Synthesis of N-(β-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy- β-D-glucopyranosyl) amides as inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1016/j.bmc.2004.07.013

2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl- and 2-acetamido-3,4,6-tri- O-acetyl-2-deoxy-β-D-glucopyranosyl azides were transformed into the corresponding per-O-acetylated N-(β-D-glycopyranosyl) amides via a PMe ₃ mediated Staudinger protocol (ge

Full text of DOI:10.1016/j.bmc.2004.07.013

Bioorganic & Medicinal Chemistry 12 (2004) 4861–4870
Synthesis of N-(b-D-glucopyranosyl)- and
N-(2-acetamido-2-deoxy-b-D-glucopyranosyl) amides
as inhibitors of glycogen phosphorylase
a,
Zoltan Gyorgydeak, Zsuzsa Hadady, Nora Felfoldi, Attila Krakomperger,
a
a
a
*
´
´
´
Veronika Nagy, Marietta Toth, Attila Brunyanszki, Tibor Docsa,
¨
¨
a
a
b
c
´
´
Pal Gergely and Laszlo Somsak
b
a,
*
´
´
´
´
aDepartment of Organic Chemistry, Faculty of Science, PO Box 20, H-4010 Debrecen, Hungary
b
´
Department of Medical Chemistry, Medical and Health Science Centre, Bem ter 18/b, H-4026 Debrecen, Hungary
cSignalling and Apoptosis Research Group of the Hungarian, Academy of Sciences, Research Center for Molecular Medicine,
University of Debrecen, Hungary
Received 30 March 2004; accepted 6 July 2004
Available online 31 July 2004
Abstract—2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl- and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl azides were
transformed into the corresponding per-O-acetylated N-(b-D-glycopyranosyl) amides via a PMe3 mediated Staudinger protocol
(generation of N-(b-D-glycopyranosyl)imino-trimethylphosphoranes followed by acylation with carboxylic acids, acid chlorides
´
or anhydrides). The deprotected compounds obtained by Zemplen deacetylation were evaluated as inhibitors of rabbit muscle gly-
cogen phosphorylase b. The best inhibitor of this series has been N-(b-D-glucopyranosyl) 3-(2-naphthyl)-propenoic amide
(Ki =3.5lM).
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
into glycosyl donors thereby rendering this functionality
to be a protecting group at the anomeric centre.15
N-Glycosyl amides represent a long known class of car-
bohydrate derivatives readily available by acylation of
glycosylamines1 or more advantageously from glycosyl
azides and carboxylic acids or their activated derivatives
via an N-glycosyl iminophosphorane intermediate
(Staudinger reaction).2 Contradictory results can be
found in the literature for the preparation of 2-acetam-
ido-2-deoxy-D-glucopyranosyl derivatives by the latter
procedure.3–5 Other methods of preparation have been
surveyed and critically evaluated recently.2 Nowadays
growing interest in constructing N-glycopyranosyl
amides is fuelled by the recognition of the importance
of glycoproteins in which one sort of the linkages be-
tween sugar and peptide is of glycosylamide type.6–14
Very recently N-glycosyl amides have been converted
Some N-(b-D-glucopyranosyl) amides (e.g., A–C) were
investigated as inhibitors of glycogen phosphorylase
(GP) enzymes during the pioneering studies by Fleet,
OH
O
HO
NH
R
HO
HO
O
A R = CH3
Ki = 32 µM
B R = C6H5 Ki = 81 µM
C R = NH2
Ki = 140 µM
OH
O
HO
HO
NH
NH
R
HO
O
O
D R = CH3
Ki = 370 µM
E R = C6H5 Ki = 4.6 µM
Keywords: N-Glycosylamides; Inhibitors; Glycogen phosphorylase.
*
F R = C10H7
Ki = 0.4 µM
(2-naphthyl)
Corresponding authors. Tel.: +36-525129002348; fax: +36-
52453836; e-mail: somsak@tigris.klte.hu
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.013

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Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4862
Johnson and Oikonomakos exploring glucose analogue
inhibitors of GP.16 Besides the academic aspects of this
research inhibition of liver GP is one of several inten-
sively investigated approaches to find novel treatments
for type 2 diabetes mellitus.17–24
(PPh3, P(n-Bu)3, PEt3) was investigated in detail by sev-
eral groups.3,4,26,27 Even the latest works demonstrate
that the most widely applied PPh3 results in variably
moderate yields disregarding difficulties of work-up
and purification due to the formation of P(@O)Ph3.28
Recently we have introduced the use of PMe3 offering
advantages over the above mentioned reagents:2 (a)
enhanced nucleophilicity of the iminophosphorane
due to the small size of this phosphane allows the use
of carboxylic acids as acylation agents; (b) volatility
of P(@O)Me3 ensures simplified work-up and separa-
tion of the target compound. Following this methodol-
ogy and starting with per-O-acetylated b-D-gluco-
pyranosyl azide (1) a variety of carboxylic acids (or in
some cases derivatives) were used as acylating agents
to give N-(b-D-glucopyranosyl) amides with diverse
alkyl, aralkyl, aralkenyl and aralkynyl moieties (3a–
16a, Table 1).
Lately we have found that N-(b-D-glucopyranosyl)-N0-
acyl urea derivatives D and E are also inhibitors of
GP,25 and F represents the most efficient glucose ana-
logue inhibitor known to date.24 A unique property
for E and F is that they can also bind to the so-called
new allosteric site of GP besides the catalytic centre,25
which has been known to be the sole specific binding site
for glucose analogues.
Based on these preliminaries we set out to prepare novel
glucopyranosylamides to compare their effects on GP to
those of acyl ureas having the same R group. Further-
more, in order to divert the potential inhibitors from
the highly glucose specific catalytic site, 2-acetamido-2-
deoxy-D-glucopyranosyl amides were also designed. In
this paper we report on the synthesis of these glycosyl-
amides by a modified Staudinger protocol, and enzyme
assays of the deprotected derivatives.
