Novel design principle validated: Glucopyranosylidene-spiro-oxathiazole as new nanomolar inhibitor of glycogen phosphorylase, potential antidiabetic agent

Article abstract of DOI:10.1016/j.bmcl.2008.08.052

2-Naphthyl-substituted glucopyranosylidene-spiro-oxathiazole prepared following a novel design principle was found to be the best known glucose analogue inhibitor of rabbit muscle glycogen phosphorylase b (K_i 160 nM).

Full text of DOI:10.1016/j.bmcl.2008.08.052

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5680–5683
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel design principle validated: Glucopyranosylidene-spiro-oxathiazole
as new nanomolar inhibitor of glycogen phosphorylase,
potential antidiabetic agent
László Somsák a, , Veronika Nagy a,b, Sébastien Vidal b,c,d, Katalin Czifrák a, Eszter Berzsényi a,
*
Jean-Pierre Praly b,c,d,
*
a Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
b CNRS, UMR5246, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2—Glycochimie,
43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
c Université de Lyon, F-69622 Lyon, France
d Université Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Naphthyl-substituted glucopyranosylidene-spiro-oxathiazole prepared following a novel design princi-
ple was found to be the best known glucose analogue inhibitor of rabbit muscle glycogen phosphorylase
b (Ki 160 nM).
Received 23 July 2008
Revised 14 August 2008
Accepted 15 August 2008
Available online 22 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Nikos G.
Oikonomakos passed away on August 31st,
2008
Keywords:
Glycogen phosphorylase
Inhibitor
Glucose analogue
Oxathiazole
Spirocyclization
Spiro-bicyclic sugar
Glycogen phosphorylase (GP) is a peculiar glycoenzyme in-
volved in the breakdown of the storage polysaccharide glycogen.1
The liver isoform of GP is the rate limiting enzyme of glycogen
metabolism and is, therefore, directly responsible for regulating
blood sugar levels. Evidence are accumulating that in the non-insu-
lin dependent (type 2) form of diabetes mellitus,2 comprising more
than 90% of all diagnosed cases,3,4 elevated hepatic glucose output
is the most important cause of hyperglycemia.5–8 Thus, GP is a val-
idated target for the treatment of type 2 diabetes and its inhibition
appears of great interest in both academia and industry.9–11 GP has
six known binding sites for which several inhibitors have been
identified.12,13 Among these, glucose-based compounds represent
a large family with the capability of binding at the catalytic site
of the enzyme in most cases with very high selectivity.14–16
GPb (RMGPb). Analogous compounds with aromatic substituents
as 217,18 and 319 showed weaker binding properties, and 419 was
only slightly better than 1. As a corollary of early inhibitor design
based on glucose derivatives, spiro-hydantoin 518,20 reached the
low micromolar range and its thiohydantoin analogue 618 proved
similarly efficient. Extensive protein crystallographic investiga-
tions of the corresponding GP-inhibitor complexes showed that a
H-bridge between the b-anomeric NH and His 377 main chain car-
bonyl of the enzyme exists for both N-acyl-b-D-glucopyranosylam-
ines17,21 1–4 and spiro-hydantoins22–24 5 and 6 (see outline A in
Chart 1). This feature was then considered as a main contribution
to the strong binding of glucose analogues at the catalytic site of
GP, and became almost a dogma for further inhibitor design. In
the cases of the spiro-hydantoins, the rigid structure of the planar
(thio)hydantoin rings, and that of the bicyclic ring system as a
whole was also accounted for the tight binding.22,23
N-Acetyl-b-D
-glucopyranosylamine17 (1, Chart 1) was among
the first efficient glucose analogue inhibitors of rabbit muscle
In recent years, we have introduced several new classes of
glucose-based compounds as inhibitors of GP displaying inhibi-
tion constants in the low micromolar range, among others
* Corresponding authors. Tel.: +36 52 512 900; fax: +36 52 453 836.
