Design of an amide N-glycoside derivative of β-glucogallin: A stable, potent, and specific inhibitor of aldose reductase

Article abstract of DOI:10.1021/jm401311d

β-Glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original two-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent, and selective therapeutic lead toward the treatment of diabetic eye disease.

Full text of DOI:10.1021/jm401311d

Article
pubs.acs.org/jmc
Design of an Amide N‑Glycoside Derivative of β‑Glucogallin: A
Stable, Potent, and Specific Inhibitor of Aldose Reductase
Linfeng Li,† Kun-Che Chang,†,‡ Yaming Zhou,† Biehuoy Shieh,‡ Jessica Ponder,† Adedoyin D. Abraham,†
Hadi Ali,† Anson Snow,‡ J. Mark Petrash,†,‡ and Daniel V. LaBarbera*,†
†Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Science, University of Colorado Anschutz
Medical Campus, Aurora, Colorado 80045, United States
‡Department of Ophthalmology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045,
United States
S
* Supporting Information
ABSTRACT: β-Glucogallin (BGG), a major component of the Emblica officinalis medicinal
plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). New linkages (ether/
triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester,
and an original two-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was
assessed in vitro and using transgenic lens organ cultures, which identified the amide linked
glucoside (BGA) as a stable, potent, and selective therapeutic lead toward the treatment of
diabetic eye disease.
Our previous research identified 1-O-galloyl-β-D-glucose (β-
glucogallin or BGG or 1) shown in Scheme 1, purified from
Indian gooseberry (Emblica officinalis), as a noncytotoxic,
selective, and relatively potent AKR1B1 inhibitor that reduces
sorbitol accumulation in vitro and in organ culture assays of
transgenic mouse lenses.15,16 Thus, BGG is a viable lead
compound to develop novel therapies for inflammatory
diseases, particularly diabetic eye disease.
BGG belongs to one of the simplest classes of hydrolyzable
tannins, the gallotannins, and consists of a polyphenol
monomer (gallic acid) linked to a β-D-glucose ring by an
ester functionality. During our biological evaluation of BGG we
observed that the glycosyl 1-ester is labile in aqueous solution.
Therefore, our initial goal in developing novel inhibitors of
AKR1B1, based on the BGG pharmacophore, was to design an
optimal stable linkage between the sugar moiety and the gallate
ring while maintaining or improving potency and specificity for
AKR1B1 over other aldo−keto reductases. By use of this
rationale, new linkages between the sugar moiety and the
gallate ring were introduced to replace the labile ester, including
ether, triazol, and amide functional groups. High yielding
efficient syntheses were developed to prepare BGG derivatives,
including an original two-step ∼90% yield preparation of BGG
(Scheme 1).17 Derivatives were compared to BGG for their
ability to inhibit AKR1B1 using recombinant enzyme, cell-
based, and ex vivo lens organ cultures.
INTRODUCTION
■
Human aldose reductase (AKR1B1) is a member of the aldo−
keto reductase superfamily, which consists of 15 families, 3 of
which are mammalian containing the 13 human aldo−keto
reductase enzymes currently identified.1 AKR1B1 functions in
the polyol pathway as an NADPH-dependent enzyme,
catalyzing the reduction of glucose to sorbitol, which is then
converted to fructose by sorbitol dehydrogenase.2 The
increased reduction of glucose to sorbitol under hyperglycemic
conditions has been implicated in tissue injury and the
progression of a wide variety of diabetic complications,
including neuropathy and retinopathy.3,4 Inhibition of
AKR1B1 has been shown to both prevent and reverse diabetic
tissue injury that arises from the accumulation of sorbitol.3,5−7
Diabetes mellitus has become a pandemic affecting both
affluent countries and the developing world, with prevalence
expected to double by 2030.8 Currently, there is no medical
treatment that prevents the onset and progression of diabetic
eye diseases like cataracts and retinopathy, which account for
the majority of vision loss in diabetics.9 Surgical procedures for
diabetic eye diseases are expensive, and diabetic patients have
significantly higher complication rates.10
In general, aldose reductase inhibitors (ARIs) developed to
target AKR1B1 are nonselective and inhibit other members of
the aldo−keto reductase superfamily such as AKR1B10 (small
intestine reductase) and AKR1A1 (aldehyde reductase), which
may contribute to toxicity and adverse effects.1 Despite the
failure of ARIs such as sorbinil, zopalrestat, and tolrestat in
clinical trials,11 the role of AKR1B1 in diabetic tissue damage
has been thoroughly substantiated.12−14 Thus, the discovery of
selective AKR1B1 inhibitors that can both prevent and reverse
complications of diabetes remains of paramount clinical
importance.
RESULTS AND DISCUSSION
■
Chemistry. The first modification entailed the bioisosteric
replacement of the ester with an amide linkage. A PMe3-
mediated Staudinger reaction with glucosylazide and benzoyl
Received: August 23, 2013
Published: December 16, 2013
© 2013 American Chemical Society
71
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
Scheme 1. Synthesis of β-Glucogallin (BGG), 1
chloride resulted in the formation of N-glycosylamide,18 which
was smoothly converted to the β-glucogallin N-glycoside amide
(BGA or 2) by exposure to NaOMe followed by debenzylation
(Scheme 2, 79% yield). The amide linkage was confirmed by
and the respective alcohol acceptor,21 followed by the removal
of acetyl and benzyl ether protecting groups, led to the
formation of β-glycosides (Scheme 4A,B). In addition, we
prepared 6, which contains a mixed ether and triazole linkage.