Contrary to the reported failure with PPh3 and P(n-
5
Bu)3 the PMe3-mediated Staudinger protocol per-
formed well with the per-O-acetylated 2-acetamido-2-
deoxy-b-D-glucopyranosyl azide (2) as well, and gave
the corresponding amides 17a–23a in acceptable to good
yields (Table 1). It is noteworthy that reaction times
were generally longer with 2 as compared to 1. In order
to demonstrate the potential of the method more com-
plex carboxylic acids were also shown to produce glu-
copyranosyl amides 24a and 25a. Amide 25a was
prepared earlier by various acylations of the corre-
sponding glycosylamine obtained by reduction of azide
2.29–31
2. Results and discussion
2.1. Synthesis
Acylation of N-glycosyl iminophosphoranes obtained
from protected glycosyl azides by various phosphanes
Table 1. Synthesis of N-(b-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy-b-D-glucopyranosyl) amides and inhibition data with RMGPba
OAc
O
OR''
O
AcO
AcO
R''O
R''O
N3
1. Me3P, PhCH3, CH2Cl2,
2. RCOX
NHCOR
R'
R'
1 R' = OAc
A-F
2 R' = NHAc
3a-16a R' = OAc, R'' = Ac
NaOMe/MeOH
NaOMe/MeOH
4b, 5b, 7b-16b R' = OH, R'' = H
17a-25a R' = NHAc, R'' = Ac
19b, 21b, 22b R' = NHAc, R'' = H
Entry
1
Starting material
R
X
Product (yield [%])
Ki (lM)
IC50 (mM)
CH3
A
3216
3132
2
C6H5
NH2
B
8116
14432
14016
37025
4.625
0.424
3
4
5
6
C
D
E
F
NHCOCH3
NHCOC6H5
NHCOC10H7
(2-naphthyl)
7
8
1
1
n-C5H11
(CH3)3C
OH
Cl
3a (70)
4a (72)
4b (96)
5a (67)
5b (88)
6a (25)
7ab (88)
7b (83)
7.5
1.1
9
1
c-C6H11
OH
289
10
11
1
1
C10H15 (1-adamantyl)
C6H5CH2
OH
OH

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Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4863
Table 1 (continued)
Entry
12
Starting material
R
X
Product (yield [%])
Ki (lM)
IC50 (mM)
1
1
1
1
1
1
1
1
1
(C6H5)2CH
OH
8a (21)
8b (17)
No inhibition up to 0.7mM
13
14
15
16
17
18
19
20
C6H5CH2CH2
C6H5CH@CH
C6H5C„C
OH
OH
OH
OH
OH
OH
Cl
9a (64)
9b (99)
85
18
61
10a (80)
10b (87)
11a (82)
11b (98)
12a (37)
12b (48)
13a (55)
13b (85)
14a (52)
14b (75)
15a (62)
15bc (92)
16a (71)
16b (93)
4-CH3–C6H4
4-C6H5–C6H4
4.5
281
C
10H7
(1-naphthyl)
10H7
444
10
C
(2-naphthyl)
C10H7CH@CH
(2-naphthyl)
OH
3.5
21
2
CH3
OH
17ad (69)
(68)
OCOCH3
OCOCF3
Cl
22
23
2
2
CF3
n-C11H23
18a (77)
19ae (91)
19b (87)
20af (43)
21a (67)
21b (78)
22a (54)
22b (88)
23a (45)
g
g
24
25
2
2
C6H5
3,4,5-(CH3O)3–C6H2
OH
Cl
g
g
g
g
26
27
2
2
C10H7
(2-naphthyl)
4-Cl–C6H4–O–CH2
Cl
OH
CH3
28
29
2
2
OH
OH
24a (73)
25a (69)
H
BocNH
BnO2C
CH2
NHBoc
a Rabbit muscle glycogen phosphorylase b.
b This compound was obtained as a minor product (yield ꢀ10%) together with its anomer from the reaction of 1 with PPh3 and 2-thiopyridyl
phenylacetate.33
c Performed with KCN in MeOH.
d Prepared earlier from the corresponding glycosylamine by acetic anhydride in pyridine.34–37
e Prepared earlier from the corresponding glycosylamine by dodecanoic anhydride in pyridine.35
f Prepared earlier from the corresponding glycosylamine by benzoic anhydride in pyridine35 or MeOH.34
g Because of poor solubility of the compound the value could not be determined.
´
Deprotections were performed by the Zemplen method
phenyl moiety as in 10b and 11b (entries 14 and 15)
makes better inhibitors. The size and the orientation
of the aromatic group of the amides are further decisive
factors illustrated by 14b and 15b (entries 18 and 19).
Putting together the last two structural features in 16b
results in the best inhibitor of this series (entry 20).
Comparing benzoyl- (E) and 2-naphthoyl ureas (F) with
amides 9b, 10b and 16b (entries 5, 6, 13, 14 and 20),
respectively, reveals that the presence of the acyl urea
motif is essential for the strong binding. The deprotected
N-(2-acetamido-2-deoxy-b-D-glucopyranosyl)amide deri-
vatives 19b, 21b and 22b (entries 23, 25 and 26), proved
poorly soluble to such an extent that the intended diver-
sion of the inhibitors from the catalytic site could not be
proven. X-ray crystallographic investigation of com-
plexes of RMGPb with several inhibitors of this series
is in progress.
or KCN in MeOH to give compounds 4b, 5b, 7b–16b,
19b, 21b and 22b (Table 1).
2.2. Evaluation of the inhibitors
A comparison of inhibitors A, 4b and 5b (entries 1, 8
and 9) shows that an increase in the size of the aliphatic
substituent makes the inhibition significantly weaker.
