3′-O-(3-Chloropivaloyl)quercetin, α-glucosidase inhibitor with multi-targeted therapeutic potential in relation to diabetic complications

Article abstract of DOI:10.1515/chempap-2016-0078

The novel derivative of quercetin 3′-O-(3-chloropivaloyl)quercetin (CPQ) inhibited α-glucosidase in a non-competitive manner with an efficacy exceeding that of the parent quercetin. In addition, it inhibited aldose reductase isolated from rat lenses with an IC₅₀ in the low micromolar range and attenuated sorbitol accumulation in isolated rat eye lenses with an activity comparable with that of quercetin. Moreover, it scavenged stable free-radicals of DPPH more efficiently than did quercetin. By inhibiting α-glucosidase and affecting both the polyol pathway and oxidative stress, CPQ represents a promising agent for the multi-targeted pharmacology of diabetic complications.

Full text of DOI:10.1515/chempap-2016-0078

Chemical Papers 70 (11) 1439–1444 (2016)
DOI: 10.1515/chempap-2016-0078
ORIGINAL PAPER
3ꢀ- -(3-Chloropivaloyl)quercetin, α-glucosidase inhibitor
with multi-targeted therapeutic potential in relation
to diabetic complications
b
a
aMarta Soltesova-Prnova, Ivana Milackova, Milan Stefek*
aInstitute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences,
Dúbravská cesta 9, 84104 Bratislava, Slovakia
bFaculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232 Bratislava, Slovakia
Received 20 January 2016; Revised 1 March 2016; Accepted 17 March 2016
The novel derivative of quercetin 3ꢀ-O-(3-chloropivaloyl)quercetin (CPQ) inhibited α-glucosidase
in a non-competitive manner with an efficacy exceeding that of the parent quercetin. In addition,
it inhibited aldose reductase isolated from rat lenses with an IC50 in the low micromolar range
and attenuated sorbitol accumulation in isolated rat eye lenses with an activity comparable with
that of quercetin. Moreover, it scavenged stable free-radicals of DPPH more efficiently than did
quercetin. By inhibiting α-glucosidase and affecting both the polyol pathway and oxidative stress,
CPQ represents a promising agent for the multi-targeted pharmacology of diabetic complications.
c
ꢀ 2016 Institute of Chemistry, Slovak Academy of Sciences
Keywords: 3ꢀ-O-(3-chloropivaloyl)quercetin, α-glucosidase inhibitor, aldose reductase inhibitor,
antioxidant, diabetic complications
Introduction
Nijveldt et al., 2001; Bors & Michel, 2002; Matsuda et
al., 2002, 2003; Williams et al., 2004; Amic et al., 2007;
Boots et al., 2008; Kelsey et al., 2010; Majumdar &
Srirangam, 2010; Stefek, 2011; Singh et al., 2013; Chen
et al., 2015).
In type 2 diabetes, the inhibition of α-glucosidase
reduces the rate of glucose absorption via delayed car-
bohydrate digestion and extended digestion time, re-
sulting in a decrease in postprandial blood glucose lev-
els. Accordingly, α-glucosidase represents a significant
therapeutic target in diabetes and other carbohydrate-
mediated diseases. Much attention has been devoted
to the design and development of pharmacologically
applicable α-glucosidase inhibitors (Park et al., 2008;
Hakamata et al., 2009). Among them, flavonoids have
been widely studied as α-glucosidase inhibitors (Cao
& Chen, 2012; Xiao et al., 2013). In addition to in-
hibiting α-glucosidase, flavonoids have been exten-
sively reported as affecting other multiple key molec-
ular mechanisms involved in the development of di-
abetic complications, including oxidative stress, non-
enzymatic glycation, and polyol pathway (reviewed in:
Recently, 21 novel semi-synthetic derivatives of
quercetin have been prepared and their inhibition of
aldose reductase, the first enzyme of the polyol path-
way, and their antioxidant action were studied (Vev-
erka et al., 2013; Milackova et al., 2013). Among
the compounds studied, 2-chloro-1,4-naphthoquinone
derivative (CHNQ), 3-chloropivaloyl derivative (CPQ)
and monoacetylferuloyl derivative (MAFQ), shown
in Fig. 1, exhibited the highest biological activities.
