Design, synthesis, and evaluation of bromo-retrochalcone derivatives as protein tyrosine phosphatase 1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.04.057

A series of bromo-retrochalcones was designed, synthesized and evaluated as PTP1B inhibitors based on licochalcone A and E. Compounds 6, 12, 13, 14, 25, 36, 37, 39, and 41 showed potent inhibitory effects against PTP1B, and compound 37, the most potent am

Full text of DOI:10.1016/j.bmcl.2011.04.057

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3755–3758
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and evaluation of bromo-retrochalcone derivatives
as protein tyrosine phosphatase 1B inhibitors
Zhiguo Liu a, Woojung Lee b, Su-Nam Kim b, Goo Yoon c, , Seung Hoon Cheon a,
⇑
⇑
a College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 300 Yongbong-Dong, Buk-Gu, Gwangju 500-757, Republic of Korea
b KIST Gangneung Institute, Gangneung 210-340, Republic of Korea
c College of Pharmacy, Mokpo National University, 1666 Youngsan-ro, Cheonggye-myeon, Muan-gun, Jeonnam, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 February 2011
Revised 3 April 2011
Accepted 13 April 2011
Available online 23 April 2011
A series of bromo-retrochalcones was designed, synthesized and evaluated as PTP1B inhibitors based on
licochalcone A and E. Compounds 6, 12, 13, 14, 25, 36, 37, 39, and 41 showed potent inhibitory effects
against PTP1B, and compound 37, the most potent among the series, had an IC50 value of 1.9 lM, about
two-fold better than that of the positive control, ursolic acid.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bromo-retrochalcone
Protein tyrosine phosphatase 1B
Licochalcone
Synthetic
The critical down-regulatory step in the insulin signaling path-
way is associated with protein tyrosine phosphatase. Protein tyro-
sine phosphatase 1B (PTP1B) plays a major role in modulating
insulin and leptin signaling pathways. PTP1B knockout mice show
enhanced insulin sensitivity, lower plasma glucose and insulin lev-
els, and are protected against weight gain when fed a high-fat diet
compared to control mice as a result of prolonged phosphorylation
of the insulin receptor substrate proteins.1 The PTP1B-null mice
also have normal development and longevity. In addition, anti-
sense-based oligonucleotides targeting PTP1B have shown efficacy
in type 2 diabetes and have entered phase 2 clinical trials.2 Accord-
ingly, inhibition of PTP1B has been proposed as one of the best val-
idated biological targets for drug discovery in the treatment of type
2 diabetes and obesity.3 Although several types of PTP1B inhibitors
have been reported, the low selectivity and poor pharmacokinetic
properties of these synthetic inhibitors has led to a continued
search for new types of PTP1B inhibitors with improved pharmaco-
logical properties.4
of the licochalcone A derivatives, methyllicochalcone A, which is
methylated at the 40-hydroxy position of licochalcone A, exhibited
approximately two-fold better activity than licochalcone A.5
Thus, it has been postulated that the retrochalcones with di-
versely substituted aryl groups could display enhanced PTP1B
inhibitory activity. Interestingly, replacement of the substituted al-
lyl group in licochalcone E with bromine provided a compound
with much better activity than allyl retrochalcones as a PTP1B
inhibitor. For example, compound 1 had an IC50 of 13.7
lM com-
pared to licochalcone A and E with IC50s of 19.1 M and 20.7
l
lM,
respectively. Herein, we report the design, synthesis, and evalua-
tion of bromo-retrochalcones as a new class of PTP1B inhibitor.
General method for the synthesis of the retrochalcone is depicted
in Schemes 1 and 2. Bromination of 2,4-dihydroxybenzaldehyde fol-
lowed by selective THP protection of the 4-hydroxyl group provided
5-bromo-2-hydroxy-4-(tetrahydropyran-2-yloxy)-benzaldehyde.
We have been searching for a lead compound from natural
products as a potential preclinical candidate for the treatment of
type 2 diabetes mellitus over the last few years. Recently, we re-
ported that the licochalcones A and E, with a 3,3-dimethylallyl
and a 2,3-dimethylallyl group at position 5 in the B ring, respec-
tively, showed good PTP1B inhibitory activities (Fig. 1).5 And one
5
OH
OH
B
B
HO 4'
HO
A
A
OCH3
OCH3
O
O
⇑
Corresponding authors. Tel.: +82 614502682; fax: +82 614502689 (G.Y.); tel.:
+82 625302929; fax: +82 625302911 (S.H.C.).
E-mail addresses: gyoon@mokpo.ac.kr (G. Yoon), shcheon@chonnam.ac.kr
(S.H. Cheon).
Licochalcone A
Licochalcone E
Figure 1. Structures of licochalcone A and E.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.057