Saturation of the aromatic ring of B (compare entries
2 and 9) as well as the presence of substituents in the
4-position of the phenyl ring (12b and 13b in entries
16 and 17) also weakens the inhibition. The distance
of the phenyl ring from the anomeric carbon (compare
B, 7b and 9b in entries 2, 11 and 13) seems very impor-
tant. Restriction of the conformational mobility of the

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4864
´
4.3. General procedure II for the Zemplen-deacetylation
to give compounds 4b, 5b, 7b–14b, 16b, 19b, 21b and 22b
3. Conclusion
The PMe3 mediated Staudinger reaction of glycopyrano-
syl azides and carboxylic acids in the per-O-acetylated
b-D-gluco and 2-acetamido-2-deoxy-b-D-gluco series
proved to be a simple and efficient method for the prep-
aration of a variety of the corresponding N-glycopyrano-
syl amides. Removal of the protecting groups carried
To a solution of an acetyl protected compound in dry
MeOH 1–2 drops of a ꢀ1M methanolic NaOMe solu-
tion were added, and the reaction mixture was kept at
rt until completion of the transformation (TLC). Am-
berlyst 15 (H+ form) was then added to remove sodium
ions, the resin was filtered off, and the solvent removed
in vacuo. If the residue was chromatographically not
uniform it was purified by column chromatography.
For NMR data see Tables 2–5.
´
out by the Zemplen-protocol furnished inhibitors of
glycogen phosphorylase (GP). These compounds
were tested against rabbit muscle GP and the best
inhibitor constants (Ki) were in the micromolar range.
It was shown that a properly positioned and large
enough hydrophobic group attached to the amide
moiety (as in N-(b-D-glucopyranosyl) 3-(2-naphthyl)-
propenoic amide 16b, Ki =3.5lM) makes the inhibition
one order of magnitude stronger than that of the best
amide inhibitor known earlier (N-(b-D-glucopyranosyl)
acetamide A, Ki =32lM). On the other hand, this
compound is still much less efficient than the best
kown inhibitor of GP (N-(b-D-glucopyranosyl)-N0-(2-
naphthoyl) urea F, Ki =0.4lM). It can be concluded
that the acyl urea moiety is essential for the strong
inhibition.
4.4. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
hexanoic amide (3a)
Prepared by general procedure I: r. time 17h, eluent:
EtOAc–hexane 1:1, 70%, white crystals from diethyl-
ether–hexane, mp 84–86ꢁC; [a]D +18 (c 0.19, CHCl3).
4.5. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
2,2-dimethylpropanoic amide (4a)
Prepared by general procedure I: r. time 4d, eluent:
EtOAc–hexane 1:1, 72%, white crystals, mp 165–
167ꢁC; [a]D +22 (c 0.20, CHCl3).
4. Experimental
4.6. N-(b-D-Glucopyranosyl) 2,2-dimethylpropanoic
amide (4b)
4.1. General methods
Melting points were measured in open capillary tubes
or on a Kofler hot-stage and are uncorrected. Optical
rotations were determined with a Perkin–Elmer 241
polarimeter at room temperature. NMR spectra were
recorded with Bruker WP 200 SY (200/50MHz for
1H/13C) or Avance DRX 500 (500/125MHz for
1H/13C) spectrometers. Chemical shifts are referenced
to Me4Si (1H), or to the residual solvent signals
(13C). TLC was performed on DC-Alurolle Kieselgel
60 F254 (Merck), and the plates were visualized by
gentle heating. For column chromatography Kieselgel
60 (Merck, particle size 0.063–0.200mm) was used.
Organic solutions were dried over anhydrous MgSO4
and concentrated in vacuo at 40–50ꢁC (water bath).
The compounds were analyzed for C, H and N. The
found percentages were within 0.4% of the theoretical
values.
Prepared by general procedure II: r. time 2h, 96%,
syrup; [a]D +4 (c 0.25, MeOH).
4.7. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
cyclohexanecarboxamide (5a)
Prepared by general procedure I: r. time 20h, eluent: Et-
OAc–hexane 1:1, 67%, white crystals, mp 178–181ꢁC;
[a]D +15 (c 0.19, CHCl3).
4.8. N-(b-D-Glucopyranosyl) cyclohexanecarboxamide
(5b)
Prepared by general procedure II: r. time 20h,
88%, white crystals, mp 206–208ꢁC; [a]D ꢁ5 (c 0.18,
MeOH).
4.2. General procedure I for the preparation of N-(2,3,4,6-
tetra-O-acetyl-b-D-glucopyranosyl)- (3a–16a) and N-(2-
acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyrano-
syl) amides (17a–25a) from the corresponding azide
4.9. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
adamantane-1-carboxamide (6a)
Prepared by general procedure I: r. time 1d, eluent:
EtOAc–hexane 1:1, 25%, white crystals, mp > 350ꢁC;
[a]D +12 (c 0.16, CHCl3).
An azide (1mmol of 138 or 239) was dissolved in dry
CH2Cl2 (7mL) and PMe3 (1.04mL of a 1M toluene solu-
tion) was added. After cessation of the nitrogen evolution
(ꢀ10min) a carboxylic acid or its derivative (1mmol, see
Table 1) was added and the mixture stirred at rt for the
time indicated with the particular compounds. The vola-
tiles were removed in vacuo, and the residue was crystal-
lized or purified by column chromatography to give the
target amide. For NMR data see Tables 2–5.
4.10. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
phenylacetamide (7a)
Prepared by general procedure I: r. time 17h, eluent:
EtOAc–hexane 1:1, 88%, white crystals, mp 129–
132ꢁC (lit.33 mp 158–159ꢁC); [a]Dꢁ5 (c 0.17, CHCl3).