CHNQ was reported as an efficient aldose reduc-
tase inhibitor and anti-inflammatory agent (Milack-
ova et al., 2015). The anti-inflammatory action of
CPQ was reported in cellular models of immortalised
mouse microglial cell lines BV-2 (Mrvová et al., 2015)
*Corresponding author, e-mail: milan.stefek@savba.sk
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M. Soltesova-Prnova et al./Chemical Papers 70 (11) 1439–1444 (2016)
tion (1 U mL−1 of 0.067 M phosphate buffer pH
6.9) were pre-incubated in 96 well plates at 25◦C for
10 minutes. The reaction was initiated by the addi-
tion of 50 µL of substrate PNPG (5 mM solution
in 0.067 M phosphate buffer; pH 6.9) to each well
at timed intervals. The reaction was monitored at
25◦C for 5 min. The absorbance of the resulting p-
nitrophenol was determined at 405 nm using a spec-
trofluorimeter Infinite M200 TECAN analyser. The
control reaction contained only the vehicle (dimethyl-
sulphoxide (DMSO) or water for acarbose), enzyme
and substrate. The mixtures without enzyme and sam-
ple served as blanks. IC50 values (concentration of
the inhibitor required to produce 50 % inhibition of
the enzyme reaction) were determined both by the
least-squares analysis of the linear portion of the semi-
logarithmic inhibition curves and by non-linear regres-
sion analysis. Each curve was generated using at least
four concentrations of the inhibitor, causing an inhi-
bition in the range from 25–75 %.
The most efficient inhibitor CPQ was tested in ex-
periments to determine the type of inhibition exerted.
The reaction mixture was as described above, except
that the concentration of the substrate varied from
0.1 mM to 1 mM and the concentration of the CPQ
was kept constant at 7.5 µM, 15 µM and 30 µM. The
results were used to construct Lineweaver–Burk plots
and for the determination of Km and Ki values by
using the Graf Pad Prism 5 program.
Fig. 1. Structures of compounds under study.
and rat primary microglia (Kuniaková et al., 2015).
A protective effect of CPQ against injury to the
sarco/endoplasmic reticulum calcium-ATPase by per-
ˇ
oxynitrite was recorded (Zižková et al., 2014).
In the present study, the compounds were screened
for the inhibition of α-glucosidase. For CPQ, the most
efficient α-glucosidase inhibitor, the enzyme kinetics
was studied. A marked inhibition of aldose reductase
and free-radical scavenging activity were recorded for
CPQ, which is thus reported as a promising multi-
target agent of therapeutic potential.
Experimental
CPQ, CHNQ, MAFQ (purity > 99.5 mass %) were
synthesised, purified and verified by BEL/NOVA-
MANN (Bratislava, Slovakia) as described previ-
ously (Veverka et al., 2013). Quercetin, α-glucosidase
from Saccharomyces cerevisiae, p-nitrophenyl-α-D-
glucopyranoside (PNPG), 1,1ꢀ-diphenyl-2-picrylhydr-
azyl (DPPH), trolox, acarbose, diaphorase, resazurin,
M-199 medium (M 3769), D,L-glyceraldehyde,
NADPH, D-glucose and epalrestat were obtained from
Sigma–Aldrich (St. Louis, MO, USA). Other chem-
icals were purchased from local commercial sources
and were of analytical grade quality.
Aldose reductase inhibition assay
ALR2 from rat lenses was partially purified us-
ing a procedure adapted from Hayman and Kinoshita
(1965) as described previously (Veverka et al., 2013).
ALR2 activities were assayed spectrophotometri-
cally as described previously (Veverka et al., 2013)
by determining NADPH consumption at 340 nm and
were expressed as a decrease in the optical density
(O.D.) per second per mg of the protein.