Starting from readily available benzylazide 20, triazole 6 was
assembled in three convenient steps using copper-catalyzed
azide−alkyne cycloaddition reaction described above (Scheme
4C). Importantly, the anomeric configuration of the glucoside
products were readily assigned by the NMR coupling constant
(∼7−8 Hz) between H-1 and H-2 based on the Karplus
equation.22
Scheme 2. Synthesis of β-Glucogallin Amide BGA, 2
Biological Evaluation and Stability Studies. Previously,
we have shown that BGG is a potent and selective inhibitor of
AKR1B1 in vitro and in ex vivo lens organ cultures.16 BGG
appears to act via noncompetitive inhibition through binding
the active site of AKR1B1 and occupies both the “anionic” and
the “specificity” pockets.23 This noncompetitive inhibition and
active site binding is not uncommon and has been reported for
many AKR1B1 inhibitors.24−26 Thus, BGG derivatives were
first assessed using enzyme inhibition studies with recombinant
human AKR1B1 in the presence of the natural substrate
glyceraldehyde (Figure 1). Interestingly, the N-glycoside BGA
was the only derivative that maintained inhibitory activity
against AKR1B1 (Figure 1A). In fact, BGA potency (IC50 = 9
μM) was virtually identical to that of BGG (IC50 = 8 μM). BGA
also replicated BGG in specificity for AKR1B1 over AKR1B10
and AKR1A1 (Figure 1B). On the basis of these results, it
appears that by extending the linker chain length by just one
carbon (e.g., two-carbon ether) compared to BGG or BGA, all
AKR1B1 inhibitor activity is lost.
HMBC 2D NMR spectroscopy, which proved connectivity with
correlations between the amide carbonyl, the sugar moiety, and
the gallate ring (Supporting Information).
We then replaced the ester/amide functionality with a
triazole linkage 3, which mimics amide functionality but would
not be substrates for proteases in vivo and thus may be
potentially much more stable. Coupling of substituted phenyl-
acetylene 13 and glucosylazide 11 using click chemistry19
generated 3 in greater than 86% yield overall after deprotection
(Scheme 3).
However, the loss of activity for the ether or triazole
derivatives 3−6 may also be due to the absence of the carbonyl
group and resulting electronic effect. To further investigate the
role of the carbonyl functionality, we prepared amide 7, a BGA
analogue, which contains an extra carbon between the carbonyl
group and the gallate ring. In a similar approach, N-
phenylacetyl-β-D-glucopyranosylamine 7 was constructed in
three steps from acid 23 and azide 11 (Scheme 5). The loss of
activity for amide 7 (Figure 1A) indicates the impact of linker
chain length on AKR1B1 enzyme inhibition. Thus, we
hypothesize that the linker group cannot exceed one carbon
in order to maintain inhibitory activity against AKR1B1.
Previously, we utilized molecular modeling to help explain
the enzyme inhibition profile of BGG. Likewise, to understand
this profound structure−activity relationship, we turned to
molecular modeling. By use of Discovery Studio software
(Accelrys), BGG derivatives were docked into the crystal
structure of human AKR1B1 (PDB code 1US0). Although we
observed comparable binding energies to BGG, BGA was the
only derivative that was minimized in the AKR1B1 site with a
similar pose as BGG (Figure 2A). Specifically, in addition to
binding energies we considered and analyzed the top 20 poses
for all compounds (based on dock score). Interestingly, we
observed a trend where BGG and BGA favorably bind with the
Scheme 3. Synthesis of Triazole, 3
In addition, a vast majority of biologically and therapeutically
active carbohydrates exist as monosaccharide units joined via
glycosidic bonds.20 Hence, we set our sights on glycoside BGG
derivatives where we varied the carbon tether length. We first
attempted to prepare the phenolic ether (no carbon) and
benzyl type (one-carbon) glycosides but quickly dismissed
these linkages because of their instability at room temperature.
However, glycosides 4 (two-carbon) and 5 (three-carbon) were
stable and were prepared accordingly. Silver carbonate
promoted Koenigs−Knorr coupling of glucosyl bromide 16
72
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
Scheme 4. Synthesis of Glucosides 4, 5, and 6
Figure 1. Aldose reductase inhibitor studies. (A) Compounds 3−7 show no inhibitory activity, and the IC50 values of BGG and BGA were
determined to be 8 1 and 9 2 μM, respectively, in the presence of the natural substrate glyceraldehyde. (B) BGG and BGA showed no activity
against AKR1B10 and AKR1A1.
carbon linker limit. As a result of their inactivity, 3−7 were no
longer investigated as inhibitors of AKR1B1.
Scheme 5. Synthesis of Amide, 7
The stability of BGG and BGA was investigated using
quantitative HPLC (see calibration curves in the Supporting
Information) after treatment in aqueous sulfuric acid solutions
(pH 0.33) while heating at 80 °C (Figure 3). As expected from
our previous observations and from literature reports regarding
glycosyl 1-ester stability,27,28 we found that BGG degraded by
76% after 15 min and completely decomposed within 30 min.
The major degradation product was determined to be gallic
acid based on HPLC retention time. In stark contrast and to
our surprise, 96% of BGA remained intact after 6 days under
the same conditions. BGA proves to be significantly more stable
than BGG even under extreme conditions.
Once the stability of BGA was determined, we then evaluated
whether or not BGA could effectively inhibit AKR1B1 using a
Raw264.7 murine macrophage cell based assay. Previously, we
found that BGG exhibited low cytotoxicity in Raw264.7 cells
and effectively inhibited sorbitol accumulation.15 In this same
study, sorbinil, a reference aldose reductase inhibitor, gave
similar results reducing sorbitol accumulation by 44%. Likewise,
BGG and BGA inhibited AKR1B1 activity in Raw264.7 cells
sugar moiety in the “anionic” pocket and the gallate ring
extending into the “specificity” pocket. However, all the other
derivatives 3−7 bound opposite to this configuration with the
sugar moiety in the “specificity” pocket (Figure 2B and Figure
S1; see Supporting Information). Given that glucose is a natural
substrate that binds in the “anionic” site and the sugar moiety
of BGG and BGA appear to mimic this, it seems logical that this
type of binding pose would be preferential and may explain the
loss of activity for 3−7, which exceed our hypothesized one-
73
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
Figure 2. Representative binding poses for BGG derivatives 2−7 bound to AKR1B1 using the top 20 poses ranked by docking score: (A) favorable
inhibitory binding pose, represented with BGA, where the sugar moiety is positioned in the “anionic” pocket (orange surface) and the gallate ring is
positioned in the “specificity” pocket (blue surface); (B) unfavorable binding pose represented by glycoside 3 depicting an opposite configuration
compared to BGG and BGA.
Figure 3. Stability studies with BGG and BGA under thermal acidic
conditions showing the % compound remaining (mean concentration)
over time. Statistical analysis was done using the Student’s t test:
(∗∗∗) P ≤ 0.0001.
blocking sorbitol accumulation by approximately 50% (Figure
4A).