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Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4865
Table 2. 1H NMR data for N-(b-D-glucopyranosyl) amides 3–16 (d [ppm], J [Hz])
Compound
Solvent
H-1
(J1,2
H-2
(J2,3
H-3
(J3,4
H-4
(J4,5
H-5
(J5,6
H-6
(J6,6
H-60
NH
(J1,NH)
OAca
or OHb
Aliphatic
Aromatic
0
0
)
)
)
)
)
)
)
(J5,6
3a
CDCl3
4a
5.32, 5.30, 5.07, 4.93
4 pseudo t, Jꢀ9.5Hz in each
5.33, 5.24, 5.08, 4.95
3.83
4.32
4.08
(2.1)
4.07
(2.1)
6.48
(9.1)
6.44
(9.5)
7.72
(8.8)
6.25
(9.5)
8.16
(8.2)
6.39
(9.1)
2.09, 2.05,
2.04, 2.03
2.09, 2.04,
2.03, 2.02
4.97, 4.89,
4.76, 4.51
2.08, 2.04,
2.03, 2.02
5.0–4.6,
2.4–2.0,
1.7–0.8
1.17
––
––
––
––
––
––
(4.1)
3.82
(4.2)
(12.8)
4.34
(12.6)
CDCl3
4b
4 pseudo t, Jꢀ9.5Hz in each
4.73
(8.8)
3.7–3.6, 3.3–3.0 (m)
1.11
DMSO-d6
5a
5.32, 5.27, 5.07, 4.93
3.82
(4.1)
4.32
(12.4)
3.64
4.07
(2.1)
3.41
1.9–1.1
2.2–1.1
CDCl3
5b
4 pseudo t, Jꢀ9.5Hz in each
4.66
(9.1)
3.2–2.9 (m)
DMSO-d6
6a
CDCl3
(12.1, 1.5) (4.1)
3.7–3.3
2.09, 1.92,
1.80
5.32, 5.26, 5.08, 4.95
4 pseudo t, Jꢀ9.8Hz in each
3.82
(4.1)
4.33
(12.4)
4.07
(2.1)
2.08–2.00
(+1 OAc)
1.78–1.62
3.58, 3.49
(J=15.3)
3.39
7a
CDCl3
7b
5.26, 5.23, 5.03, 4.85
3.82
(4.5)
4.30
(12.4)
4.07
(2.1)
6.56
(9.4)
8.62
(8.8)
6.44
(9.3)
8.46
(8.6)
6.33
(8.8)
––
2.07, 2.02,
1.98, 1.84
5.01, 4.91,
4.90, 4.51
2.07, 2.02,
1.99, 1.77
4.98, 4.87,
4.74, 4.50
2.08, 2.03,
2.01, 1.94
––
7.4–7.2
4 pseudo t, Jꢀ9.5Hz in each
4.71
(9.2)
3.6–3.0 (m)
7.34–7.18
7.4–7.1
DMSO-d6
8a
5.29, 5.28, 5.04, 4.85
4 pseudo t, Jꢀ9.8Hz in each
3.81
(4.3)
4.33
(12.5)
4.06
(2.2)
4.82
CDCl3
8b
4.9–4.5, 3.7–3.0 (m)
2.86
7.4–7.0
DMSO-d6
9a
5.30, 5.26, 5.05, 4.88
4 pseudo t, Jꢀ9.6Hz in each
3.82
(4.4)
4.31
(12.5)
4.08
(1.5)
2.93, 2.50
2.87, 2.56,
7.29–7.17
7.32–7.21
7.52–7.38
CDCl3
9b
D2O
4.87
(8.8)
3.51–3.28 (m)
10a
5.40, 5.36, 5.10, 5.00
4 pseudo t, Jꢀ9.6Hz in each
3.88
(4.4)
4.34
(12.5)
4.10
(2.2)
6.42
(9.6)
––
2.08, 2.05
(2·), 2.04
––
7.66, 6.33
(J=15.4)
6.61
CDCl3
10b
D2O
5.12
(7.4)
3.94–3.49 (m)
7.60–7.45
+HC@
7.56–7.35
(J=15.4)
––
11a
5.33, 5.32, 5.09, 5.00
4 pseudo t, Jꢀ9.6Hz in each
3.85
(4.3)
4.33
(12.6)
4.11
(2.2)
6.68
(9.6)
––
2.09 (2·),
2.05, 2.03
––
CDCl3
11b
D2O
5.06
(8.9)
3.62–3.44 (m)
7.65–7.44
2.38
2.37
––
12a
CDCl3
12b
5.44, 5.38, 5.08, 5.05
4 pseudo t, Jꢀ9.6Hz in each
3.89
(4.1)
4.34
(12.3)
4.09
(2.3)
7.09
(9.1)
8.78
(7.9)
7.13
(9.1)
8.95
(8.8)
7.29
(9.2)
9.02
(8.9)
7.29
(9.3)
––
2.07, 2.05
(2·), 2.03
5.06, 5.00–4.91,
4.57
7.64, 7.22
(J=8.1)
5.00–4.91, 3.3.8–3.08 (m)
7.84, 7.29
(J=8.0)
7.85–7.38
DMSO-d6
13a
5.47, 5.41, 5.13, 5.09
4 pseudo t, Jꢀ9.5Hz in each
3.92
(4.5)
4.36
(12.4)
4.12
(2.1)
2.08, 2.06
(3·)
5.2–4.9,
4.61
CDCl3
13b
5.2–4.9, 3.8–3.0 (m)
––
8.2–7.3
DMSO-d6
14a
5.52, 5.42, 5.14, 5.13
4 pseudo t, Jꢀ9.6Hz in each
3.93
(3.9)
4.31
(12.5)
4.12
(1.9)
2.08, 2.06
(2·), 2.05
5.2–4.8,
4.61
8.34–7.28
8.34–7.51
8.3–7.5
CDCl3
14b
5.2–4.8, 3.8–3.0 (m)
––
––
––
DMSO-d6
15a
5.52, 5.42, 5.14, 5.12
4 pseudo t, Jꢀ9.3Hz in each
3.91
(3.9)
4.38
(12.5)
3.88
4.13
(1.3)
3.71
2.07, 2.05
(2·), 2.04
––
CDCl3
15b
5.20
9.0
3.6–3.3(m)
8.5–7.5
CD3OD
16a
(11.5, 1.5) (5.4)
5.44, 5.38, 5.12, 5.03
4 pseudo t, Jꢀ9.6Hz in each
3.90
(4.2)
4.35
(12.5)
4.41
(2.2)
6.56
(8.8)
8.74
(8.8)
2.08, 2.06, 2.05, 6.46
7.92–7.49
+HC@
8.08–7.53
CDCl3
16b
DMSO-d6
2.04
––
(J=15.4)
7.65, 6.80
(J=16.2)
4.88
(8.1)
3.68–2.98 (m)
a Refers to spectra of per-O-acetylated compounds 3a–16a.
b Refers to spectra of deprotected compounds b in DMSO-d6.