Male Wistar rats, 8–9 weeks old, weighing 200–
250 g, were used as organ donors. The animals came
from the Breeding Facility of the Institute of Exper-
imental Pharmacology and Toxicology, Dobrá Voda
(Slovak Republic). The study was approved by the
Ethics Committee of the Institute and performed in
accordance with the Principles of Laboratory Ani-
mal Care (NIH publication 83–25, revised 1985) and
the Slovak law regulating animal experiments (Decree
289, Part 139, July 9th 2003).
Eye lens sorbitol assay
The freshly dissected eye lenses (1 lens per tube)
were incubated in M-199 medium at pH 7.4, bubbled
at 37◦C with pneumoxide (5 vol. % CO2, 95 vol. % O2)
in the presence of the compound studied dissolved in
DMSO. The final concentration of DMSO in all incu-
bations was 1 %. After 30 min of pre-incubation, the
reaction was initiated by adding glucose to the final
concentration of 50 mM and incubation then contin-
ued at 37◦C. The incubations proceeded for 3 hours
and were terminated by cooling the mixtures in an ice
bath, followed by triple washing of the lenses with ice-
cold phosphate buffered saline (1 mL). The washed
lenses were kept deep-frozen for the sorbitol assay,
which was performed according to Mylari et al. (2003)
as previously described by Stefek et al. (2011).
α-Glucosidase inhibition assay
The α-glucosidase inhibition activity was deter-
mined by partial modification of the procedure re-
ported by Kwon et al. (2006): 50 µL of 0.067 M
phosphate buffer (pH 6.9), 50 µL of the sample so-
lution or vehicle and 50 µL of the enzyme solu-
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DPPH test
To examine the anti-radical activity of the com-
Table 1. Inhibition of α-glucosidase
Compound
IC50/µM
pounds studied, the ethanolic solution of DPPH
(50 µM) was incubated in the presence of the com-
pounds tested (50 µM) at ambient temperature, as
described previously (Stefek et al., 2008). The ab-
sorbance drop, monitored at λmax = 518 nm, during
the first 75-s interval was taken as a measure of the
anti-radical activity. During the 75-s interval used, an
approximately linear decrease in DPPH absorbance
was observed, which was considered to be a good es-
timate of the initial rate of the radical reaction. The
radical studies were performed at ambient tempera-
ture.
CPQ
14.86
49.28
74.83
39.78
303.30
4.35
4.86
12.79
2.46
5.22
CHNQ
MAFQ
QC
Acarbose
Experimental results are mean values
experiments.
SD from at least three
In the present study, the ability of three novel
derivatives of quercetin to inhibit α-glucosidase ac-
tivity, using quercetin and acarbose as references, was
evaluated. The IC50 values shown in Table 1 point
to CPQ, the 3ꢀ-substituted derivative of quercetin,
as being the most efficient inhibitor of α-glucosidase,
exceeding the inhibition activity of unsubstituted
quercetin. Structural modifications of quercetin at po-
sition 4ꢀ resulted in the less active derivatives CHNQ
and MAFQ.
In the next step, the enzyme kinetics for CPQ, the
most efficient inhibitor of α-glucosidase, was analysed.
Non-competitive inhibition was observed in relation
to the substrate 4-nitro-phenyl-α-D-glucopyranoside
with an inhibition constant of Ki = (15.6 3.5) µM
(Fig. 2).
Results and discussion
The synthetic pathways for CPQ, CHNQ and
MAFQ were previously reported by the present study
group (Veverka et al., 2013). CHNQ and MAFQ
were synthesised by the direct acylation of quercetin
with 3-chloro-2,2-dimethylpropanoyl chloride and 4-
O-acetylferulic acid chloride, respectively, in the mix-
ture of N,N-diisopropylethylamine and toluene. The
final products were isolated by silica gel chromatog-
raphy and crystallised from toluene–methanol (3 : 1,
vol.).