In addition to cell based assays we assessed AKR1B1
Figure 4. (A) Macrophages were incubated with either BGG or BGA
for 24 h before they were harvested. (B) Lenses extracted from wild
type or AR transgenic mice were incubated with hyperglycemic
conditions in the presence or absence of BGA for 72 h. The sorbitol
levels in the macrophages or lenses were measured using a sorbitol
colorimetric assay. The amount of sorbitol was normalized to total
protein. Statistical analysis was done using the Student’s t test: (∗) P ≤
0.05; (∗∗) P ≤ 0.01.
inhibitory activity of BGA using a transgenic lens organ culture
model measuring sorbitol accumulation under hyperglycemic
conditions. This mouse model overexpresses human AKR1B1
in lenses, which express low levels of endogenous aldose
reductase. Thus, this model is a direct measure of AKR1B1
activity. Furthermore, these animals develop cataracts as a result
of sorbitol accumulation.16 Briefly, lenses are extracted from the
eyes of transgenic mice and cultured ex vivo supplemented with
27.5 mM glucose. Lenses were treated with vehicle controls
(H2O) or BGA for 72 h. At both 25 and 50 μM concentrations
BGA blocked sorbitol accumulation by 80% (Figure 4B).
Similarly, we have shown that BGG blocks sorbitol
accumulation in this lens organ culture model by 74%.16
glucogallin pharmacophore, a relatively potent but specific
inhibitor of AKR1B1. We have determined that the chain
length between the glucose moiety and the gallate ring of BGG
is crucial and may not exceed one carbon. We observed a major
flaw in the natural product pharmacophore to be the ester
linkage, which decomposes under neutral aqueous solutions
slowly and rapidly decomposed under extreme conditions
within 30 min. By design, we overcame this instability through
CONCLUSION
In summary, this report demonstrates the design, synthesis, and
biological evaluation of a new series of glycosides based on β-
■
74
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
indicated the complete transformation of 11 (∼15 min). Benzoyl
chloride 9 (354.1 mg, 0.772 mmol) was added, and stirring continued
for 48 h at room temperature. The organic solvent was removed under
reduced pressure, and chromatographic purification on silica gel (40%
ethyl acetate in hexane) afforded 12 (398.6 mg, 0.518 mmol, 81%) as a
white solid. Mp 171−172 °C; [α]23D −32.3 (c 0.2, CHCl3); IR (neat)
νmax 3297, 3029, 2945, 1748, 1662, 1583, 1532, 1497, 1204 cm−1; TLC
(35% ethyl acetate in hexane) Rf = 0.30; 1H NMR (500 MHz, CDCl3)
δ 7.44−7.23 (m, 15H), 7.08 (s, 2H), 6.99 (d, J = 9.0 Hz, 1H), 5.389 (t,
J = 9.5 Hz, 1H), 5.386 (t, J = 9.0 Hz, 1H), 5.12 (s, 4H), 5.11 (t, J = 9.5
Hz, 1H), 5.10 (s, 2H), 5.03 (t, J = 10.0 Hz, 1H), 4.36−4.33 (dd, J =
4.5, 12.5 Hz, 1H), 4.11−4.08 (dd, J = 2.0, 12.5 Hz, 1H), 3.92−3.88
(ddd, J = 2.0, 4.0, 10.0 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 6H), 2.00 (s,
3H); 13C NMR (125.7 MHz, CDCl3) δ 171.7, 170.7, 169.9, 169.7,
166.8, 152.9, 141.9, 137.5, 136.6, 128.7, 128.6, 128.3, 128.1, 128.1,
127.6, 106.9, 79.2, 75.2, 73.7, 72.7, 71.3, 71.0, 68.3, 61.7, 20.9, 20.8,
20.7; ESI-HRMS calcd for C42H43NO13Na [M + Na]+, 792.2627;
found, 792.2632.
isosteric replacement of the ester for an amide to yield the
novel derivative BGA. BGA proves to be stable under extreme
heat and strong acid for an extended time course of 6 days.
Furthermore, BGA maintained both potency and specificity for
AKR1B1 in vitro and in a transgenic ex vivo organ culture
model. With compatible activity and greatly improved stability,
BGA becomes an attractive therapeutic lead toward the
treatment of diabetic complications. Further structure based
drug design is presently ongoing to improve the pharmaco-
logical profile of BGA, and more sophisticated animal models
will be used to test BGA efficacy in vivo.
EXPERIMENTAL SECTION
■
General Procedures. All commercial chemicals were used as
supplied unless otherwise indicated. All reactions were performed
under an inert atmosphere of ultrapure nitrogen with oven-dried
1
glassware. H and 13C NMR spectra were recorded on a Varian 500
N-Galloyl-β-D-glucopyranosylamine (BGA, 2). General deace-
tylation procedure followed by general hydrogenolysis procedure with
12 (114.2 mg, 0.148 mmol) provided amide 2 (47.3 mg, 0.143 mmol,
MHz spectrometer. High-resolution mass spectra data were acquired
on a Bruker Q-TOF-2 capable of ESI ion source. Analysis of sample
purity was performed on a Shimadzu Prominence HPLC system with a
Phenomenex Kinetex C18 reversed phase column (5 μm, 100 Å, 250
mm × 4.6 mm). HPLC conditions were the following: solvent A =
H2O, solvent B = MeCN; flow rate = 1.0 mL/min. Compounds were
eluted with a gradient of water to MeCN over 30 min. All tested
compounds have a purity of ≥95%.
General Deacetylation Procedure. To a stirred solution of the
acetyl protected compound in dry MeOH (0.1 M) were added 1−2
drops of 1 M methanolic NaOMe solution, and the resulting mixture
was stirred for 1 h at room temperature. The reaction mixture was
neutralized with solid Amberlyst-15 (H+ form) ion-exchange resin,
filtered, and concentrated under reduced pressure to yield the product.
General Hydrogenolysis Procedure. A 0.05 M solution of the
substrate and 10% mol Pd/C in a mixture of MeOH/EtOAc (v/v, 5:1)
were shaken in a Parr hydrogenator for 5 h under 50 psi of H2. After
filtration of the catalyst, evaporation of the filtrate under reduced
pressure gave a solid or syrup.