4.11. N-(b-D-Glucopyranosyl) phenylacetamide
(7b)
4.12. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
diphenylacetamide (8a)
Prepared by general procedure II: r. time 1d,
83%, white crystals, mp 211–213ꢁC; [a]D +1 (c 0.19,
MeOH).
Prepared by general procedure I: r. time 21h, eluent: Et-
OAc–hexane 2:1, 21%, white crystals, mp 139–141ꢁC;
[a]D +4 (c 0.06, CHCl3).

´
Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4866
Table 3. 1H NMR data for N-(2-acetamido-2-deoxy-b-D-glucopyranosyl) amides 17–25 (d [ppm], J [Hz])
Compound H-1
(J1,2
Solvent
H-2
(J2,3
H-3
(J3,4
H-4
(J4,5
H-5
(J5,6
H-6
(J6,6
H-60
NH
OAc,
NHAc
Aliphatic
Aromatic
––
0
0
)
)
)
)
)
)
)
(J5,6
17a
CDCl3
5.09
(8.3)
4.16
(10.2)
5.15
(9.2)
5.08 4.33
(10.2) (4.3) (12.5) (2.1)
3.80 4.12
7.02
(8.0)
6.11 2.14, 2.12,
(8.3) 2.10, 2.02,
1.99
––
––
18a
5.13
(9.5)
5.05
(9.9)
4.25
5.11
(8.1)
5.01
(9.5)
5.07
(9.6)
5.11
(9.9)
3.87 4.31
(4.4) (12.5) (2.2)
3.37 4.28 4.07
(4.4) (12.5) (2.2)
4.13
8.37
(7.4)
6.84
(8.5)
6.45 2.10 (2·),
(8.1) 2.06, 1.97
5.90 2.07, 2.05,
(8.2) 2.02, 1.92
––
––
CDCl3
19a
CDCl3
(8.8)
4.10
2.15–2.09,
1.54, 1.28–
1.21, 0.86
1.49–0.77
(10.8)
19b 4.77
DMSO-d6– (8.1)
3.75–2.95 (m)
––
1.79
––
D2O
20a
5.23
(9.6)
5.29
(9.5)
5.16
(9.6)
5.50
4.25
(10.8)
4.28
(9.9)
3.47
(8.8)
4.17
(9.6)
5.09
(9.5)
5.25
(9.5)
3.64
(9.6)
5.25
(9.6)
5.17
(10.0) (4.3) (12.5) (2.2)
3.82 4.32
4.11
7.80
(7.6)
7.83
(8.4)
––
6.03 2.08, 2.07,
(7.8) 2.05, 1.92
6.54 2.10 (2·),
(8.4) 2.07, 1.87
2.08
––
7.76, 7.51,
7.40
7.10
CDCl3
21a
5.18
(8.9)
3.93
(10.3)
4.90
(9.6)
3.91 4.36
(4.2) (12.3)
3.52 3.87
4.14
3.73
3.91 (2·),
3.89 (CH3O)
3.91 (2·),
3.81 (CH3O)
––
CDCl3
21b
7.13
D2O
22a
(12.5) (4.6)
4.03
3.95 4.22
9.20
(8.8)
2.00 (2·),
1.95, 1.72
8.55–7.52
+NH
DMSO-d6– (8.8)
D2O
22b
5.18
DMSO-d6– (9.6)
3.37
(8.8)
3.58
(9.6)
3.90
(10.3)
3.45 3.80
3.65
(11.4) (5.1)
––
1.91
––
8.39,
8.10–8.01,
7.87–7.85
7.25 (9.2),
6.90 (9.2)
D2O
23a
5.08
(9.2)
4.24
(10.6)
5.07
(9.2)
5.16
(10.6) (4.0) (11.9)
3.82 4.32 4.13
8.05
(7.9)
5.95 2.12, 2.10,
(7.9) 2.08, 1.85
4.51, 4.38
(15.6)
CDCl3
(COCH2)
4.21–4.07
24a
CDCl3
5.21
(9.2)
4.21–4.07 5.18–5.07
4.12–4.04 5.10–4.98
3.82 4.29
(4.0)
4.21–4.07 7.40
(7.9)
6.48 2.08, 2.07,
(7.9) 2.04, 1.94
––
(CH3CH), 1.44
(C(CH3)3)1.33
(6.6) (CH3CH)
5.20, 5.11
25a
5.10–
4.98
4.98
3.74 4.28
(12.6)
4.12–4.04 7.20 (8.0)
2.08, 2.05,
2.04, 1.86
7.35–7.34
(12.3) (OCH2),
4.59 (CHCH2),
2.86, 2.69
CDCl3
6.01 (7.1)
5.76 (9.6)
(4.0, 16.6)
(CHCH2),
1.41(C(CH3)3)
4.13. N-(b-D-Glucopyranosyl) diphenylacetamide (8b)
4.16. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
3-phenylpropenoic amide (10a)
Prepared by general procedure II: r. time 4h, 20%, white
crystals from MeOH, mp 186–189ꢁC; [a]D ꢁ2 (c 0.10,
MeOH).
Prepared by general procedure I: r. time 24h, eluent: Et-
OAc–hexane 1:1, 80%, white crystals, mp 177–179ꢁC;
[a]D ꢁ27 (c 0.44, CHCl3).
4.14. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl) 3-
phenylpropanoic amide (9a)
4.17. N-(b-D-Glucopyranosyl) 3-phenylpropenoic amide
(10b)
Prepared by general procedure I: r. time 24h, eluent: Et-
OAc–hexane 3:1, 64%, white crystals, mp 133–136ꢁC;
[a]D ꢁ1 (c 0.40, CHCl3).
Prepared by general procedure II: r. time 2h, 87%,
syrup, [a]D ꢁ5 (c 0.44, MeOH).
