3-Glucosylated 5-amino-1,2,4-oxadiazoles: Synthesis and evaluation as glycogen phosphorylase inhibitors

Article abstract of DOI:10.3762/bjoc.11.56

Glycogen phosporylase (GP) is a promising target for the control of glycaemia. The design of inhibitors binding at the catalytic site has been accomplished through various families of glucose-based derivatives such as oxadiazoles. Further elaboration of t

Full text of DOI:10.3762/bjoc.11.56

3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and
evaluation as glycogen phosphorylase inhibitors
Marion Donnier-Maréchal1, David Goyard1, Vincent Folliard1, Tibor Docsa2, Pal Gergely2,
Jean-Pierre Praly1 and Sébastien Vidal*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 499–503.
1Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
(UMR 5246), Laboratoire de Chimie Organique 2, Université Claude
Bernard Lyon 1 and CNRS; 43 Boulevard du 11 Novembre 1918,
F-69622, Villeurbanne, France and 2Department of Medical
Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér
1, H-4032 Debrecen, Hungary
doi:10.3762/bjoc.11.56
Received: 26 February 2015
Accepted: 31 March 2015
Published: 17 April 2015
Associate Editor: T. P. Yoon
Email:
Sébastien Vidal* - sebastien.vidal@univ-lyon1.fr
© 2015 Donnier-Maréchal et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
amidoxime; carbodiimide; glycogen phosphorylase; oxadiazole;
Vilsmeier salt
Abstract
Glycogen phosporylase (GP) is a promising target for the control of glycaemia. The design of inhibitors binding at the catalytic site
has been accomplished through various families of glucose-based derivatives such as oxadiazoles. Further elaboration of the
oxadiazole aromatic aglycon moiety is now reported with 3-glucosyl-5-amino-1,2,4-oxadiazoles synthesized by condensation of a
C-glucosyl amidoxime with N,N’-dialkylcarbodiimides or Vilsmeier salts. The 5-amino group introduced on the oxadiazole scaf-
fold was expected to provide better inhibition of GP through potential additional interactions with the enzyme’s catalytic site;
however, no inhibition was observed at 625 µM.
Introduction
Glycogen phosphorylase (GP) is a homodimeric enzyme that is molar to even sub-micromolar Ki values against GP (Figure 1)
responsible for the depolymerization of glycogen into glucose- [9-13]. Benzo-fused aglycons [14,15] (A–C) were initially iden-
1-phosphate, which is further converted into glucose delivered tified as beneficial for the inhibition of GP. 1,2,3-Triazolyl-
into the blood stream [1,2]. The control of GP activity could based aglycon D [16,17] proved valuable for the inhibition of
find application in the treatment of hyperglycemia for type 2 GP and further design around the triazole moiety was also
diabetes patients [3-7]. Seven binding sites have been identified reported [18,19]. The isomeric 1,2,4-triazole E was recently
for GP and the design of various classes of inhibitors has identified as a sub-micromolar GP inhibitor [20,21] and high-
attracted much attention [8-12]. C-Glycosylated heterocycles lights the influence of the aromatic moiety used in these studies.
have been designed and synthesized and displayed low micro- The influence of the heterocyclic moiety was also clearly
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Beilstein J. Org. Chem. 2015, 11, 499–503.
Figure 1: Structures of the glycosylated heterocyclic GP inhibitors and corresponding Ki values against RMGPb.
demonstrated in a structure–activity relationship study with could provide better ligands for this enzyme through additional
several isomeric oxadiazoles. The regioisomeric substitution interactions with the β-channel amino acid residues (Figure 2).
around the 1,2,4-oxadiazoles (F [22,23] vs G [23,24]) plays a Nevertheless, introduction of a tetrahedral atom in the aglycon
role in the inhibition observed with the glucosyl group at the usually weakens the inhibitory properties [8-12]. The introduc-
5-position of the 1,2,4-oxadiazole ring being preferred. Isomeric tion of an amino functionality between the 1,3,4-oxadiazole
1,3,4-oxadiazole H [25] was practically inactive against GP in core and glucose [26] (I) or aromatic [27] (J) groups was
comparison to its 1,2,4-oxadiazole congeners (F and G). Never- recently investigated (Figure 1). The present study reports on
theless, inhibition could be restored by introducing a nitrogen the introduction of such amino groups between the oxadiazole
atom (NH) between the glucosyl and aromatic aglycon (I [26]), and aromatic cores. Two synthetic strategies were used to