CPQ was synthesised in a two-step procedure: 3,7-
bis-benzyloxy-2-(4ꢀ-benzyloxy-3ꢀ-hydroxyfenyl)-5-
hydroxy-chromen-4-one was treated with chloropival-
oyl chloride in dry acetone under a nitrogen atmo-
sphere. The intermediate product, 3,7-bis-benzyloxy-
2-(4-benzyloxy-3-(chlorpivaloyloxy)fenyl)-5-hydroxy-
chromen-4-one (A), was purified by silica gel chro-
matography and crystallised from ethylacetate–hex-
ane (2 : 3, vol.). In the second step, the final prod-
uct CPQ was obtained by catalytic hydrogenation
of the compound A in methanol catalysed by 10 %
Pd/carbon under a hydrogen atmosphere (415 kPa) at
25◦C. The reaction mixture was filtered through celite
and the product was isolated by silica gel chromatog-
raphy using methylene chloride–methanol (18 : 1,
vol.).
The non-competitive type of α-glucosidase inhibi-
tion indicates that carbohydrate substrates of meal
origin would not compete with the inhibitor for the
enzyme.
Aldose reductase inhibition
In diabetic patients, some of the excessive glucose
is metabolised in the polyol pathway. Aldose reduc-
tase, the first enzyme of this pathway, reduces glu-
cose to the organic osmolyte sorbitol in an NADPH-
dependent manner. Due to its poor membrane pen-
etration, sorbitol accumulates in the cells, resulting
in disruption of the osmotic homeostasis of the cells.
Depletion of NADPH due to aldose reductase activ-
ity reduces intracellular GSH, an endogenous antiox-
idant, thereby inducing oxidative stress. In this way,
the polyol pathway in cells is thought to contribute to
the aetiology of chronic diabetic complications (Yabe-
Nishimura, 1998; Srivastava et al., 2005). Aldose re-
ductase thus became a therapeutic target to be inhib-
ited and the search for inhibitors of the enzyme has be-
come an important pharmacological goal (Miyamoto,
2002; Alexiou et al., 2009; Chatzopoulou et al., 2012).
Aldose reductase, apart from its involvement in
diabetic complications via reducing glucose, was
found to efficiently reduce lipid peroxidation-derived
aldehydes and their glutathione conjugates. Lipid
peroxidation-derived lipid aldehydes, such as 4-hydr-
α-Glucosidase inhibition
α-Glucosidase inhibitors decrease the rate of glu-
cose absorption, hence have been suggested as means
of adjunct therapy, in addition to insulin and/or an-
tihyperglycemic drug treatment, to control blood glu-
cose in diabetic patients. Innovative strategies in the
treatment of disorders of multifactorial origin, includ-
ing diabetic complications, are focused on the rational
design of chemical entities able to simultaneously af-
fect multiple key mechanisms. This approach increases
the possibility of successful therapeutic intervention,
decreases the risk of side effects and is economical.
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M. Soltesova-Prnova et al./Chemical Papers 70 (11) 1439–1444 (2016)
Fig. 2. Inhibitory effect of CPQ on α-glucosidase. Michaelis–Menten plot (A); Lineweaver–Burk transformation (B). Initial enzyme
velocity versus concentration of substrate 4-nitrophenyl-α-D-glucopyranoside in the absence ( ) or presence of inhibitor:
•
7.5 µM (ꢀ),15 µM ( ), 30 µM ( ). Non-competitive inhibition, Ki = (15.6
3.5) µM.
Table 2. Inhibition of rat lens aldose reductase
Compound
IC50/µM
CPQ
QC
Epalrestat
14.09
13.60
0.25
0.02
3.60
0.05
Experimental results are mean values
experiments.
SD from at least three
oxy-trans-2-nonenal (HNE), and their glutathione
conjugates (e.g. GS-HNE) were found to be effi-
ciently reduced by aldose reductase to the corre-
sponding alcohols DHN (1,4-dihydroxy-nonene) and
GS-DHN (glutathionyl-1,4-dihydroxynonene), which
mediate inflammatory signals (Chatzopoulou et al.,
2013).