4.15. N-(b-D-Glucopyranosyl) 3-phenylpropanoic amide
(9b)
4.18. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
3-phenylpropynoic amide (11a)
Prepared by general procedure II: r. time 3h, 99%, white
crystals from MeOH, mp 182–185ꢁC; [a]D +8 (c 0.42,
MeOH).
Prepared by general procedure I: r. time 72h, eluent: Et-
OAc–hexane 1:2, 82%, white crystals, mp 166–169ꢁC;
[a]D ꢁ30 (c 0.76, CHCl3).

´
Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4867
Table 4. 13C NMR data for N-(b-D-glucopyranosyl) amides 3–16 (d [ppm], J [Hz])
Compound
Solvent
C-1 C-2–C-5
C-6 CO
CH3
Aliphatic
Aromatic
––
3a
CDCl3
81.7 73.4, 72.3, 70.7, 68.6 61.7 177.9, 171.1, 170.9, 169.8, 169.6 20.7, 20.4
25.2 (1),
43.2–40.7
(4)
4a
CDCl3
4b
78.5 73.6, 72.5, 70.6, 68.2 61.6 178.6, 171, 170.5, 169.8, 169.5
80.0 78.6, 77.6, 72.1, 70.0 60.9 177.8
20.7, 20.5
––
27.1 (3)
84.1 (1)
27.2 (3),
85.6 (1)
45.1–25.3
––
––
––
––
––
DMSO-d6
5a
78.0 73.5, 72.6, 70.6, 68.2 60.6 176.2, 171.0, 170.6, 169.8, 169.5 20.7, 20.6, 20.5
79.4 78.4, 77.5, 72.4, 70.0 61.0 175.5 ––
78.3 73.5, 72.6, 70.6, 68.3 61.6 171.0, 170.6, 169.9, 169.6, 166.1 20.7, 20.6, 20.55
CDCl3
5b
43.9–25.2
40.7–27.8
43.8
DMSO-d6
6a
CDCl3
7a
78.2 73.5, 72.6, 70.1, 68.1 61.6 171.2, 170.5 (2·), 169.7, 169.4
20.7, 20.5, 20.3
––
133.7–127.3
135.9–126.3
138.4–127.4
141.4–126.5
140.2–126.3
141.1–127.0
134.2–128.0
134.6–128.8
132.8–119.5
132.7–127.3
133.7–127.3
141.4–127.6
145.2–127.2
143–126.4
CDCl3
7b
79.6 78.5, 77.5, 72.5, 69.9 60.8 170.4
42.2
DMSO-d6
8a
78.4 73.6, 72.6, 70.1, 68.1 61.5 172.2, 170.6, 170.5, 169.8, 169.5 20.7, 20.5, 20.2
80.3 79.0, 78.0, 72.8, 70.3 61.1 171.9 ––
78.1 73.5, 72.6, 70.5, 68.1 61.6 172.3, 170.9, 170.5, 169.8, 169.5 20.7, 20.5
79.8 78.0, 77.1, 72.4, 69.9 61.2 177.4 ––
78.5 73.6, 72.7, 70.7, 68.2 61.7 171.3, 170.6, 169.8, 169.6, 165.8 20.7, 20.6
58.8
CDCl3
8b
56.8
DMSO-d6
9a
38.0, 30.8
37.9, 31,5
143.3, 119.3
143.8, 119.8
87.3, 82.0
88.3, 81.3
CDCl3
9b
D2O
10a
CDCl3
10b
D2O
80.1 78.2, 77.1, 72.5, 69.9 61.2 170.2
––
11a
78.0 73.7, 72.7, 70.3, 68.1 61.6 170.9, 170.6, 169.8, 169.5, 15.3
79.4 77.7, 76.5, 71.8, 69.1 60.5 156.3
20.7, 20.6
––
CDCl3
11b
D2O
12a
CDCl3
12b
78.2 73.4, 72.7, 70.4, 68.1 60.8 174.3, 170.7 (2·), 171.2, 169.8,
20.7, 20.6 (2·), 20.5 29.2
80.2 78.7, 77.6, 73, 70
78.9 73.6, 72.6, 70.8, 68.2 61.6 171.5, 170.6, 169.8, 169.6, 166.8 20.7 (2·), 20.6 (2·)
80.3 78.7, 77.6, 72.1, 70.2 61.0 166.4 ––
78.9 73.6, 72.6, 70.8, 68.2 61.6 171.5, 170.6, 169.8, 169.5, 167.2 20.7 (2·), 20.5 (2·)
80.0 78.8, 77.6, 72.2, 70 61.0 168.8 ––
78.9 73.6, 72.7, 70.9, 68.3 61.6 170.8, 170.5, 169.5, 167.2, 164.6 20.6 (2·), 20.5 (2·)
81.9 79.8, 79.1, 73.9, 71.5 62.7 171.1 ––
78.4 73.5, 72.7, 70.7, 68.2 61.6 171.1, 170.6, 169.8, 169.5, 165.9 20.7, 20.5
79.7 78.6, 77.5, 72.6, 70.0 61.0 165.4 ––
61.0 166.5
––
21.0
DMSO-d6
13a
––
CDCl3
13b
––
DMSO-d6
14a
––
135–123.3
CDCl3
14b
––
134.1–124.8
135.1–123.3
136.5–125.1
134.1–123.4
133.5–123.4
DMSO-d6
15a
––
CDCl3
15b
––
CD3OD
16a
143.3, 119.4
139.8, 122.4
CDCl3
16b
DMSO-d6
4.19. N-(b-D-Glucopyranosyl) 3-phenylpropynoic amide
(11b)
4.20. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
4-methylbenzamide (12a)
Prepared by general procedure II: r. time 16h, 98%,
white crystals from MeOH, mp 237–240ꢁC (decomp.);
[a]D ꢁ2 (c 0.38, MeOH).
Prepared by general procedure I: r. time 27h, eluent: Et-
OAc–hexane 1:1, 37%, white crystals, mp 185–187ꢁC;
[a]D ꢁ19 (c 0.22, CHCl3).

