Study of kaempferol glycoside as an insulin mimic reveals glycon to be the key active structure

Article abstract of DOI:10.1021/ml100171x

Diabetes mellitus is increasing in prevalence with patient numbers rising throughout the world. Current treatments for diabetes mellitus focus on control of blood glucose levels. Certain kinds of flavonoids or their glycosides stimulate cells to improve glucose uptake and lower blood glucose levels. We synthesized kaempferol 3-O-neohesperidoside (1), a naturally occurring substance present in Cyathea phalerata Mart., reported to mimic the action of insulin. Synthetic 1 promoted glucose uptake in the cultured cell line, L6. Further studies to determine the core structure responsible for this activity using synthetic compounds revealed neohesperidose to be the primary pharmacophore. These findings support the use of certain saccharides as a potential novel treatment for diabetes mellitus by replacing or supporting insulin.

Full text of DOI:10.1021/ml100171x

pubs.acs.org/acsmedchemlett
Study of Kaempferol Glycoside as an Insulin Mimic
Reveals Glycon To Be the Key Active Structure
Kazuaki Yamasaki,† Ryogo Hishiki,‡ Eisuke Kato,*,† and Jun Kawabata†
†Laboratory of Food Biochemistry, Division of Applied Bioscience, Graduate School of Agriculture and ‡Laboratory of Food
Biochemistry, Department of Bioscience and Chemistry, Faculty of Agriculture, Hokkaido University, Kita-ku, Sapporo,
Hokkaido 060-8589, Japan
ABSTRACT Diabetes mellitus is increasing in prevalence with patient numbers
rising throughout the world. Current treatments for diabetes mellitus focus on
control of blood glucose levels. Certain kinds of flavonoids or their glycosides
stimulate cells to improve glucose uptake and lower blood glucose levels. We
synthesized kaempferol 3-O-neohesperidoside (1), a naturally occurring substance
present in Cyathea phalerata Mart., reported to mimic the action of insulin.
Synthetic 1 promoted glucose uptake in the cultured cell line, L6. Further studies
to determine the core structure responsible for this activity using synthetic
compounds revealed neohesperidose to be the primary pharmacophore. These
findings support the use of certain saccharides as a potential novel treatment for
diabetes mellitus by replacing or supporting insulin.
KEYWORDS Diabetes mellitus, insulin, flavonoid glycoside, glucose uptake
nsulin, a peptide secreted from β-cells located in the
pancreatic islets of Langerhans, is the hormone respon-
sible for reducing the blood glucose level to maintain
DM. Other than metals, some natural organic compounds,
notably flavonoids and their glycosides, are also known to
enhance glucose uptake.10-13 Although most of the reported
flavonoids are PPAR agonists that enhance the activity of
insulin, kaempferol 3-O-neohesperidoside (1) isolated from
Cyathea phalerata Mart. was reported to exhibit an insulin-
like activity and is thus a potential “insulin mimetic”.14 The
flavonoid structure of 1 is similar to a flavonoid reported
previously as a PPAR agonist. However, the insulin-mimetic
activity is unique to 1 and has not been reported in any of the
other flavonoids. In this paper, we investigate the molecular
component responsible for this unique activity of 1. We
synthesized 1 and several related compounds containing
substructures of 1 and tested their activity in cultured cells.
The synthesis of 1 has not been reported previously. Thus,
we followed the synthetic procedure for related compounds
that involves the reaction of neohesperidosyl bromide (7)
with a flavonol (14).15 Commercially available 2 was sub-
jected to deacetylation and subsequent benzylation to give
3. The double bond of 3 was then oxidized by dimethyldiox-
irane (DMDO) to form an R-epoxide, which was selectively
opened by an addition of acetic acid to form 4.16,17
This selectively protected glucose (4) was then reacted with
rhamnose imidate (5) in the presence of TMSOTf as the cata-
lyst.18 The resulting compound (6) was diastereoselectively
brominated in HBr/acetic acid solution to give 7 (Scheme 1).
The flavonol (14) was then synthesized by a previously
I
homeostasis. Impairment in insulin secretion and resistance
to the activity of insulin are both causally linked to the
development of diabetes mellitus (DM), a disease becoming
increasingly prevalent worldwide.1 DM is termed as chronic
hyperglycemia caused either by decreased availability of
insulin due to deletion of β-cells (type 1 DM) or by decreased
sensitivity to insulin, often accompanied by obesity (type 2
DM). Although the underlying cause of the disease can vary,
the treatment of both types of DM is focused on the control of
blood glucose levels. Current therapeutic strategies targeted
at insulin action include the use of exogenous insulin to lower
blood glucose levels; a sulfonylurea, a dipeptidylpeptidase-4
inhibitor, a glucagon-like peptide-1 analogue to improve
secretion of insulin; and a peroxisomal proliferator-activated
receptor (PPAR) agonist to tackle insulin resistance.2-6 All of
these drugs work to improve the symptoms of DM, but none
of them except for insulin itself directly works on somatic
cells to regulate the uptake of blood glucose. Thus, in the
insulin-resistant type 2 DM, there is a continued need for
pharmacological treatments to reduce the levels of blood
glucose.