E-mail address: somsak@tigris.unideb.hu (L. Somsák).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.052

L. Somsák et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5680–5683
5681
N-acyl-N0-b-
D
-glucopyranosyl ureas13,16,25–28 7–10 and C-(b-
D-glu-
HO
HO
HO
O
H
N
copyranosyl) derivatives of aromatic heterocycles such as 1,3,4-
oxadiazole, benzothiazole and benzimidazole,29,30 as well as 1,2,
4-oxadiazoles.31,32 The latter heterocyclic derivatives (apart from
the benzimidazole) cannot form H-bridges similar to those dis-
cussed above because of the lack of suitable hydrogens. On the
other hand and rather surprisingly, the absence of this particular
H-bond to His 377 was demonstrated by crystallography for 8–
1025,27,28 (note that 7 binds to the enzyme in a different conforma-
tion25 in which the b-anomeric NH is involved in an intramolecular
H-bridge with the acetyl CO). Comparison of the efficiency of inhi-
bition for the pairs 2 and 8, 3 and 9 and 4 and 10 shows a signifi-
cant increase in affinity to the enzyme in favour of the acyl ureas
by a factor of ꢀ18, ꢀ89 and ꢀ29, respectively. Thus, even in the ab-
sence of that most important H-bond, very strong binding is possi-
ble which must be ascribed to the interactions of the inhibitor with
the so-called b-channel9,16 (an empty space in the direction of the
R
H
OH
N
O
His-377
HN
R
Ki [μM]
32
N
1
CH3
H
O
2
3
4
phenyl
81
O
1-naphthyl
2-naphthyl
444
10
H
N
O
HO
HO
HO
HO
O
O or S
O
H
N
HO
N
H
HO
X
HO
O
N
H
A
H-bridges between His-377 and
-acyl-β-D-glucopyranosylamine
as well as spiro-hydantoin type
X
Ki [μM]
3.1
N
5
O
inhibitors at the catalytic site of GP
4.3
b-anomeric substituent of bound D-glucose surrounded by amino
6
S
5.1
acid side chains of mixed character) of the enzyme next to the
catalytic site. This is further corroborated by the comparison of
inhibition by 9 and 10 (ꢀ14-fold increase) showing that the orien-
tation of the aromatic part of the molecule is extremely important
in order to properly fit into the b-channel as it was also demon-
strated by X-ray crystallography.28
HO
HO
O
H
H
N
N
R
HO
OH
O
O
No H-bridge of the above type!
Based on these findings, we envisaged that a novel design prin-
ciple for efficient glucose-based inhibitors of GP can be set up
which unifies the properties of the best inhibitors (see generalized
formula B in Chart 1): (i) such molecules should have a rigid spiro-
R
Ki [μM]
305
4.6
7
8
CH3
phenyl
9
1-naphthyl
2-naphthyl
5
bicyclic scaffold in which
a
(preferably five-membered het-
-glucopyranose,
10
0.35
ero)cycle is attached to the anomeric carbon of b-
D
HO
(ii) this cycle, although it may, should not necessarily be a H-bond
donor towards His 377 and (iii) a suitably oriented, large aromatic
appendage must be present on this cycle to fit into the b-channel.
In this letter we present some glucopyranosylidene-spiro-oxa-
thiazoles as the first compounds which meet the above design
principle and one of them is the most efficient glucose analogue
inhibitor of GP known to date.
O
HO
Ar
HO
Het
HO
B
Synthetic goal: rigid bicyclic structure having a properly
oriented/substituted aromatic group with or without a H-bond donor
capacity towards His 377
The synthesis of glycopyranosylidene-spiro-oxathiazoles in a
minimum number of steps was previously reported.33,34 Besides
the known 14a,33 we synthesized substituted phenyl derivatives
14b and 14c as well as 2-naphthyl derivative 14d (Scheme 1).
Chart 1. Some glucose-based GP inhibitors (1–10) with their inhibition constants
(Ki against RMGPb); characteristic binding mode of some inhibitors (A); and general
structure of the spiro-bicyclic inhibitors (B).
