4(5)-Aryl-2-C-glucopyranosyl-imidazoles as New Nanomolar Glucose Analogue Inhibitors of Glycogen Phosphorylase

Article abstract of DOI:10.1021/acsmedchemlett.5b00361

Inhibition of glycogen phosphorylases may lead to pharmacological treatments of diseases in which glycogen metabolism plays an important role: first of all in diabetes, but also in cardiovascular and tumorous disorders. C-(β-d-Glucopyranosyl) isoxazole, pyrazole, thiazole, and imidazole type compounds were synthesized, and the latter showed the strongest inhibition against rabbit muscle glycogen phosphorylase b. Most efficient was 2-(β-d-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole (11b, K_i = 31 nM) representing the best nanomolar glucose derived inhibitor of the enzyme.

Full text of DOI:10.1021/acsmedchemlett.5b00361

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Letter
4(5)-Aryl-2-C-glucopyranosyl-imidazoles As New Nanomolar
Glucose Analog Inhibitors of Glycogen Phosphorylase
Éva Bokor, Sándor Kun, Tibor Docsa, Pál Gergely, and László Somsák
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00361 • Publication Date (Web): 19 Oct 2015
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4(5)-Aryl-2-C-glucopyranosyl-imidazoles As New Nanomolar Glu-
cose Analog Inhibitors of Glycogen Phosphorylase
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Éva Bokor,a Sándor Kun,a Tibor Docsa,b Pál Gergely,b and László Somsáka∗
aDepartment of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary
bDepartment of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-
4032 Debrecen, Hungary
KEYWORDS. C-Glucopyranosyl derivative, isoxazole, pyrazole, thiazole, imidazole, glycogen phosphorylase, inhibitor.
ABSTRACT: Inhibition of glycogen phosphorylases may lead to pharmacological treatments of diseases in which glycogen
metabolism plays an important role: first of all in diabetes, but also in cardiovascular and tumorous disorders. C-(β-
Glucopyranosyl) isoxazole, pyrazole, thiazole, and imidazole type compounds were synthesized and the latter showed the
strongest inhibition against rabbit muscle glycogen phosphorylase b. Most efficient was 2-(β- -glucopyranosyl)-4(5)-(2-
naphthyl)-imidazole (11b, Ki = 31 nM) representing the best nanomolar glucose derived inhibitor of the enzyme.
D-
D
Glycogen phosphorylase inhibitors (GPIs) have poten-
tial for multifaceted biomedical applications. By far the
most intensively studied field is the use of GPIs in antidi-
abetic research due to the fact that glycogen phosphory-
lase (GP) in the liver is directly responsible for the regula-
tion of blood sugar levels.1 Since hepatic glucose output
was shown to be elevated especially in type 2 diabetes
mellitus GP became a validated target in combating this
disease.2-4 In addition, GPIs were shown to have potential
against cerebral5, 6 and cardiac7 ischemias, cardiovascular
disorders,7, 8 and tumors.9, 10
induced diabetic rats18 and, in addition, restored whole
body insulin sensitivity.19 Besides these effects TH and N-
(3,5-dimethyl-benzoyl)-N’-(β-D-glucopyranosyl) urea were
also shown to elicit unexpected metabolic changes, such
as enhanced mitochondrial oxidation and mTORC2
(mammalian target of rapamycin complex 2) signaling,
which need further explorations to be understood and
exploited.20
Among the first C-(β-D-glucopyranosyl) heterocycles
studied as GPIs21, 22 were benzothiazole 2 and benzimidaz-
ole 3 (Chart 1). The significant difference in the binding
strength of these compounds was ascribed to the H-bond
forming capacity of the NH moiety in 3 to the main chain
C=O of His377 next to the catalytic site of the protein as
revealed by X-ray crystallography of the RMGPb-3 com-
GPIs comprise a very broad array of compounds with
high structural diversity due to the peculiarities of several
binding clefts (the catalytic, allosteric and new allosteric,
inhibitor, glycogen storage, benzimidazole, and quercetin
sites) discovered so far.11, 12 Several nanomolar inhibitors
plex.22 Further studies with each isomer of C-glucosyl
23, 24
with various heterocyclic scaffolds, amply discussed in
oxadiazoles21,
4-6 indicated that the constitution of
11, 12
review articles,
bind to the allosteric or the new allo-
the heterocycle significantly influenced the inhibition.