96%) as a yellow oil. [α]24 −20.2 (c 0.1, CH3OH); IR (neat) νmax
D
3264, 2926, 1642, 1604, 1522, 1332, 1210 cm−1; 1H NMR (500 MHz,
CD3OD) δ 6.97 (s, 2H, H-10/H-14), 5.10 (d, J = 9.0 Hz, 1H, H-1),
3.89−3.86 (dd, J = 2.0, 12.0 Hz, 1H, H-6a), 3.73−3.69 (dd, J = 5.5,
12.0 Hz, 1H, H-6b), 3.49−3.46 (m, 2H, H-2/H-4), 3.45−3.41 (m, 1H,
H-5), 3.39−3.37 (m, 1H, H-3); 13C NMR (125.7 MHz, CD3OD) δ
171.2 (C-8), 146.6 (C-11/C-13), 138.7 (C-12), 125.5 (C-9), 108.3
(C-10/C-14), 81.8 (C-1), 79.7 (C-5), 79.0 (C-2), 73.7 (C-4), 71.4 (C-
3), 62.7 (C-6); ESI-HRMS calcd for C13H17NO9 [M + H]+ 332.0976,
found 332.0977.
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3,4,5-tri-
benzyloxyphenyl)-1,2,3-triazole (14). To a stirred solution of
azide 11 (53.4 mg, 0.143 mmol) and alkyne 13 (60.1 mg, 0.143 mmol)
in EtOH/H2O (6 mL, v/v, 1:1) were added CuSO4·5H2O (5.4 mg,
21.5 μmol) and sodium ascorbate (12.7 mg, 64.4 μmol). The
heterogeneous mixture was stirred vigorously for 24 h at 70 °C. The
reaction mixture was diluted with H2O and extracted with CH2Cl2.
The organic layer was dried over Na2SO4, filtered, and concentrated.
Chromatographic purification on silica gel (10% ethyl acetate in
dichloromethane) gave 14 (100.2 mg, 0.129 mmol, 90%) as a white
2,3,4,6-Tetra-O-benzyl-1-O-(tri-O-benzylgalloyl)-β-D-gluco-
pyranose (10). To a stirred solution of 8 (301.5 mg, 0.557 mmol)
and 3 Å molecular sieves in CH2Cl2 was added triethylamine (805 μL,
5.77 mmol) dropwise. After 10 min of stirring at room temperature,
benzoyl chloride 929 (383.9 mg, 0.836 mmol) was then added to the
resulting solution in four portions over 20 min, and the stirring was
continued for 3 h. The reaction mixture was filtered through a pad of
Celite and washed with CH2Cl2, after which the filtrate was washed
with brine and extracted with CH2Cl2. The combined organic layer
was separated, dried over Na2SO4, and concentrated. Purification by
column chromatography on silica gel, eluting with 15% ethyl acetate in
hexane, afforded the corresponding ester 10 (505.2 mg, 0.524 mmol,
solid. Mp 232 °C (decompose); [α]24 −3.5 (c 0.92, CHCl3); IR
D
(neat) νmax 3033, 2926, 2854, 1750, 1584, 1369, 1210 cm−1; TLC
(35% ethyl acetate in hexane) Rf = 0.25; 1H NMR (500 MHz, CDCl3)
δ 7.94 (s, 1H), 7.46−7.18 (m, 17H), 5.93 (d, J = 9.5 Hz, 1H), 5.53 (t, J
= 9.5 Hz, 1H), 5.44 (t, J = 9.5 Hz, 1H), 5.28 (t, J = 10.0 Hz, 1H), 5.16
(s, 4H), 5.08 (s, 2H), 4.36−4.32 (dd, J = 5.0, 12.5 Hz, 1H), 4.16 (d, J
= 12.5 Hz, 1H), 4.05−4.01 (ddd, J = 2.0, 5.0, 10.0 Hz, 1H), 2.09 (s,
3H), 2.08 (s, 3H), 2.04 (s, 3H), 1.89 (s, 3H); 13C NMR (125.7 MHz,
CDCl3) δ 170.6, 170.0, 169.5, 169.1, 153.4, 148.4, 139.0, 137.8, 137.0,
128.7, 128.6, 128.3, 128.0, 127.9, 127.6, 125.6, 117.7, 105.8, 85.9, 75.4,
75.3, 72.9, 71.5, 70.4, 67.9, 61.7, 20.8, 20.6, 20.3; ESI-HRMS calcd for
C43H43N3O12Na [M + Na]+ 816.2739, found 860.2726.
94%) as a clear oil. [α]22 −229.9 (c 0.42, CHCl3); IR (neat) νmax
D
3062, 3033, 2926, 2862, 1732, 1590, 1496, 1433, 1204 cm−1; TLC
(20% ethyl acetate in hexane) Rf = 0.55; 1H NMR (500 MHz, CDCl3)
δ 7.41−7.12 (m, 37H), 5.85 (d, J = 7.5 Hz, 1H), 5.15−5.06 (m, 6H),
4.92−4.82 (m, 3H), 4.69−4.60 (m, 3H), 4.55 (d, J = 10.5 Hz, 1H),
4.48 (d, J = 12.5 Hz, 1H), 3.84−3.62 (m, 6H); 13C NMR (125.7 MHz,
CDCl3) δ 164.5, 152.7, 143.0, 138.5, 138.1, 137.9, 137.8, 137.4, 136.7,
128.7, 128.5, 128.4, 128.3, 128.1, 127.98, 127.96, 127.9, 127.5, 124.3,
109.7, 94.9, 85.0, 81.1, 77.3, 75.8, 75.7, 75.2, 75.1, 73.7, 71.3, 68.1. ESI-
HRMS calcd for C62H58O10Na [M + Na]+ 985.3922, found 985.3934.