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Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4868
Table 5. 13C NMR data for N-(2-acetamido-2-deoxy-b-D-glucopyranosyl) amides 17-25 (d [ppm], J [Hz])
Compound C-1
Solvent
C-2 C-3–C-5
C-6 CO
CH3
Aliphatic
––
Aromatic
––
17a
80.5 53.6 73.7, 73.1, 67.8 61.9 176.8, 172.8,
170.7, 169.3
80.4 53.1 73.9, 72.6, 67.7 61.6 172.4, 171.8,
23.4, 23.1,
20.8, 20.7
22.7,
CDCl3
18a
CDCl3
115.4 (JC,F 288) (CF3) ––
170.6, 169.2,
157.9 (JC,F 38)
(CF3CO)
20.6 (2·), 20.5
19a
CDCl3
80.3 53.5 73.6, 73.1, 67.7 61.8 173.9, 172.0, 171.8, 23.1, 20.9,
170.7, 169.2
36.7, 31.9,
29.6 (2·), 29.5,
29.3 (2·),
––
20.8, 20.7
29.2, 25.2,
22.7, 14.1
35.4, 31.2,
28.9 (2·),
19b
DMSO-d6
78.8 54.5 78.6, 74.3, 70.4 60.9 172.4, 169.7
22.0
––
28.8, 28.7,
28.6, 28.4,
25.0, 22.7, 13.8
20a
82.2 54.6 74.6, 74.0, 68.7 62.7 173.5, 173.3, 171.9, 24.0, 21.6 (2·), 21.5 ––
170.4, 168.6
133.0–127.3
CDCl3
21a
CDCl3
80.9 60.7 73.3, 72.7, 68.0 61.7 172.2, 171.5, 170.6, 56.1 (2·),
––
153.1 (2·), 141.2,
128.0, 104.6 (2·)
169.2, 167.3
53.4 (CH3O) 22.9,
20.6 (2·), 20.5
57.4 (2·), 55.8
(CH3O)23.6
21b
D2O
80.8, 62.0 79.0, 75.0, 70.9 61.8 175.0, 169.9
––
153.9 (2·), 141.6,
129.8, 106.2 (2·)
134.3–124.1
22a
CDCl3
22b
78.9 52.3 73.2, 72.4, 68.4 61.8 170.0, 169.7, 169.6, 22.6, 20.5, 20.4 (2·) ––
169.3, 166.6
80.5 55.5 78.9, 75.0, 70.7 61.5 173.8, 169.4
23.4
––
135.6–124.7
DMSO-d6
23a
79.7 52.7 73.4, 72.7, 67.8 61.6 171.7, 171.5, 170.6, 22.7, 20.6 (2·), 20.5 67.2 (COCH2)
169.2, 155.7
129.6, 129.4,
116.0, 115.8
––
CDCl3
24a
79.9 53.5 73.5, 72.8, 68.0 61.8 173.8, 171.9, 171.5, 28.2 (3·), 23.0,
170.6, 169.3, 155.0
20.6 (2·), 20.5, 18.4 19.0 (CH3CH)
80.1 53.2 73.5, 72.7, 67.7 61.7 172.3, 171.7,
80.1 (C(CH3)3),
CDCl3
25a
CDCl3
28.2 (3·), 22.9,
20.6 (2·), 20.5
80.0 (C(CH3)3),
67.0 (OCH2),
50.1 (CH2CH),
37.7 (CH2CH)
135.6, 128.4 (2·),
128.2, 127.9
171.3, 171.0,
170.6, 169.2, 155.5
4.21. N-(b-D-Glucopyranosyl) 4-methylbenzamide (12b)
4.25. N-(b-D-Glucopyranosyl) 1-naphthoic amide (14b)
Prepared by general procedure II: r. time 1h, eluent:
CHCl3–MeOH 7:1, 48%, white crystals from MeOH,
mp 245–247ꢁC; [a]D ꢁ3 (c 0.21, MeOH).
Prepared by general procedure II: r. time 2h, 75%, white
crystals from MeOH, mp 209–212ꢁC; [a]D +45 (c 0.16,
DMSO).
4.22. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
4-phenylbenzamide (13a)
4.26. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
2-naphthoic amide (15a)
Prepared by general procedure I: r. time 4.5d, eluent:
EtOAc–hexane 1:1, 55%, white crystals, mp 210–
212ꢁC; [a]D ꢁ33 (c 0.20, CHCl3).
Prepared by general procedure I: r. time 1d, eluent: Et-
OAc–hexane 1:1, 62%, white crystals, mp 173–174ꢁC;
[a]D ꢁ30 (c 0.41, MeOH).
4.23. N-(b-D-Glucopyranosyl) 4-phenylbenzamide (13b)
Prepared by general procedure II: r. time 3h, 85%, white
crystals from MeOH, mp 279–280ꢁC; [a]D +34 (c 0.14,
DMSO).
4.27. N-(b-D-Glucopyranosyl) 2-naphthoic amide (15b)
Amide 15a (150mg) was dissolved in dry MeOH (3mL),
KCN (5mg) was added, and the mixture kept at rt for
11days. Amberlyst 15 (H+ form) was then added, and
after filtration of the resin the solvent was removed in
vacuo. The residue crystallized slowly from EtOH, and
was recrystallized from the same solvent to give 15b as
white crystals (96mg, 92%). Mp 177–180ꢁC; [a]D +26
(c 0.2, DMSO).
4.24. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
1-naphthoic amide (14a)
Prepared by general procedure I: r. time 1d, eluent: Et-
OAc–hexane 1:1, 52%, white crystals from Et2O, mp
138–140ꢁC; [a]D +38 (c 0.21, CHCl3).

´
Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
4869
4.28. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)
3-(2-naphthyl)-propenoic amide (16a)
4.36. N-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)
3,4,5-trimethoxybenzamide (21b)
Prepared by general procedure I: r. time 24h, eluent: Et-
OAc–hexane 1:1, 71%, white crystals, mp 207–209ꢁC;
[a]D ꢁ42 (c 0.40, CHCl3).