Fig. 3. Effect of CPQ on sorbitol accumulation in isolated rat
lenses cultivated with high glucose in comparison with
quercetin. Glucose, 50 mM; time of incubation, 3 h;
37◦C. Control samples were incubated in the absence
In a previous study (Veverka et al., 2013), screen-
ing of the novel derivatives of quercetin revealed the
aldose reductase inhibitory activity of CPQ. In the
present study, the interaction of CPQ with aldose re-
ductase was studied in greater detail. The CPQ inhi-
bition of the in vitro reduction of glyceraldehyde by
rat lens aldose reductase in comparison with quercetin
and standard epalrestat was determined and charac-
terised by the IC50 value shown in Table 2. 3ꢀ-O-(3-
chloropivaloyl) substitution of quercetin did not sig-
nificantly affect the IC50.
of glucose. Results are mean values
SEM from n ≥
3 independent incubations. **p < 0.01 vs. 0, ***p <
0.001 vs. 0, parametric Student’s t-test for independent
samples.
take of the compound by eye lens tissue, followed by
inhibition of the cytosolic aldose reductase.
Free-radical scavenging activity
Next, the inhibitory effect of CPQ was determined
at the organ level in isolated rat eye lenses. As shown
in Fig. 3, increased sorbitol levels were recorded in
the isolated rat eye lenses incubated with glucose, in
comparison with control incubations without glucose,
reflecting the increased flux of glucose through the cy-
tosolic lens aldose reductase. Sorbitol accumulation
was significantly, and in a concentration-dependent
way, inhibited by CPQ starting at a concentration as
low as 10 µM. This finding indicates the ready up-
As a weak hydrogen atom abstractor, DPPH is
considered to be a good kinetic model for peroxyl
ROO radicals (Blois, 1958; Ratty et al., 1988). The
DPPH assay is routinely used as a primary screen-
ing test of anti-radical efficacy. Fig. 4 shows the time-
dependent decrease in the characteristic absorbance
of the ethanolic solution of DPPH at 518 nm in the
presence of CPQ and QC. The initial fast absorbance
decrease, corresponding to the transfer of the most
labile H atoms, is followed by a slow absorbance de-
.
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Table 3. Anti-radical activities of CPQ and QC in DPPH test
ited α-glucosidase in a non-competitive manner with
an efficacy exceeding that of the parent quercetin; ii)
inhibited ALR2 isolated from rat lenses and atten-
uated sorbitol accumulation in isolated rat eye lenses
with an activity comparable with that of quercetin; iii)
scavenged stable free radical of DPPH more efficiently
than did quercetin. By inhibiting α-glucosidase and af-
fecting both the polyol pathway and oxidative stress,
CPQ represents an example of a promising agent for
the multi-targeted pharmacology of diabetic compli-
cations.
in comparison with standard trolox
Absorbance decrease
Compound
–ΔA at 75 s
–ΔA at 135 s
CPQ
QC
Trolox
0.446
0.376
0.520
0.024
0.010
0.031
0.466
0.442
0.533
0.030
0.033
0.029
The ethanol solution of the DPPH radical (50 µM) was incu-
bated in the presence of the compound tested (50 µM). The
absorbance decrease at 518 nm in the first 75 s and 135 s in-
Acknowledgements. This work was supported by grants
VEGA 2/0041/15 and the Agency of the Ministry of Edu-
cation, Science, Research and Sport of the Slovak Republic
for the Structural Funds of EU, OP R&D of ERDF within
the project ”Evaluation of natural substances and their selec-
tion for prevention and treatment of lifestyle diseases” (ITMS
26240220040).
terval was determined. The results are the mean values
from at least three measurements.
SD
References
Alexiou, P., Pegklidou, K., Chatzopoulou, M., Nicolaou, I.,
&
Demopoulos, V. J. (2009). Aldose reductase enzyme
and its implication to major health problems of the 21st
century. Current Medicinal Chemistry, 16, 734–752. DOI:
10.2174/092986709787458362.
Amic, D., Davidovic-Amic, D., Beslo, D., Rastija, V., Lucic, B.,
& Trinajstic, N. (2007). SAR and QSAR of the antioxidant
activity of flavonoids. Current Medicinal Chemistry, 14, 827–
845. DOI: 10.2174/092986707780090954.
Blois, M. S. (1958). Antioxidant determinations by the use
of
a stable free radical. Nature, 181, 1199–1200. DOI:
10.1038/1811199a0.
Boots, A. W., Haenen, G. R. M. M., & Bast, A. (2008).