In an effort to overcome this deficit, there have been a
number of recent reports describing substances that directly
stimulate cells to enhance glucose uptake and decrease
blood glucose levels. The essential trace elements, vanadium
(or its complexes) and zinc, are both known to work in
this way.7-9 However, the risk of side effects such as metal
intoxication precludes accurate estimation of an appropriate
dosage and prevents their utilization as a novel therapy for
Received Date: July 15, 2010
Accepted Date: October 6, 2010
Published on Web Date: October 11, 2010
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used process starting from 8.19 After two hydroxyl groups of
8 were protected, the resulting 9 was subjected to the
aldol condensation with 10. Subsequent cyclization in the
presence of a catalytic amount of iodine gave 12. The flavone
(12) was then oxidized using DMDO, which added a hydro-
xyl group at the 3-C position to give 13. Although 13 had an
amenable structure for the synthesis of 1, a glycosylation
reaction with 7 did not proceed. We suspect that the hydro-
gen bond between the 3-OH and the carbonyl group was
interfering with the reaction. Thus, the benzyl-protecting
group of 5-OH was selectively removed by heating in
an aqueous acetic acid solution to give 14 (Scheme 2). The
flavonol (14) was then coupled with 7 in CHCl3-water
biphasic solution with K2CO3 as a base and tetrabutylam-
monium bromide (TBAB) as a phase transfer catalyst to give
15 with 47% yield. Finally, the acetyl and benzyl groups of
15 were subsequently removed to yield 1 (7% overall yield)
(Scheme 3).20
Scheme 1. Synthesis of Neohesperidosyl Bromide (7)a
The previous report on the insulin-mimetic properties of 1
used rat muscle segments to test its activity.14 To evaluate the
activity of a large number of compounds, we required
enhanced throughput and reproducibility than would be
available with a native tissue assay. Cultured cell lines satisfy
these requirements, and a muscle model cell line, L6, was
selected to test the compounds generated in our study.
The insulin-mimetic activity was measured by quantifying
the glucose uptake promoted by each sample compound,
using 2-deoxyglucose (2-DG) as a nonmetabolic glucose
substitute. The amount of 2-DG transported was quantified
a Reagents and conditions: (a) NaOMe, MeOH. (b) BnBr, NaH, DMF
(52% from 2). (c) DMDO, acetone and then AcOH (68%). (d) Com-
pound 5, TMSOTf, CH2Cl2 (58%). (e) 33% HBr/AcOH, CH2Cl2 (90%).
Scheme 2. Synthesis of Flavonol (14)a
a Reagents and conditions: (a) BnBr, K2CO3, DMF (85%). (b) Compound 10, NaH, DMF, 0 °C (80%). (c) I2, DMSO, 120 °C (95%). (d) DMDO, acetone,
CH2Cl2 (67%). (e) AcOH, H2O, 110 °C (56%).
Scheme 3. Synthesis of Kaempferol 3-O-Neohesperidoside (1)a
a Reagents and conditions: (a) TBAB, K2CO3, CHCl3, H2O (47%). (b) NaOMe, MeOH, CHCl3 (65%). (c) H2, Pd(OH)2, THF, MeOH (quant.).
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Figure 1. Insulin-mimetic activity of 1 at various concentrations. Differentiated L6 cells were treated with the indicated concentrations of
1 for 4 h. Control cells were incubated without sample; 100 nM insulin was used as a positive control. After incubation, cells were incubated
with 2-DG for 20 min, and uptake was measured. Insulin-mimetic activity (i.e., 2-DG uptake) at each concentration of 1 is expressed as a
percentage of 2-DG uptake in control cells. Data are means ( SEMs from five independent repeats of the experiment. Each data point was
performed in quadruplicate in each experiment. *** denotes a statistically significant difference vs control (p e 0.01).