Prepared by general procedure II: r. time 1h, 78%, white
crystals from MeOH, mp 268–271ꢁC; [a]Dꢁ29 (c 1.05,
H2O).
4.37. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) 2-naphthoic amide (22a)
4.29. N-(b-D-Glucopyranosyl) 3-(2-naphthyl)-propenoic
amide (16b)
Prepared by general procedure I: r. time 1day, 54%,
white crystals from EtOH, mp 266–269ꢁC; [a]D ꢁ34
(c 1.05, DMSO).
Prepared by general procedure II: r. time 24h, 93%,
white crystals from MeOH, mp 243–246ꢁC; [a]D ꢁ15
(c 0.38, MeOH).
4.38. N-(2-Acetamido-2-deoxy-b-D-glucopyranosyl) 2-
naphthoic amide (22b)
4.30. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) acetamide (17a)
Prepared by general procedure II: r. time 1h, 88%, elu-
ent: CHCl3–MeOH 6:1, white crystals, mp 191–194ꢁC;
[a]D ꢁ46 (c 0.38, DMSO).
Prepared by general procedure I: r. time 3d, 69%, eluent:
EtOAc–MeOH 20:1, white crystals, mp 240–243ꢁC
(lit.34 mp 236–237ꢁC; lit.35 mp 244–246ꢁC; lit.37 mp
235ꢁC); [a]D +6 (c 1.02, CHCl3) (lit.34 [a]D +18.5 (c
2.0, CHCl3); lit.35 [a]D +41 (c 1.0, CHCl3); lit.37 [a]D
+18 (c 0.5, pyridine)).
4.39. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) 4-chlorophenoxyacetamide (23a)
Prepared by general procedure I: r. time 3days, 45%,
eluent: toluene–EtOH 8:1, white crystals, mp 286–
291ꢁC; [a]Dꢁ40 (c 0.42, CHCl3).
4.31. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) trifluoroacetamide (18a)
Prepared by general procedure I: r. time 30min, eluent:
EtOAc–hexane 1:1, 56%, white crystals, mp 183–186ꢁC;
[a]D +6 (c 1.02, CHCl3).
4.40. N-(N tert-Butyloxycarbonyl-L-alanyl)-N-(2-acet-
amido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)
amine (24a)
Prepared by general procedure I: r. time 8days, 73%,
eluent: toluene–EtOH 7:1, white crystals, mp 195–
197ꢁC; [a]D +0.5 (c 0.23, CHCl3).
4.32. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) dodecanoic amide (19a)
Prepared by general procedure I: r. time 2.5h, 91%,
white crystals from EtOH, mp 178–182ꢁC (lit.35 mp
176–178ꢁC); [a]D ꢁ2 (c 0.99, CHCl3) (lit.35 [a]D ꢁ3.5
(c 1.1, CHCl3)).
4.41. N-[1-Benzyl-N-(tert-butyloxycarbonyl)-L-aspart-4-
oyl]-N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glu-
copyranosyl) amine (25a)
Prepared by general procedure I: r. time 4days, 69%,
eluent: EtOAc–EtOH 600:1, white crystals from EtOH,
mp 165–167ꢁC (lit.29 mp 157–158ꢁC); [a]D +11
(c 0.392, CHCl3) (lit.29 [a]D +6.5 (c 1, CHCl3).
4.33. N-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)
dodecanoic amide (19b)
Prepared by general procedure II: r. time 3h, 87%, white
crystals from MeOH, mp 252–255ꢁC; [a]D +26 (c 0.36,
DMSO).
4.42. Enzyme assays
Glycogen phosphorylase b was prepared from rabbit
skeletal muscle according to the method of Fischer
and Krebs,40 using 2-mercaptoethanol instead of L-cys-
teine, and recrystallized at least three times before use.
The kinetic studies with glycogen phosphorylase were
performed as described previously.41 Kinetic data for
the inhibition of rabbit skeletal muscle glycogen phos-
phorylase by monosaccharide compounds were col-
lected using different concentrations of a-D-glucose-1-
phosphate (4, 6, 8, 10, 12 and 14mM) and constant con-
centrations of glycogen (1% w/v) and AMP (1mM). The
enzymatic activities were presented in the form of dou-
ble-reciprocal plots (Lineweaver–Burk) applying a non-
linear data-analysis program. The inhibitor constants
(Ki) were determined by Dixon plots, by replotting the
slopes from the Lineweaver–Burk plots against the
4.34. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) benzamide (20a)
Prepared by general procedure I: r. time 14days, eluent:
EtOAc–MeOH 40:1, 43%, white crystals, mp 248–250ꢁC
(lit.35 mp 246–248ꢁC; lit.34 mp 246–247ꢁC); [a]D ꢁ46 (c
1.02, CHCl3) (lit.35 [a]D ꢁ37 (c 0.57, CHCl3); lit.34 [a]D
ꢁ16 (c 2.0, CHCl3)).
4.35. N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl) 3,4,5-trimethoxybenzamide (21a)
Prepared by general procedure I: r. time 1.5h, eluent:
EtOAc–hexane 4:1, 67%, white crystals, mp 233–
235ꢁC; [a]D ꢁ52 (c 1.06, CHCl3).

´
Z. Gyo¨rgydeak et al. / Bioorg. Med. Chem. 12 (2004) 4861–4870
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This work was supported by the Hungarian Scientific
Research Fund (OTKA T37210 and T43550), the Hun-
garian Ministry of Health (ETT 030/2003), and the Na-
tional Research and Development Program (NKFP 88/
2001). Prof. Dr. N. G. Oikonomakos (National Hellenic
Research Foundation, Athens, Greece) is thanked for
the enzymatic test of compound 8b. ZsH is grateful to
CMS Chemicals Ltd, Oxford, UK for a stipend for
her Ph.D. studies. Prof. Dr. R. Csuk (Martin-Luther-
Universita¨t, Halle-Wittenberg, Germany) is thanked
for his help in carrying out elemental analyses for some
of the compounds.
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