The 1,2,4-triazoles 7, with the heteroatoms in the same
relative position as in the oxadiazoles, proved even
stronger inhibitors. Although no X-ray structure of the
corresponding enzyme-inhibitor complex has yet been
available, it may be assumed that formation of a H-bridge
from the triazole NH, similar to that of 3, contributes to
the binding. In each series of compounds 5-7 also the
aromatic part had an important impact on the efficiency:
the 2-naphthyl derivatives 5b-7b were better inhibitors
than the phenyl substituted counterparts 5a-7a. This
trend was also observed and discussed in other types of
glucose derived GPIs.13, 14
steric sites of GP. The most populated class of GPIs is
represented by glucose derivatives which bind primarily
to the catalytic site of the enzyme showing competitive
inhibition.13, 14 From the variety of the investigated glucose
analog GPIs glucopyranosylidene-spiro-heterocycles, N-
acyl-N’-β-D-glucopyranosyl ureas, and C-glucopyranosyl
heterocycles13, 14 (cf 1 in Chart 1), especially 1,2,4-triazoles,15,
16
emerged as submicromolar inhibitors against rabbit
muscle glycogen phosphorylase b (RMGPb) the prototype
of glycogen phosphorylases.17
Some of the glucose derived GPIs were also studied in
hepatic cellular systems and in vivo. Thus, glucopyra-
nosylidene-spiro-thiohydantoin (TH, Ki = 29.8 μM against
rat liver GP) was demonstrated to exert considerable
blood sugar diminishing activity in streptozotocin-
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Chart 1. Selected C-Glucosyl Heterocycles as Inhibi-
thiazole 10, and imidazole 11 type compounds have been
carried out and are disclosed here.
tors of Glycogen Phosphorylase and Their Efficiencya
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4
5
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8
9
Some 3-C-glycopyranosyl isoxazoles were reported in
the literature prepared by cycloadditions of C-glycosyl
nitrile-oxides with alkynes,25, 26 however, the required aryl
substituted ones remained unknown. No literature prece-
dents could be located for 3-C-glycopyranosyl pyrazoles,
although, a furanoid derivative was obtained from the
corresponding glycosyl alkynyl ketone and hydrazine.27 In
order to have a common intermediate for both planned
heterocycles the use of glucopyranosyl phenylethynyl
ketone 13 (Scheme 1) was envisaged.
1
Het
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Scheme 1. Synthesis of 3-(β-D-Glucopyranosyl)-5-
phenyl-isoxazole (8) and pyrazole (9)
2
3
22921
7622
1121
922
N N
O
N O
N
4a R = Ph
5a R = Ph
10 % at 625 μM24
5b R = 2-naphthyl
3824
10 % at 625 μM23
4b R = 2-naphthyl
10 % at 625 μM23
O N
N
HN N
N
6a R = Ph
6423
6b R = 2-naphthyl
1223,b
7a R = Ph
715, 16
7b R = 2-naphthyl
0.4115, 16
target compounds of this work
8
9
i) 1. 1 equiv PhC≡CSnBu3, 0.05 equiv Pd(PPh3)4 dry toluene,
Ar atm., 50 °C, 2. 1 equiv Et3N, rt; ii) 1 equiv PhC≡CSnBu3,
0.05 equiv Pd(PPh3)4, dry toluene, Ar atm., 50 °C; iii) 1 equiv
NH2OH⋅HCl, dry EtOH, reflux; iv) 1 equiv NH2NH2⋅AcOH,
dry pyridine, rt; v) ~1M NaOMe in MeOH, rt.
10
11
aKi [μM] against RMGPb.
Literature syntheses of glycopyranosyl alkynyl ketones
comprise In catalysed reactions of C-glycosyl aldehydes
with alkynyl iodides followed by oxidation,28 or methyla-
tion of 2-C-glycosyl benzothiazoles followed by alkynyla-
tion with the corresponding Grignard-reagent and subse-
quent hydrolysis.29 For the preparation of ynones in gen-
eral, several methods were proposed from acid chlorides
as starting materials. Under a variety of these conditions
the glucose derived acid chloride 1230 and metalated phe-
nylethyne derivatives gave no reaction (see Supporting
Information for details). In a Pd-catalyzed transfor-
mation31 of 12 with PhC≡CSnBu3 the expected ynone was
bA Ki value of 2.4 μM was measured independently by N.
G. Oikonomakos and co-workers cited as an unpublished
result in ref.23
Since the constitution of the heterorings had a strong
bearing on the inhibition of the oxadiazoles, we set out to
investigate C-glucopyranosyl heterocycles with two het-
eroatoms in 1,2- and 1,3-positions with and without H-
bond forming capabilities. Thus, the syntheses and en-
zyme kinetic tests of C-glucosyl isoxazole 8, pyrazole 9,
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with phenacyl bromide or 2-bromo-acetonaphthone in
formed, however, during usual silica gel column chroma-
1
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3
4
5
6
7
8
tography only the elimination product 14 could be isolat-
ed in 31 % yield. By using flash chromatography 13 could
aqueous THF in the presence of K2CO3 as an acid scaven-
ger (Scheme 3). The respective imidazoles 21a and 21b
were obtained in moderate yields due to the formation of
N-benzoyl-amidine 20 as a result of benzoyl group migra-
tion under the alkaline conditions. This compound was
obtained in good yield under the same conditions in the
absence of an α-haloketone. Any attempt to increase the
yield of the imidazoles by using non-aqueous solvents
(THF, 1,4-dioxane, MeCN, CHCl3, DMF, acetone, MeOH)
or different bases (KHCO3, NaHCO3, NaOAc, Et3N, pyri-
dine) failed. Deprotection was effected by the Zemplén
protocol to give the test compounds 11a and 11b in very
good yields.
be obtained in 61
% yield. Reaction of 12 with
PhC≡CSnBu3 and subsequent treatment by Et3N in a one-
pot manner yielded 14 in higher yield (63 %). Reactions of
13 with H2NOH and H2NNH2 gave the expected isoxazole
15 and pyrazole 16, from which the protecting groups
were removed by Zemplén transesterification to give the
test compounds 8 and 9, respectively. The constitution of
8 was proven by mass spectrometry:32, 33 the appearance of
a m/z = 105 peak for [PhCO]+ indicated the depicted
structure for this compound (see Supporting Information
for the mass spectrum and fragmentation patterns).
