9: 1385–1390.
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