while introduction on the other position (J [27]) did not help.
obtain such scaffolds based on recent and unprecedented litera-
ture reports.
The structure–activity relationship of 5-aryl-1,2,4-oxadiazoles F
and G towards GP inhibition highlighted a set of interactions of
the aryl moieties with the enzyme’s β-channel [22-24]. The
amino acids present in this empty pocket are of mixed char-
acter and can accommodate hydrophobic groups such as aryl
moieties, with 2-naphthyl identified as the best pharmacophore
for the series discussed above (Figure 1, D–I). Nevertheless,
hydrogen bonds might also be created in this secondary binding
site with other residues. The introduction of hydrogen bond
donors and/or acceptors at the 5-position of the oxadiazole
Results and Discussion
Synthesis of 3-glucosylated 5-amino-1,2,4-
oxadiazoles
The target GP inhibitor scaffold was obtained from the conden-
sation of Vilsmeier salts with the C-glucosyl-amidoxime 3 [28]
in the presence of a base. This condensation was very recently
reported in the context of heterocyclic chemistry [29] and we
have applied it with success to our GP inhibitor design. The di-
methylamino group (Scheme 1, a) was chosen as a small phar-
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Beilstein J. Org. Chem. 2015, 11, 499–503.
Figure 2: Structures of the two targeted 3-glucosyl-5-amino-1,2,4-oxadiazoles.
macophore that can be readily accommodated in the GP’s
catalytic site. Aromatic moieties were also selected (Scheme 1,
b and c) for their expected hydrophobic contact with the
enzyme. The tetrahydroisoquinoline moiety (Scheme 1, c) was
particularly interesting due to its structural analogy with the
2-naphthyl residue, which is identified as the best pharma-
cophore in the GP inhibitor series. The morpholinyl (Scheme 1,
d) and piperidinyl (Scheme 1, e) residues were also selected as
candidates for their hydrophobic properties, although they are
bulkier than aromatic rings.
The synthesis started with commercially available ureas (2a and
2e) or through the synthesis of such ureas. While the synthesis
from carbonyl diimidazole was not successful [30], and since
phosgene was not considered due to its hazardous reaction
conditions, ureas 2b–d could be readily prepared from triphos-
gene 1 (as a phosgene precursor) and the corresponding amines
(Scheme 1). While treatment of triphosgene with the corre-
sponding amine at room temperature in dichloromethane [31]
was sufficient for ureas 2a,c–e, heating (40 °C) and the add-
ition of triethylamine [32] were required for condensation with
N-methylbenzylamine to obtain urea 2b. The Vilsmeier salt was
then generated in situ with oxalyl chloride from the corre-
sponding ureas and condensation with C-glucosyl-amidoxime 3
afforded the desired 3-glucosylated 5-amino-1,2,4-oxadiazoles
4a–e in moderate yields. Even though these results are modest,
they are in agreement with the yields reported in the literature
[29] for such condensations. Removal of the benzoate esters
provided the desired GP inhibitor candidates 5a–e.
The syntheses of 3-glucosyl-5-alkylamino-1,2,4-oxadiazoles
7a,b were readily achieved by condensation of the C-glucosyl
amidoxime 3 [28] with N,N’-dialkylcarbodiimides under
refluxing toluene (Scheme 1) [33-35]. To this end, conden-
Scheme 1: Synthesis of 3-glucosyl-5-amino-1,2,4-oxadiazoles.
sation of amidoxime 3 [28] with commercially available although the starting material was consumed. The mechanism
carbodiimides (R = iPr, C6H11, tolyl) provided the desired proposed by Ispikoudi et al. [33] proposes the amine moiety as
5-alkylaminooxadiazoles 6a,b in quantitative yields and depro- a leaving group during this process. Anilines (R = tolyl) are
tection of the glucopyranose ring under Zemplén conditions worse leaving groups than alkylamines (R = iPr, C6H11), thus
afforded the O-unprotected GP inhibitor candidates 7a,b. No providing a likely explanation regarding the non-reactivity
reaction was observed with the N,N’-ditolylcarbodiimide, observed for this substrate.
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Beilstein J. Org. Chem. 2015, 11, 499–503.
Enzymatic inhibition studies (RMGPb)
are gratefully acknowledged for mass spectrometry analyses.
The seven 3-glucosyl-5-amino-1,2,4-oxadiazoles 5a–e and 7a,b Tibor Docsa is a recipient of the Bolyai Fellowship from the
were evaluated as GP inhibitors using rabbit muscle glycogen Hungarian Academy of Sciences.
phosphorylase b (RMGPb) as the model enzyme (see
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