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Scheme
3.
Synthesis
of
4(5)-Aryl-2-(β-D-
Scheme 2. Synthesis of 4-Aryl-2-(β-
thiazoles (10)
D-glucopyranosyl)-
glucopyranosyl)-imidazoles (11)
i) 1 equiv ArCOCH2Br, dry DMF, 100 °C; ii) ~1M NaOMe in
MeOH, rt.
i) 1 equiv K2CO3, THF-H2O 8 : 1, rt; ii) 1 equiv ArCOCH2Br, 1
equiv K2CO3, THF-H2O 8 : 1, rt;; iii) ~1M NaOMe in MeOH,
rt.
For the synthesis of 2-C-glycopyranosyl thiazoles, the
addition of 2-metalated-thiazoles to glyconolactones,34
cyclocondensation of anhydro-aldononitriles with cyste-
ine derivatives followed by oxidation,35 and the reaction of
anhydro-aldonothioamides with α-haloketones36 are the
most frequently used procedures. According to the latter
method, C-glucopyranosyl thioformamide37 17 (Scheme 2)
was reacted with phenacyl bromide or 2-bromo-
acetonaphthone to give high yields of the protected 2-β-
The C-glucopyranosyl heterocycles were assayed against
RMGPb as described earlier39 and the kinetic results,
indicating that the compounds are competitive inhibitors,
are summarized in Table 1 together with data for the best
1,2,4-oxadiazoles 6 and 1,2,4-triazoles 7. Phenyl isoxazole
8 showed no significant binding, but the pyrazole coun-
terpart 9 had weak inhibition. This might indicate that
the H-bond donor nature of the latter heterocycle con-
tributed to the binding. The inhibition by phenyl thiazole
10a was stronger than that of the pyrazole 9 suggesting
that the 1,3-position of the heteroatoms was more favora-
ble than the 1,2-arrangement. Phenyl imidazole 11a bound
considerably stronger (by a factor of ~1100) than thiazole
10a, and this again might be attributed to the H-bond
forming capacity of the former. The 2-naphthyl substitut-
ed compounds 10b and 11b proved better inhibitors than
the phenyl substituted ones 10a and 11a, respectively, in
accordance with previous observations13, 14 regarding the
D-glucopyranosyl thiazoles 18a and 18b, whose deprotec-
tion by the Zemplén method furnished the test com-
pounds 10a and 10b, respectively.
2-C-Glycopyranosyl imidazoles appear in a sole publica-
tion in the literature: reaction of lithiated imidazole with
O-perbenzylated
moval of the hemiacetalic OH and the protecting groups
gave 2-β-
-glucopyranosyl imidazole.38 To get 4(5)-aryl-2-
C-glucopyranosyl imidazoles, amidine 1930 was reacted
D-glucono-1,5-lactone followed by re-
D
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nature of the aromatic substituent of the heterocycles (cf
the pairs 6a and 6b, 7a and 7b). The 2-(β-
thiazole, and imidazole were synthesized. The com-
1
2
3
4
5
6
7
8
D-
pounds were tested for their inhibition of rabbit muscle
glycogen phosphorylase b and the 4(5)-(2-naphthyl)-
imidazole derivative proved the best glucose derived in-
hibitor known to date,41 regarding the very low nanomolar
Ki value.
glucopyranosyl)-4(5)-(2-naphthyl)-imidazole (11b), being
~5000-fold more efficient than its thiazole counterpart
10b, is the presently known most efficient glucose derived
inhibitor of RMGPb. Further investigations to clear up the
binding modes and detailed molecular interactions of the
new inhibitors and especially the comparison of imidaz-
oles to 1,2,4-triazoles by X-ray crystallography and com-
putational methods are in progress and will be published
in due course.
Supporting Information. Synthetic procedures, compound
characterization, and enzyme kinetic measurements. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Corresponding Author
Table 1. Inhibition (Ki [µM]) of RMGPb by C-
Glucopyranosyl Heterocycles
* L. Somsák – Tel.: +3652512900 ext. 22348, fax: +3652512744,
e-mail: somsak@tigris.unideb.hu.
ACKNOWLEDGMENT
R
This work was supported by the Hungarian Scientific Re-
search Fund (OTKA CK77712, PD105808). TD thanks the
Hungarian Academy of Sciences for a János Bolyai research
fellowship. A. Kiss and L. Nagy are thanked for running the
mass spectrometric measurements.
Het
b
a
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