1-O-Galloyl-β-D-glucopyranoside (BGG, 1). General hydro-
genolysis procedure with ester 10 (128.9 mg, 0.134 mmol) afforded
1 (41.1 mg, 0.127 mmol, 95%) as a pale yellow oil that when solidified
becomes off-white in color. All spectral analysis results were in
accordance with our previously reported values for BGG.16
1-(β-D-Glucopyranosyl)-4-(3,4,5-trihydroxyphenyl)-1,2,3-tri-
azole (3). General procedures for deacetylation followed by
hydrogenolysis with 14 (84.1 mg, 0.106 mmol) provided 3 (36.4
mg, 0.102 mmol, 96%) as a yellow oil. [α]23D −0.46 (c 0.6, CH3OH);
1
IR (neat) νmax 3424, 2927, 2854, 1590, 1501, 1367, 1036 cm−1; H
NMR (500 MHz, CD3OD) δ 8.20 (s, 1H), 6.75 (s, 2H), 5.52 (d, J =
9.5 Hz, 1H), 3.85 (t, J = 9.5 Hz, 1H), 3.81−3.42 (m, 5H); 13C NMR
(125.7 MHz, CD3OD) δ 149.4, 147.4, 134.9, 122.5, 120.4, 106.1, 89.6,
81.1, 78.5, 74.0, 70.9, 62.4; ESI-HRMS calcd for C14H17N3O8Na [M +
Na]+ 378.0908, found 378.0900.
2-(3,4,5-Tribenzyloxyphenyl)ethyl-β-D-glucopyranoside
(17). A mixture of alcohol 15 (188.2 mg, 0.441 mmol) and Ag2CO3
(139.0 mg, 0.504 mmol) in CH2Cl2 (2 mL) was stirred over 3 Å
molecular sieves for 15 min before a solution of bromide 16 (172.8
mg, 0.420 mmol) in CH2Cl2 (2 mL) was added dropwise. The
reaction mixture was covered in aluminum foil and stirred at room
temperature for 24 h. The reaction mixture was filtered through a pad
N-(3,4,5-Tri-O-benzylgalloyl)-2,3,4,6-tetra-O-acetyl-β-D-glu-
copyranosylamine (12). To a stirred solution of azide 10 (240.0 mg,
0.643 mmol) in CH2Cl2 (3.2 mL) was added PMe3 (707 μL, 1.0 M
solution in THF, 0.707 mmol) dropwise. The mixture was stirred at
room temperature until nitrogen evolution had ceased and TLC had
75
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
1
of Celite and washed with ethyl acetate. The filtrate was then
concentrated under reduced pressure. The crude mixture was
dissolved in CH3OH (4 mL). Two drops of 1 M methanolic
NaOMe solution were added, the resulting mixture was stirred for 1 h
at room temperature. The reaction mixture was neutralized with solid
Amberlyst-15 (H+ form) ion-exchange resin, filtered, and concen-
trated. Chromatographic purification on silica gel (35% ethyl acetate in
hexane to 5% CH3OH in CH2Cl2) provided 17 (139.1 mg, 0.231
Rf = 0.65; H NMR (500 MHz, CDCl3) δ 7.41−7.26 (m, 16H), 6.55
(s, 2H), 5.38 (d, J = 15.0 Hz, 1H), 5.34 (d, J = 15.0 Hz, 1H), 5.19 (t, J
= 9.5 Hz, 1H), 5.09 (t, J = 10.0 Hz, 1H), 5.07 (s, 4H), 5.04 (s, 2H),
5.00 (t, J = 8.0 Hz, 1H), 4.90 (d, J = 12.5 Hz, 1H), 4.78 (d, J = 12.5
Hz, 1H), 4.68 (d, J = 8.0 Hz, 1H), 4.28−4.24 (dd, J = 5.0, 12.5 Hz,
1H), 4.16−4.13 (dd, J = 2.0, 12.5 Hz, 1H), 3.74−3.71 (m, 1H), 2.06
(s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.88 (s, 3H); 13C NMR (125.7
MHz, CDCl3) δ 170.7, 170.3, 169.5, 169.4, 153.3, 144.6, 139.0, 137.7,
136.7, 129.9, 128.6, 128.3, 128.1, 128.0, 127.6, 122.7, 108.1, 100.1,
75.3, 72.8, 72.0, 71.4, 71.3, 68.4, 63.1, 61.9, 54.4, 20.7; ESI-HRMS
calcd for C45H47N3O13Na [M + Na]+ 860.3001, found 860.3017.
[1-(3,4,5-Trihydroxybenzyl)-1,2,3-triazole-4-yl]methyl-β-D-
glucopyranoside (6). General procedures for deacetylation followed
by hydrogenolysis with 22 (169.6 mg, 0.202 mmol) provided 6 (77.6
mg, 0.194 mmol, 96%) as a yellow oil. [α]23D −19.3 (c 0.1, CH3OH);
mmol) in 55% yield as a white solid. Mp 76−77 °C; [α]23 −75.7 (c
D
0.148, CH3OH); IR (neat) νmax 3348, 2924, 2880, 1590, 1507, 1431,
1145 cm−1; TLC (10% CH3OH in CH2Cl2) Rf = 0.45; 1H NMR (500
MHz, CD3OD) δ 7.49−7.22 (m, 15H), 6.73 (s, 2H), 5.11 (s, 4H),
4.95 (s, 2H), 4.34 (d, J = 7.5 Hz, 1H), 4.13−4.09 (dt, J = 7.0, 9.5 Hz,
1H), 3.93−3.90 (dd, J = 2.0, 12.5 Hz, 1H), 3.80−3.75 (dt, J = 7.0, 9.5
Hz, 1H), 3.73−3.69 (dd, J = 5.5, 12.5 Hz, 1H), 3.41 (t, J = 9.0 Hz,
1H), 3.36−3.29 (m, 2H), 3.25 (t, J = 9.0 Hz, 1H), 2.90 (t, J = 7.0 Hz,
2H); 13C NMR (125.7 MHz, CD3OD) δ 153.9, 139.1, 138.7, 137.4,
136.6, 129.4, 129.1, 128.9, 128.8, 109.5, 104.3, 78.1, 78.0, 76.3, 75.1,
72.1, 71.7, 71.4, 62.8, 37.3; ESI-HRMS calcd for C35H38O9Na [M +
Na]+ 625.2408, found 625.2411.
2-(3,4,5-Trihydroxyphenyl)ethyl-β-D-glucopyranoside (4).