AcO
AcO
AcO
AcO
AcO
AcO
RO
O
O
a
O
b
RO
SH
OAc
S
N
S
Ar
RO
AcO
RO
Ar
O
N
HO
c
11
12
13
(R = Ac)
14
(R = H)
Ar
Yield (%)
Yield (%)
9033
Ki* [μM]
a
b
9041
6541
4633
3033
26 2.1
79
79
94
28 2.8
F
c
d
71
78
8
0.9
69
36
H3CO
0.16 0.04
Scheme 1. Synthetic route to the glucopyranosylidene-spiro-oxathiazoles 14a–d. Reagents and conditions: (a) ArC(Cl)@NOH, Et3N, CH2Cl2, rt; (b) NBS, h
45 min; (c) NaOMe, MeOH, rt. *Inhibition constants (Ki) measured for 14 against RMGPb.
m, CCl4, reflux,

5682
L. Somsák et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5680–5683
16. Somsák, L.; Czifrák, K.; Tóth, M.; Bokor, É.; Chrysina, E. D.; Alexacou, K. M.;
Hayes, J. M.; Tiraidis, C.; Lazoura, E.; Leonidas, D. D.; Zographos, S. E.;
Oikonomakos, N. G. Curr. Med. Chem., in press.
Reaction of nitrile oxides, obtained in situ by base treatment of
hydroximoyl chlorides,35 with the readily available 2,3,4,6-tetra-
O-acetyl-1-thio-b-D
-glucopyranose36 (11) afforded the correspond-
17. Watson, K. A.; Mitchell, E. P.; Johnson, L. N.; Cruciani, G.; Son, J. C.; Bichard, C. J.
F.; Fleet, G. W. J.; Oikonomakos, N. G.; Kontou, M.; Zographos, S. E. Acta Cryst.
1995, D51, 458.
ing thiohydroximates 12a–d37 in good yields. The spiro-cyclization
under photochemical conditions afforded the acetylated
glucopyranosylidene-spiro-oxathiazoles 13a–d38 and subsequent
deacetylation under basic transesterification conditions provided
the O-unprotected target molecules 14a–d.39 The spiro-cyclization
process was stereoselective with the oxygen atom adopting
predominantly the axial position as previously demonstrated and
the main product was isolated by column chromatography.
The GP inhibitor candidates were evaluated for their inhibition
against RMGPb enzyme as previously described40 and the obtained
inhibitor constants (Ki) are shown in Scheme 1. The phenyl deriv-
ative 14a proved ꢀ5 times weaker inhibitor than the correspond-
ing acyl urea 8. Substitution of the phenyl ring in the 4-position
by a fluorine (14b) brought about no change probably due to the
similar size of the H and F atoms. Introduction of a methoxy group
into the same position (14c) made a ꢀ3 times better inhibitor than
14a suggesting that a bulky substituent on the phenyl ring can be
beneficial. Finally, the 2-naphthyl derivative (14d) inhibited the
enzyme ꢀ2 times stronger than 10. These preliminary results dem-
onstrate that the combination of a rigid spiro-bicyclic structure
with the introduction of a large hydrophobic aromatic moiety in
a proper orientation for an optimal interaction with the enzyme
significantly improves the biological activity of the molecules.
The 2-naphthyl substituted derivative 14d is the most potent
glucose-based inhibitor of GP to date with an inhibition in the
nanomolar range. Based on these preliminary results, we are now
synthesizing a more populated family of glucopyranosylidene-
spiro-oxathiazoles for their biological evaluation as GP inhibitors.
These molecules are expected to bind at the catalytic site of GP
and further enzymatic and crystallographic investigations will be
reported elsewhere.
}
18. Somsák, L.; Kovács, L.; Tóth, M.; Osz, E.; Szilágyi, L.; Györgydeák, Z.; Dinya, Z.;
Docsa, T.; Tóth, B.; Gergely, P. J. Med. Chem. 2001, 44, 2843.
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Lett. 1995, 36, 2145.
21. Anagnostou, E.; Kosmopoulou, M. N.; Chrysina, E. D.; Leonidas, D. D.; Hadjiloi,
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}
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Tóth, B.; Gergely, P. Bioorg. Med. Chem. 2002, 10, 261.
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28. Chrysina, E. D.; Nagy, V.; Felföldi, N.; Telepó, K.; Praly, J.-P.; Docsa, T.; Gergely,
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29. Hadady, Z.; Tóth, M.; Somsák, L. Arkivoc 2004, 140.
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33. Praly, J.-P.; Faure, R.; Joseph, B.; Kiss, L.; Rollin, P. Tetrahedron 1994, 50, 6559.