Health effects of quercetin: From antioxidant to nuhaceuti-
cal. European Journal of Pharmacology, 585, 325–337. DOI:
10.1016/j.ejphar.2008.03.008.
Bors, W., & Michel, C. (2002). Chemistry of the antioxidant ef-
fect of polyphenols. Annals of the New York Academy of Sci-
ences, 957, 57–69. DOI: 10.1111/j.1749-6632.2002.tb02905.x.
Butkovi´c, V., Klasinc, L., & Bors, W. (2004). Kinetic study
of flavonoid reactions with stable radicals. Journal of
Agricultural and Food Chemistry, 52, 2816–2820. DOI:
10.1021/jf049880h.
Cao, H., & Chen, X. Q. (2012). Structures required of flavonoids
for inhibiting digestive enzymes. Anti-Cancer Agents in
Medicinal Chemistry, 12, 929–939. DOI: 10.2174/187152012
802650110.
Chatzopoulou, M., Alexiou, P., Kotsampasakou, E., & De-
mopoulos, V. J. (2012). Novel aldose reductase inhibitors: A
patent survey (2006–present). Expert Opinion on Therapeu-
tic Patents, 11, 1303–1323. DOI: 10.1517/13543776.2012.72
6615.
Chatzopoulou, M., Pegklidou, K., Papastavrou, N., & De-
mopoulos, V. J. (2013). Development of aldose reductase
inhibitors for the treatment of inflammatory disorders.
Expert Opinion on Drug Discovery, 8, 1365–1380. DOI:
10.1517/17460441.2013.843524.
Chen, J., Mangelinckx, S., Adams, A., Wang, Z. T., Li, W.
L., & De Kimpe, N. (2015). Natural flavonoids as poten-
tial herbal medication for the treatment of diabetes mellitus
and its complications. Natural Product Communications, 10,
187–200.
Fig. 4. Continual absorbance decrease in ethanol solution of
DPPH radical (50 µM) in the presence of equimolar
concentrations of compounds tested at λmax = 518 nm,
quercetin ( ), CPQ ( ). Each point represents mean
•
value
SD from three experiments.
crease representing the residual anti-radical activity
of the antioxidant degradation products. The initial
velocity of DPPH decolorisation determined for the
first 75 s and 135 s intervals was used as a marker
of the anti-radical activity shown in Table 3. Based
on this kinetic parameter, CPQ appears a more effi-
cient scavenger of DPPH free radical than the parent
quercetin, yet less efficient than the standard trolox.
The initial velocity of DPPH decolorisation as a ki-
netic parameter is considered to be of primary impor-
tance in antioxidant evaluation, since a rapid reaction
with low concentrations of short-lived damaging radi-
cals is of the utmost importance for antioxidant pro-
tection. Other authors applied the kinetic approach to
rank flavonoids according to their antioxidant efficacy
(Goupy et al., 2003; Butkovi´c et al., 2004; Villan˜o et
al., 2007).
Conclusions
Goupy, P., Dufour, C., Loonis, M., & Dangles, O. (2003).
Quantitative kinetic analysis of hydrogen transfer reactions
The novel derivative of quercetin CPQ: i) inhib-
Brought to you by | University of Exeter
Authenticated
Download Date | 10/14/16 6:00 PM

1444
M. Soltesova-Prnova et al./Chemical Papers 70 (11) 1439–1444 (2016)
from dietary polyphenols to the DPPH radical. Journal
of Agricultural and Food Chemistry, 51, 615–622. DOI:
10.1021/jf025938l.
Flavonoids: A review of probable mechanisms of action and
potential applications. American Journal of Clinical Nutri-
tion, 74, 418–425.
Hakamata, W., Kurihara, M., Okuda, H., Nishio, T.,
&
Park, H. S., Hwang, K. Y., Oh, K. H., Kim, Y. H., Lee, J.
Y., & Kim, K. (2008). Discovery of novel alpha-glucosidase
inhibitors based on the virtual screening with the homology-
modeled protein structure. Bioorganic & Medicinal Chem-
istry, 16, 284–292. DOI: 10.1016/j.bmc.2007.09.036.