General hydrogenolysis procedure with 17 (54.3 mg, 90.1 μmol)
afforded 4 (27.1 mg, 83.8 μmol, 93%) as a yellow oil. [α]24D −10.1 (c
0.3, CH3OH); IR (neat) νmax 3332, 2942, 2829, 1608, 1449, 1076,
1022 cm−1; 1H NMR (500 MHz, CD3OD) δ 6.21 (s, 2H), 4.25 (d, J =
7.5 Hz, 1H), 4.00−3.94 (dd, J = 8.0, 9.0 Hz, 1H), 3.84−3.81 (dd, J =
2.0, 12.0 Hz, 1H), 3.67−3.60 (m, 2H), 3.34−3.20 (m, 3H), 3.15 (t, J =
8.5 Hz, 1H), 2.78−2.65 (m, 2H); 13C NMR (125.7 MHz, CD3OD) δ
146.8, 132.4, 130.9, 108.9, 104.3, 78.0, 77.8, 75.1, 72.0, 71.6, 62.7, 36.7.
ESI-HRMS calcd for C14H20O9Na [M + Na]+ 355.1000, found
355.0990.
IR (neat) νmax 3324, 2945, 2835, 1600, 1457, 1352, 1020 cm−1; H
1
NMR (500 MHz, CD3OD) δ 7.84 (s, 1H), 6.29 (s, 2H), 5.29 (s, 2H),
4.90 (d, J = 12.5 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.33 (d, J = 8.0
Hz, 1H), 3.83 (d, J = 11.5 Hz, 1H), 3.65−3.62 (dd, J = 4.0, 11.5 Hz,
1H), 3.21−3.14 (m, 3H), 3.17 (t, J = 8.5 Hz); 13C NMR (125.7 MHz,
CD3OD) δ 147.4, 145.8, 134.7, 127.1, 125.1, 108.3, 103.5, 77.91,
77.85, 74.9, 71.5, 63.0, 62.8, 55.0; ESI-HRMS calcd for C16H21N3O9Na
[M + Na]+ 422.1170, found 422.1182.
N-(3,4,5-Tri-O-benzylphenylacetyl)-2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosylamine (24). To a stirred solution of azide 11
(197.7 mg, 0.530 mmol) in CH2Cl2 (3.2 mL) was added PMe3 (557
μL, 1.0 M solution in THF, 0.557 mmol) dropwise. The mixture was
stirred at room temperature until nitrogen evolution had ceased and
TLC had indicated the complete transformation of 11 (∼15 min).
3,4,5-Tri-O-benzylphenylacetic acid (361.3 mg, 0.795 mmol) was
added, and stirring continued for 48 h at room temperature. The
organic solvent was removed under reduced pressure, and chromato-
graphic purification on silica gel (40% ethyl acetate in hexane) afforded
3,4,5-Tribenzyloxycinnamyl-β-D-glucopyranoside (19). Fol-
lowing the general procedure for making 17, E-(3,4,5-tribenzyloxy)-
cinnamyl alcohol30 (171.5 mg, 0.379), Ag2CO3 (119.5 mg, 0.433
mmol), and bromide 16 (148.4 mg, 0.361 mmol) were converted to
19 (100.2 mg, 0.163 mmol, 45%), a white solid. Mp 119−120 °C;
24 (274.8 mg, 0.351 mmol, 66%) as a white solid. Mp 154 °C; [α]24
D
−19.0 (c 0.23, CHCl3); IR (neat) νmax 3309, 3062, 2941, 1749, 1698,
1589, 1503, 1435, 1221 cm−1; TLC (50% ethyl acetate in hexane) Rf =
1
0.48; H NMR (500 MHz, CDCl3) δ 7.44−7.24 (m, 15H), 6.54 (s,
[α]23 −29.5 (c 0.02, CH3OH); IR (neat) νmax 3309, 3029, 2938,
D
2H), 6.35 (d, J = 9.0 Hz, 1H), 5.27 (t, J = 9.5 Hz, 1H), 5.18 (t, J = 9.5
Hz, 1H), 5.11 (s, 4H), 5.06−5.03 (m, 3H), 4.82 (t, J = 9.5 Hz, 1H),
4.33−4.30 (dd, J = 4.0, 12.5 Hz, 1H), 4.09−4.06 (dd, J = 2.0, 12.5 Hz,
1H), 3.82−3.79 (ddd, J = 2.0, 4.5, 10.0 Hz, 1H), 3.46 (d, J = 15.5 Hz,
1H), 3.38 (d, J = 15.0 Hz, 1H), 2.05 (s, 3H), 2.01 (s, 3H), 1.98 (s,
3H), 1.81 (s, 3H); 13C NMR (125.7 MHz, CDCl3) δ 171.2, 170.6,
170.6, 169.8, 169.6, 153.3, 138.0, 137.8, 137.0, 129.3, 128.6, 128.2,
128.0, 127.9, 127.5, 108.9, 78.5, 75.3, 73.7, 72.6, 71.2, 70.3, 68.2, 61.7,
44.1, 20.8, 20.6, 20.3; ESI-HRMS calcd for C43H45NO13Na [M + Na]+,
806.2783; found, 806.2769.
2856, 1581, 1505, 1427, 1126 cm−1; TLC (10% CH3OH in CH2Cl2)
Rf = 0.45; 1H NMR (500 MHz, CD3OD) δ 7.49−7.23 (m, 15H), 6.85
(s, 2H), 6.62 (d, J = 15.5 Hz, 1H), 6.33−6.26 (dt, J = 6.5, 16.0 Hz,
1H), 5.14 (s, 4H), 5.00 (s, 2H), 4.56−4.52 (ddd, J = 1.5, 6.0, 13.0 Hz,
1H), 4.40 (d, J = 8.0 Hz, 1H), 4.36−4.32 (dt, J = 1.0, 6.5, 12.5 Hz,
1H), 3.94−3.90 (dd, J = 1.5, 12.0 Hz, 1H), 3.73−3.70 (dd, J = 5.5,
12.0 Hz, 1H), 3.40 (t, J = 9.0 Hz, 1H), 3.55−3.25 (m, 3H); 13C NMR
(125.7 MHz, CD3OD) δ 154.1, 139.0, 138.8, 138.6, 134.4, 133.6,
129.8, 129.5, 129.1, 128.9, 128.8, 126.4, 107.1, 103.3, 78.1, 78.0, 76.3,
75.1, 72.1, 71.7, 70.7, 62.8; ESI-HRMS calcd for C36H38O9Na [M +
Na]+ 637.2408, found 637.2405.