34. Elek, R.; Kiss, L.; Praly, J.-P.; Somsák, L. Carbohydr. Res. 2005, 340, 1397.
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Acknowledgments
37. Typical procedure I: 2,3,4,6-Tetra-O-acetyl-1-thio-b- -glucopyranose (11,
D
0.363 g, 1 mmol) dissolved in CH2Cl2 (5 mL) and Et3N (0.42 mL, 3 mmol)
were added under an Ar atmosphere with continuous stirring to a solution of a
hydroximoyl chloride (1.2 mmol) in Et2O or CH2Cl2 (5 mL). After immediate
precipitation of Et3NꢁHCl, the mixture was stirred further at rt. When TLC
indicated completion of the transformation (ꢀ1 h), 0.5 M H2SO4 (20 mL) was
added, and the organic phase was separated, washed by water (2ꢂ 20 mL), and
dried (MgSO4). After removal of the solvent under diminished pressure, the
residue was purified by crystallization or column chromatography to afford the
Financial support for this work was provided by the Hungarian
Scientific Research Fund (OTKA 46081, 61336). Collaboration be-
tween Lyon and Debrecen was facilitated by PICS Program NO.
4576 financed by CNRS (France) and the Hungarian Academy of
Sciences (Hungary). V.N. thanks the French Embassy in Budapest
for initiating and supporting a co-tutored PhD Thesis in Debrecen
and Lyon. For the preliminary enzyme kinetic measurements the
authors are indebted to T. Docsa and P. Gergely (University of Deb-
recen, Hungary).
desired acetylated hydroximothioates 12a–d. Characterization for 12d: Rf
25
= 0.25 (PE/EtOAc, 2:1); [
a
]
D
+4.5 (c 0.29, MeOH); mp = 154–156 °C; 1H NMR
(360 MHz, CDCl3) d 1.90, 1.95, 2.05, 2.07 (4s, 12H, 4ꢂ CH3), 2.96 (ddd, 1H, H-5),
3.92 (dd, 1H, J5,6’ = 2.6 Hz, H-6’), 4.05 (dd, 1H, J5,6 = 3.9 Hz, J6,6’ = 11.9 Hz, H-6),
4.55 (d, 1H, J1,2 = 9.2 Hz, H-1), 5.09, 5.04, 4.97 (3t, 3H, J = 9.2 Hz, H-2, H-3, H-4),
7.50–8.10 (m, 7H, H-ar), 10.07 (s, 1H, OH); 13C NMR (90 MHz, CDCl3) d 20.6,
20.5, 20.4, 20.3 (CH3), 61.4 (C-6), 75.4, 73.6, 69.8, 67.6 (C-2, C-3, C-4, C-5), 88.3
(C-1), 125.6, 126.8, 127.3, 127.7, 127.9, 128.3, 129.8, 132.6, 133.5 (aromatics),
151.9 (C@N), 170.6, 170.2, 169.2 (C@O); Anal. Calcd for C25H27NO10S (533.56):
C, 56.28; H, 5.10; N, 2.63; S, 6.01. Found: C, 56.41; H, 5.06; N, 2.44; S, 5.88.
38. Typical procedure II: A solution of hydroximothioate 12a–d (1 mmol) and N-
bromosuccinimide (2 mmol) in CCl4 (20 mL) was boiled and illuminated by a
60 W heat lamp for 45 min. The reaction was diluted with EtOAc (150 mL) and
the organic layer was washed with 5% aqueous Na2SO3 (2ꢂ 100 mL) and water
(2ꢂ 100 mL), dried (Na2SO4), filtered and evaporated under reduced pressure.
The residue was purified by flash column chromatography (PE then PE/EtOAc
References and notes
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Williams, D. A., Eds.; Springer: Baltimore, 1995; pp 581–600.
3. Moller, D. E. Nature 2001, 414, 821.
4. Zimmet, P.; Alberti, K. G. M. M.; Shaw, J. Nature 2001, 414, 782.
5. Staehr, P.; Hother-Nielsen, O.; Beck-Nielsen, H. Diabetes Obes. Metab. 2002, 4,
215.