Ratty, A. K., Sunamoto, J., & Das, N. P. (1988). Interac-
tion of flavonoids with 1,1-diphenyl-2-picrylhydrazyl free rad-
ical, liposomal membranes and soybean lipoxygenase-1. Bio-
chemical Pharmacology, 37, 989–996. DOI: 10.1016/0006-
2952(88)90499-6.
Oku, T. (2009). Design and screening strategies for α-
glucosidase inhibitors based on enzymological information.
Current Topics in Medicinal Chemistry, 9, 3–12. DOI:
10.2174/156802609787354306.
Hayman, S., & Kinoshita, J. H. (1965). Isolation and properties
of lens aldose reductase. The Journal of Biological Chem-
istry, 240, 877–882.
Kelsey, N. A., Wilkins, H. M., & Linseman, D. A. (2010).
Nutraceutical antioxidants as novel neuroprotective agents.
Molecules, 15, 7792–7814. DOI: 10.3390/molecules15117792.
Kuniaková, M., Mrvová, N., Knezl, V., & Račková, Ľ. (2015).
Effect of novel quercetin pivaloyl ester on functions of adult
rat microglia. Biologia, 70, 690–702. DOI: 10.1515/biolog-
2015-0082.
Kwon, Y. I., Vattem, D. A., & Shetty, K. (2006). Evaluation of
clonal herbs of Lamiaceae species for management of diabetes
and hypertension. Asia Pacific Journal of Clinical Nutrition,
15, 107–118.
Singh, R., Kaur, N., Kishore, L., & Gupta, G. K. (2013). Man-
agement of diabetic complications: A chemical constituents
based approach. Journal of Ethnopharmacology, 150, 51–70.
DOI: 10.1016/j.jep.2013.08.051.
Srivastava, S. K., Ramana, K. V., & Bhatnagar, A. (2005). Role
of aldose reductase and oxidative damage in diabetes and
the consequent potential for therapeutic options. Endocrine
Reviews, 26, 380–392. DOI: 10.1210/er.2004-0028.
Stefek, M., Snirc, V., Djoubissie, P. O., Majekova, M., De-
mopoulos, V., Račková, Ľ., Bezakova, Z., Karasu, C., Car-
bone, V., & El-Kabbani, O. (2008). Carboxymethylated
pyridoindole antioxidants as aldose reductase inhibitors:
Synthesis, activity, partitioning and molecular modelling.
Bioorganic & Medicinal Chemistry, 16, 4908–4920. DOI:
10.1016/j.bmc.2008.03.039.
Stefek, M. (2011). Natural flavonoids as potential multifunc-
tional agents in prevention of diabetic cataract. Interdisci-
plinary Toxicology, 4, 69–77. DOI: 10.2478/v10102-011-0013-
y.
Stefek, M., Tsantili-Kakoulidou, A., Milackova, I., Juskova,
M., Snirc, V., & Triantos, N. (2011). (2-Benzyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-acetic acid: An aldose
reductase inhibitor and antioxidant of zwitterionic nature.
Bioorganic & Medicinal Chemistry, 19, 7181–7185. DOI:
10.1016/j.bmc.2011.09.053.
Majumdar, S.,
& Srirangam, R. (2010). Potential of the
bioflavonoids in the prevention/treatment of ocular disorders.
Journal of Pharmacy and Pharmacology, 62, 951–965. DOI:
10.1211/jpp.62.08.0001.
Matsuda, H., Morikawa, T., Toguchida, I.,
& Yoshikawa,
M. (2002). Structural requirements of flavonoids and re-
lated compounds for aldose reductase inhibitory activity.
Chemical & Pharmaceutical Bulletin, 50, 788–795. DOI:
10.1248/cpb.50.788.
Matsuda, H., Wang, T., Managi, H., & Yoshikawa, M. (2003).
Structural requirements of flavonoids for inhibition of pro-
tein glycation and radical scavenging activities. Bioorganic
& Medicinal Chemistry, 11, 5317–5323. DOI: 10.1016/j.bmc.
2003.09.045.