N-Phenylacetyl-β-D-glucopyranosylamine (7). General deace-
tylation procedure followed by general hydrogenolysis procedure with
24 (88.2 mg, 0.112 mmol) provided 7 (35.3 mg, 0.102 mmol, 91%) as
a yellow oil. [α]25D −3.4 (c 0.22, CH3OH); IR (neat) νmax 3410, 1637,
3-(3,4,5-Trihydroxyphenyl)propyl-β-D-glucopyranoside (5).
General hydrogenolysis procedure with 19 (59.8 mg, 97.0 μmol)
afforded 5 (32.3 mg, 93.2 μmol, 96%) as a yellow oil. [α]24D −20.3 (c
0.175, CH3OH); IR (neat) νmax 3359, 2938, 2835, 1615, 1452, 1078,
1024 cm−1; 1H NMR (500 MHz, CD3OD) δ 6.18 (s, 2H), 4.21 (d, J =
7.5, 1H), 3.87−3.81 (m, 2H), 3.66−3.62 (dd, J = 5.5, 12.0 Hz, 1H),
3.50−3.45 (dt, J = 6.5, 9.5 Hz, 1H), 3.39−3.19 (m, 3H), 3.16 (t, J =
8.0 Hz, 1H), 2.46 (t, J = 7.5 Hz, 2H), 1.80 (p, J = 7.0 Hz, 2H); 13C
NMR (125.7 MHz, CD3OD) δ 146.8, 134.3, 132.0, 108.5, 104.4, 78.1,
77.9, 75.1, 71.6, 69.9, 62.7, 32.6; ESI-HRMS calcd for C15H22O9Na [M
+ Na]+ 369.1156, found 369.1144.
[1-(3,4,5-Tribenzyloxybenzyl)-1,2,3-triazole-4-yl]methyl-
2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (22). To a stirred
solution of azide 20 (93.1 mg, 0.241 mmol) and alkyne 2131 (108.8
mg, 0.241 mmol) in CH2Cl2/H2O (4 mL, v/v, 1:1) were added
CuSO4·5H2O (9.0 mg, 36.2 μmol) and sodium ascorbate (21.5 mg,
0.108 mmol). The heterogeneous mixture was stirred vigorously for 12
h at room temperature. The reaction mixture was diluted with H2O
and extracted with CH2Cl2. The combined organic layer was dried
over Na2SO4 and concentrated to give 22 (199.5 mg, 0.238 mmol,
99%) as a clear oil. [α]23D −29.1 (c 0.65, CHCl3); IR (neat) νmax 3062,
2946, 2843, 1754, 1597, 1433, 1229, 1038 cm−1; TLC (ethyl acetate)
1604, 1532, 1448, 1333 cm−1; H NMR (500 MHz, CD3OD) δ 6.28
1
(s, 2H), 4.85 (d, J = 9.0 Hz, 1H), 3.79−3.76 (dd, J = 2.0, 12.0 Hz, 1H),
3.61−3.58 (dd, J = 5.0, 12.0 Hz, 1H), 3.37−3.20 (m, 6H); 13C NMR
(125.7 MHz, CD3OD) δ 175.5, 147.0, 133.2, 127.0, 109.4, 81.2, 79.6,
79.0, 73.9, 71.3, 62.6, 43.5; ESI-HRMS calcd for C14H15NO9Na [M +
Na]+, 368.0952; found, 368.0958.
ASSOCIATED CONTENT
* Supporting Information
Experimental methods and spectroscopic data for all synthetic
compounds, quantitative HPLC analysis, molecular modeling,
and biological assays. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: daniel.labarbera@ucdenver.edu. Phone: (303) 724-
4116. Fax: (303) 724-7266.
■
76
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77

Journal of Medicinal Chemistry
Article
́
́
(15) Chang, K.-C.; Laffin, B.; Ponder, J.; Enzsoly, A.; Nemeth, J.;
̈
Notes
LaBarbera, D. V.; Petrash, J. M. Beta-glucogallin reduces the
expression of lipopolysaccharide-induced inflammatory markers by
inhibition of aldose reductase in murine macrophages and ocular
tissues. Chem.-Biol. Interact. 2013, 202, 283−287.
(16) Puppala, M.; Ponder, J.; Suryanarayana, P.; Reddy, G. B.;
Petrash, J. M.; LaBarbera, D. V. The isolation and characterization of
β-glucogallin as a novel aldose reductase inhibitor from Emblica
officinalis. PLoS One 2012, 7, e31399.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study is supported by NIH National Eye Institute Grant
EY021498 (MPI: D.V.L. and J.M.P.), Grant EY005856
(J.M.P.), and a diversity supplement to Grant EY021498.
This research utilized services of the Medicinal Chemistry and
the Mass Spectrometry Core facilities housed within the Skaggs
School of Pharmacy and Pharmaceutical Sciences in the
Department of Pharmaceutical Sciences, University of Colo-
rado. The Medicinal Chemistry Core facility is funded in part
by the Colorado Clinical and Translational Sciences Institute
Grant 5UL1RR025780 from NIH NCRR.
(17) Bols, M.; Hansen, H. C. Simple synthesis of β-D-glucosyl esters.
Acta Chem. Scand. 1993, 47, 818−822.
́
(18) Gyorgydeak, Z.; Hadady, Z.; Felfoldi, N.; Krakomperger, A.;
̈
̈
́ ́ ́
Nagy, V.; Toth, M.; Brunyanszki, A.; Docsa, T.; Gergely, P.; Somsak,
L. Synthesis of N-(β-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy-
β-D-glucopyranosyl) amides as inhibitors of glycogen phosphorylase.
Bioorg. Med. Chem. 2004, 12, 4861−4870.
(19) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry:
diverse chemical function from a few good reactions. Angew. Chem.,
Int. Ed. 2001, 40, 2004−2021.
ABBREVIATIONS USED
■
AKR1B1, human aldose reductase; AKR1B10, small intestine
reductase; AKR1A1, aldehyde reductase; NADPH, reduced
nicotinamide adenine dinucleotide phosphate; BGG, β-
glucogallin; BGA, β-glucogallin N-glycoside amide
(20) Davis, B. G. Synthesis of glycoproteins. Chem. Rev. 2002, 102,
579−602.
(21) Koenigs, W.; Knorr, E. Ueber einige derivate des traubenzuckers
und der galactose. Ber. Dtsch. Chem. Ges. 1901, 34, 957−981.