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Souers, A. J.; Szczepankiewicz, B. G. Curr. Med. Chem. 2003, 10, 99.
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1177.
65:35) to afford the desired acetylated spiro-oxathiazoles 13a–d.
20
Characterization for 13d: Rf = 0.59 (PE/EtOAc, 3:2); [
a
]
D
+44 (c 1, CH2Cl2);
1H NMR (300 MHz, CDCl3) d 2.04, 2.06, 2.09 (3s, 12H, 4ꢂ CH3), 4.09 (dd, 1H,
J6,5 = 2.1 Hz, J6,6’ = 12.7 Hz, H-6), 4.35 (dd, 1H, J6’,5 = 3.7 Hz, J6’,6 = 12.7 Hz, H-6’),
4.45 (ddd, 1H, J5,6 = 2.1 Hz, J5,6’ = 3.7 Hz, J5,4 = 10.3 Hz, H-5), 5.28 (m, 1H, H-4),
5.66 (m, 2H, H-2 H-3), 7.51–7.62 (m, 2H, H-ar), 7.84–7.90 (m, 4H, H-ar), 8.01 (s,
1H, H-ar); 13C NMR (75 MHz, CDCl3) d 20.4, 20.6 (CH3), 61.1 (C-6), 67.5 (C-4),
68.0 (C-2 or C-3), 70.7 (C-5), 71.1 (C-2 or C-3), 122.4 (C-1), 123.5, 124.4, 127.1,
127.8, 128.0, 128.6, 128.8, 129.4, 132.7, 134.6 (aromatics), 156.5 (C@N), 169.4,
169.5, 169.7, 170.5 (C@O); MS (ESI) m/z = 531.7 [M+H]+, 554.0 [M+Na]+, 1062.6
[2M+H]+, 1084.7 [2M+Na]+; HRMS (ESI) m/z = C25H25NNaO10S [M+Na]+ Calcd
554.1097. Found 554.1097.
15. Somsák, L.; Nagy, V.; Hadady, Z.; Felföldi, N.; Docsa, T.; Gergely, P. In Frontiers in
Medicinal Chemistry; Reitz, A. B.; Kordik, C. P.; Choudhary, M. I.; Rahman, A. u.,
Eds.; Bentham, 2005; pp. 253–272.
39. Typical procedure III:
A solution of acetylated spiro-oxathiazoles 13a–d
(150 mg) and NaOMe (5 mg) in MeOH (15 mL) was stirred at rt for 3 h. The

L. Somsák et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5680–5683
5683
reaction was neutralized to pH 5–6 with Amberlite IR-120 resin (H+ form)
and the resin washed with MeOH (2ꢂ 10 mL). The solvent was evaporated
under reduced pressure to afford the desired hydroxylated spiro-
d 62.0 (C-6), 70.7, 72.7, 76.2, 77.5 (C-2 to C-5), 124.4, 126.8, 127.8, 128.2,
128.9, 129.6, 129.8, 129.9, 134.4, 136.0 (aromatics), 157.4 (C@N); MS
(ESI < 0) m/z = 397.9 [M+Cl]ꢃ; HRMS (ESI < 0) m/z = C17H17ClNO6S [M+Cl]ꢃ
Calcd 398.0465. Found 398.0467.
oxathiazoles 14a-d. Characterization for 14d: Rf = 0.34 (EtOAc/MeOH,
+53.2 (c 1, DMSO); mp = 177–179 °C; 1H NMR (300 MHz,
40. Osz, E.; Somsák, L.; Szilágyi, L.; Kovács, L.; Docsa, T.; Tóth, B.; Gergely, P. Bioorg.
20
}
85:15);
[a
]
D
CD3OD) d 3.54 (t, 1H, J = 9.4 Hz), 3.72–3.98 (m, 5H), 7.54–7.60 (m, 2H, H-ar),
Med. Chem. Lett. 1999, 9, 1385.
41. Brochard, L.; Joseph, B.; Viaud, M.-C.; Rollin, P. Synth. Commun. 1994, 24, 1403.
7.83–7.96 (m, 4H, H-ar), 8.06–8.08 (m, 1H, H-ar); 13C NMR (75 MHz, CD3OD)