Miyamoto, S. (2002). Recent advances in aldose reductase in-
hibitors: Potential agents for the treatment of diabetic com-
plications. Expert Opinion on Therapeutic Patents, 12, 621–
631. DOI: 10.1517/13543776.12.5.621.
Veverka, M., Gallovič, J., Švajdlenka, E., Veverková, E., Pró-
nayová, N., Miláčková, I.,
& Štefek, M. (2013). Novel
Milackova, I., Kovacikova, L., Veverka, M., Gallovic, E., & Ste-
fek, M. (2013). Screening for antiradical efficiency of 21 semi-
synthetic derivatives of quercetin in a DPPH assay. Inter-
disciplinary Toxicology, 6, 13–17. DOI: 10.2478/intox-2013-
0003.
Milackova, I., Soltesova Prnova, M., Majekova, M., Sotnikova,
R., Stasko, M., Kovacikova, L., Banerjee, S., Veverka, M.,
& Stefek, M. (2015). 2-Chloro-1,4-naphthoquinone deriva-
tive of quercetin as an inhibitor of aldose reductase and
anti-inflammatory agent. Journal of Enzyme Inhibition and
Medicinal Chemistry, 30, 107–113. DOI: 10.3109/14756366.
2014.892935.
quercetin derivatives: Synthesis and screening for anti-
oxidant activity and aldose reductase inhibition. Chemical
Papers, 67, 76–83. DOI: 10.2478/s11696-012-0240-5.
Villan˜o, D., Fernández-Pachón, M. S., Moyá, M. L., Troncoso,
A. M., & García-Parrilla, M. C. (2007). Radical scavenging
ability of polyphenolic compounds towards DPPH free rad-
ical. Talanta, 71, 230–235. DOI: 10.1016/j.talanta.2006.03.
050.
Williams, R. J., Spencer, J. P. E., & Rice-Evans, C. (2004).
Flavonoids: Antioxidants or signalling molecules? Free Rad-
ical Biology
& Medicine, 36, 838–849. DOI: 10.1016/j.
freeradbiomed.2004.01.001.
Mrvová, N., Škandík, M., Kuniaková, M., & Račková, L. (2015).
Modulation of BV-2 microglia functions by novel quercetin
pivaloyl ester. Neurochemistry International, 90, 246–254.
DOI: 10.1016/j.neuint.2015.09.005.
Mylari, B. L., Armento, S. J., Beebe, D. A., Conn, E. L.,
Coutcher, J. B., Dina, M. S., O’Gorman, M. T., Linhares,
M. C., Martin, W. H., Oates, P. J., Tess, D. A., Withbroe,
G. J., & Zembrowski, W. J. (2003). A highly selective, non-
hydantoin, non-carboxylic acid inhibitor of aldose reductase
with potent oral activity in diabetic rat models: 6-(5-Chloro-
3-methylbenzofuran-2-sulfonyl)-2-H-pyridazin-3-one. Jour-
-nal of Medicinal Chemistry, 46, 2283–2286. DOI: 10.1021/
jm034065z.
Xiao, J. B., Kai, G. Y., Yamamoto, K., & Chen, X. Q. (2013).
Advance in dietary polyphenols as α-glucosidases inhibitors:
A review on structure–activity relationship aspect. Critical
Reviews in Food Science and Nutrition, 53, 818–836. DOI:
10.1080/10408398.2011.561379.
Yabe-Nishimura, C. (1998). Aldose reductase in glucose toxic-
ity: A potential target for the prevention of diabetic compli-
cations. Pharmacological Reviews, 1, 50, 21–33.
ˇ
Zižková, P., Blaškovič, D., Májeková, M., Švorc, L., Račková,
L., Ratkovská, Ľ., Veverka, M., & Horáková, Ľ. (2014). Novel
quercetin derivatives in treatment of peroxynitrite-oxidized
SERCA1. Molecular and Cellular Biochemistry, 386, 1–14.
DOI: 10.1007/s11010-013-1839-8.
Nijveldt, R. J., van Nood, E., van Hoorn, D. E. C., Boelens,
P. G., van Norren, K., & van Leeuwen, P. A. M. (2001).
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