(22) Brito-Arias, M. Nuclear Magnetic Resonance of Glycosides. In
Synthesis and Characterization of Glycosides; Brito-Arias, M., Ed.;
Springer: New York, 2007; pp 314−329.
(23) Klebe, G.; Kramer, O.; Sotriffer, C. Strategies for the design of
inhibitors of aldose reductase, an enzyme showing pronounced
induced-fit adaptations. Cell. Mol. Life Sci. 2004, 61, 783−793.
(24) Ehrig, T.; Bohren, K. M.; Prendergast, F. G.; Gabbay, K. H.
Mechanism of aldose reductase inhibition: binding of NADP
+/NADPH and alrestatin-like inhibitors. Biochemistry 1994, 33,
7157−7165.
(25) El-Kabbani, O.; Rogniaux, H.; Barth, P.; Chung, R. P.; Fletcher,
E. V.; Van Dorsselaer, A.; Podjarny, A. Aldose and aldehyde
reductases: correlation of molecular modeling and mass spectrometric
studies on the binding of inhibitors to the active site. Proteins 2000, 41,
407−414.
(26) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E. Aldose reductase
inhibitors: a potential new class of agents for the pharmacological
control of certain diabetic domplications. J. Med. Chem. 1985, 28,
841−849.
(27) Wood, H. B.; Fletcher, H. G. Migration of a mesitoyl group
from C1 to C2 in α-D-glucopyranose. Derivatives of 2-O-mesitoyl-D-
glucose. J. Am. Chem. Soc. 1956, 78, 2849−2851.
(28) Yoshimoto, K.; Tsuda, Y. Utilization of sugars in organic
synthesis. XI. General path of O-acyl migration in D-glucose
derivatives: acyl migration of methyl mono-O-myristoyl-α- and β-D-
glucopyranosides and mono-O-myristoyl-D-glucopyranoses. Chem.
Pharm. Bull. 1983, 31, 4324−4334.
(29) Dodo, K.; Minato, T.; Noguchi-Yachide, T.; Suganuma, M.;
Hashimoto, Y. Antiproliferative and apoptosis-inducing activities of
alkyl gallate and gallamide derivatives related to (−)-epigallocatechin
gallate. Bioorg. Med. Chem. 2008, 16, 7975−7982.
(30) Li, L.; Chan, T. H. Enantioselective synthesis of epigalloca-
techin-3-gallate (EGCG), the active polyphenol component from
green tea. Org. Lett. 2001, 3, 739−741.
REFERENCES
■
(1) Barski, O. A.; Tipparaju, S. M.; Bhatnagar, A. The aldo−keto
reductase superfamily and its role in drug metabolism and
detoxification. Drug Metab. Rev. 2008, 40, 553−624.
(2) Petrash, J. M.; Tarle, I.; Wilson, D. K.; Quiocho, F. A. Aldose
reductase catalysis and crystallography: insights from recent advances
in enzyme structure and function. Diabetes 1994, 43, 955−959.
(3) Gabbay, K. Aldose reductase inhibition in the treatment of
diabetic neuropathy: Where are we in 2004? Curr. Diabetes Rep. 2004,
4, 405−408.
(4) Brownlee, M. Biochemistry and molecular cell biology of diabetic
complications. Nature 2001, 414, 813−820.
(5) Dvornik, D.; Simard-Duquesne, N.; Krami, M.; Sestanj, K.;
Gabbay, K. H.; Kinoshita, J. H.; Varma, S. D.; Merola, L. O. Polyol
accumulation in galactosemic and diabetic rats: control by an aldose
reductase inhibitor. Science 1973, 182, 1146−1148.
(6) Nicolucci, A.; Carinci, F.; Cavaliere, D.; Scorpiglione, N.;
Belfiglio, M.; Labbrozzi, D.; Mari, E.; Benedetti, M. M.; Tognoni, G.;
Liberati, A. A meta-analysis of trials on aldose reductase inhibitors in
diabetic peripheral neuropathy. Diabetic Med. 1996, 13, 1017−1026.
(7) Bril, V.; Buchanan, R. A. Long-term effects of ranirestat (AS-
3201) on peripheral nerve function in patients with diabetic
sensorimotor polyneuropathy. Diabetes Care 2006, 29, 68−72.
(8) Ginter, E.; Simko, V. Type 2 diabetes mellitus, pandemic in 21st
century. Adv. Exp. Med. Biol. 2012, 771, 42−50.
(9) Fong, D. S.; Aiello, L.; Gardner, T. W.; King, G. L.; Blankenship,
G.; Cavallerano, J. D.; Ferris, F. L.; Klein, R. Retinopathy in diabetes.
Diabetes Care 2004, 27, s84−s87.
(10) Pollreisz, A.; Schmidt-Erfurth, U. Diabetic cataract-pathogenesis,
epidemiology and treatment. J. Ophthalmol. 2010, 2010, 608751.
(11) Zhu, C. Aldose Reductase Inhibitors as Potential Therapeutic
Drugs of Diabetic Complications. In Diabetes Mellitus: Insights and
Perspectives; Oguntibeju, O. O., Ed.; InTech: Rijeka, Croatia, 2013; pp
17−46.
(31) Beckmann, H. S. G.; Wittmann, V. One-pot procedure for diazo
transfer and azide−alkyne cycloaddition: triazole linkages from amines.
Org. Lett. 2007, 9, 1−4.
(12) Kinoshita, J. H. A thirty year journey in the polyol pathway. Exp.
Eye Res. 1990, 50, 567−573.
(13) Ramunno, A.; Cosconati, S.; Sartini, S.; Maglio, V.; Angiuoli, S.;
La Pietra, V.; Di Maro, S.; Giustiniano, M.; La Motta, C.; Da Settimo,
F.; Marinelli, L.; Novellino, E. Progresses in the pursuit of aldose
reductase inhibitors: the structure-based lead optimization step. Eur. J.
Med. Chem. 2012, 51, 216−226.
(14) Calcutt, N. A.; Cooper, M. E.; Kern, T. S.; Schmidt, A. M.
Therapies for hyperglycaemia-induced diabetic complications: from
animal models to clinical trials. Nat. Rev. Drug Discovery 2009, 8, 417−
429.
77
dx.doi.org/10.1021/jm401311d | J. Med. Chem. 2014, 57, 71−77