by the enzymatic method reported by Yamamoto et al.21,22
Synthetic 1 exhibited insulin-mimetic activity and promoted
the uptake of 2-DG, with peak uptake observed at 1 nM
concentration (Figure 1). At this concentration, 1 showed
over 200% enhancement of 2-DG uptake as compared with
control cells. Higher and lower concentrations of 1 showed
weaker activity, and uptake of 2-DG was even decreased as
compared with control at 1 mM concentration. Some evi-
dence suggests that the flavonoid moiety may be responsi-
ble for this decreased uptake. With chronic exposure (several
days), some flavonoids enhance glucose uptake.10-13 How-
ever, in the case of more acute exposure (typically a few
hours), it is reported that certain types of flavonoids
(including kaempferol) inhibit glucose uptake.23 Thus, there
may be intramolecular conflict in 1 where different moieties
have opposite effects, and at high concentration, the effect of
the inhibitory moiety may become predominant. Alterna-
tively, it is possible that the inhibition of a glucose transporter
may account for the observed decrease in 2-DG uptake, as 1
contains a glucoselike moiety in its structure. The concentra-
tion dependence of the activity of 1 follows the result of
Zanatta et al., indicating validity of using cultured cell models
to evaluate insulin-mimetic activity.14
To identify the structural unit responsible for the activity
of 1, we then synthesized and tested several compounds
representing various substructures of 1. Kaempferol (17),
kaempferol 3-O-glucoside (18), and neohesperidose (19) are
the core structural elements of 1 so were primarily selected
for screening. Kaempferol (17) and neohesperidose (19)
were easily obtained by deprotection of benzyl and acetyl
groups in the synthetic intermediates 13 and 6, respectively.
Kaempferol 3-O-glucoside (18) was synthesized by attaching
glucose to 14, followed by removal of the protecting groups
(Scheme 4). The insulin-mimetic activity of these synthetic
compounds is summarized in Figure 2. As mentioned above,
many flavonoids or flavonoid-containing plants are reported
to show antidiabetic activity. We hypothesized that the
aglycon compound 17 might be responsible for the activity
of 1. Unexpectedly, as shown in Figure 2, kaempferol (17)
and its 3-glucoside (18) showed negligible activity. Unex-
pectedly, the major substructure responsible for the insulin-
mimetic activity appeared to be neohesperidose (19). This
compound induced 200-250% enhancement of 2-DG up-
take as compared with control cells at both 0.1 and 1 nM
concentrations. Additionally, 19 showed the highest activity
at 0.1 nM, a 10-fold lower concentration than the most
efficacious dose of 1 (Figure 2). A glycoside bond with enol
is relatively weak and may be easily hydrolyzed in aqueous
media or by endogenous intracellular glycosidase. The 10-
fold lower potency of 1 might be explained by the hydrolysis
of ∼10% of 1 to the active product, 19. We currently have no
information to confirm or refute that 1 requires hydrolysis to
become active.
Irrespective of this, we believe that the disaccharide is
the key structure for insulin-mimetic activity. The control of
glucose uptake into the muscle cell by the disaccharide (i.e.,
sugar) is perhaps intuitive, but to the best of our knowledge,
this is a new insight into the function of this disaccharide.
Structurally analogous inositol derivatives are reported to
mimic the activity of insulin and promote glucose uptake in
L6 cells and rat muscle.24,25 The apparent activity of these
inositol derivatives is equivalent to insulin, but their mechan-
ism is suggested to be divergent. Although 19 is dramatically
more potent than the inositol derivatives (being active at
subnanomolar concentrations, 106-fold lower than inositol
derivatives), 19 bears structural similarities to inositol and
may thus have a similar mechanism of action. Further
structural, mechanistic, and pharmacokinetic studies on
the active disaccharide may help to develop and optimize
a novel treatment for DM.
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Figure 2. Insulin-mimetic activity of synthetic compounds. Differentiated L6 cells were treated for 4 h with either 0.1 or 1.0 nM
concentrations of the indicated compounds. Control cells were incubated either without sample (negative control) or 100 nM insulin
(positive control). After incubation, cells were incubated with 2-DG for 20 min, and uptake was measured. The insulin-mimetic activity is
expressed relative to 2-DG uptake in control cells. Each data point was performed in quadruplicate. Data are means ( SEMs from five
independent repeats of the experiment. *** and * denote statistically significant differences (p e 0.01 and p e 0.05, respectively) in relation
to control.
Scheme 4. Synthesis of Compounds with Substructure of 1a
speridose (19). The key disaccharide structure responsible
for this unique activity discriminates 1 from other flavonoids
known to improve hyperglycemia. To our knowledge, this
is the first evidence of a disaccharide enhancing cellular
glucose uptake and may represent a novel strategy in the
development of new treatments for DM. Questions remain
with regard to the mechanism of action of 19 in muscle cells
and to the possible existence of other bioactive disaccharides.
We are currently studying disaccharide structure-activity
relationships to address these questions.
SUPPORTING INFORMATION AVAILABLE Detailed syn-
1
thetic procedure and H NMR spectrum data of new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *Tel/Fax: þ81-11-706-2496. E-mail:
eikato@chem.agr.hokudai.ac.jp.
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