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Z. Liu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3755–3758
Br
Br
Br
OTHP
OH
OH
OTHP
1) a
1) c
2) d
e
OHC
2) b OHC
OCH3
OCH3
R
R
OH
OH
O
O
(a) Br2, AcOH, rt, 83% (b) 3,4-Dihydro-2H-pyran, PPTS, CH2Cl2, rt, 89% (c) CH3I, K2CO3, acetone, rt, 88%
(d) Substituted acetophenone, KOH, EtOH-H2O, rt (e) 6N-HCl, THF, rt
R
R
R
R
HO
N
1
.
N
19.
20.
27.
28.
29.
34.
H3CO
2
.
HO
N
N
N
3
4
.
.
H3CO
O
O
35.
36.
21.
22.
H3CO
H3CO
O
N
O
N
O
N
30.
31.
32.
5
6
H3CO2SHN
HN
.
.
O
N
Ph
23.
24.
O
37.
38.
H3CO
H2N
16
.
N
HO
17
.
N
N
H2N
N
25.
26.
O
33.
18
.
HO
Scheme 1. General synthesis of bromo-retrochalcones.
Br
OR1
Br
OR1
RO
1) KOH, EtOH-H2O, rt
2) 6N-HCl, THF, rt
RO
+
OR2
OHC
OR2
O
O
R = CH3, R1 = H, R2 = H
39.
40.
R = H, R1 = THP, R2 = CH3
41. R = CH3, R1 = THP, R2 = H
Scheme 2. Bromo-retrochalcones with modified B ring.
The 2-hydroxyl group was then methylated with MeI/K2CO3 to fur-
nish the aldehyde.6 All bromo-retrochalcones were synthesized by
aldol condensation of 5-bromo-2-methoxy-4-(tetrahydropyran-2-
yloxy)-benzaldehyde with prepared acetophenones in ethanolic
KOH solution followed by removal of the THP protecting group, if
necessary.7
In the case of compounds with an ester, acid or sulfonate
functional group such as 7–15, the aldol condensation product
of 4-hydroxyacetophenone and 5-bromo-2-methoxy-4-(tetrahy-
dropyran-2-yloxy)-benzaldehyde was alkylated, acylated or sul-
fonated with the appropriate alkyl halide, acyl halide or
sulfonyl chloride and then deprotected under acidic conditions
(Scheme 3).
The inhibitory activities of the synthesized retrochalcones
against PTP1B were measured using p-nitrophenyl phosphate
(pNPP) as a substrate, and the results are summarized in Table 1.8
The known PTP1B inhibitor, ursolic acid (IC50 = 3.1 lM), was used
as the positive control. All synthetic compounds, except com-
R
Br
Br
7.
9.
CH2CO2Et
CH2CO2H
c
OTHP
OH
8.
10.
11.
12.
13.
14.
(CH2)3CO2Et
(CH2)3CO2H
COPh
COPh(p-Br)
COPh(p-t-Bu)
SO2Ph(p-Me)
1) a
c
HO
RO
2) b
OCH3
OCH3
O
O
(a) RX, K CO , acetone, rt for and
;
, pyridine, rt for 11-15
7
8 RX
2
3
15.
SO2CH3
(b) 6N-HCl,THF, rt (c) 1M NaOH, EtOH, 40oC
Scheme 3. Synthesis of bromo-retrochalcones with an ester, acid or sulfonate functional group.

Z. Liu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3755–3758
3757
Table 1
displayed comparable inhibitory activity to 16. Unlike dimethyl-
amino compounds 18–20, all compounds with a diallylamino
group on ring A, 22–24, exhibited excellent inhibitory activities
PTP1B inhibitory activity of compounds 1–41
Compound
l
Ma
Compound
l
Ma
Compound
l
Ma
(IC50 = 3.4–4.5 lM). In the case of compounds 25–27 with piperi-
dine substitution on ring A, the para-substituted compound 25
exhibited the most significant activity among the amine
1
2
3
4
5
6
7
8
13.7 0.7 15
9.9 1.4 16
11.1 0.4 17
4.2 0.3 18
3.5 0.6 19
2.9 0.1 20
15.2 2.5 21
10.8 0.4 22
18.4 0.7 29
6.2 0.9 30
6.8 0.3 31
8.0 0.5
11.3 0.1
3.4 0.2
7.1 0.2
4.4 0.5
6.9 0.1
5.3 0.1
2.9 0.3
1.9 0.1
7.0 1.2
2.6 0.1
10.3 1.4
2.9 1.2
3.1 0.3
>30
32
derivatives of the bromo-retrochalcones with an IC50 of 2.6
Compound 28 with pyrazole and 29 with morpholine at the C-40
position had IC50 values of 6.0 M and 8.0 M, respectively. Com-
pound 30 with a methanesulfonamide group at the C-30 position
lM.
13.9 0.8 33
26.4 2.0 34
6.3 0.3 35
3.4 1.1 36
3.5 0.1 37
4.5 0.6 38
2.6 0.3 39
6.8 1.0 40
4.9 0.1 41
6.0 0.1 Ursolic acid
l
l
9
>30
23
provided moderate inhibitory activity (IC50 = 11.3 lM). Substituted
10
11
12
13
14
30.0 2.8 24
4.9 0.2 25
2.3 0.1 26
2.4 0.2 27
2.7 0.1 28
benzoylation of the amine at the C-40 position as in compound 31
with p-isopropylbenzoylated amine greatly increased the inhibi-
tory activity (IC50 = 3.4 lM), following a trend similar to that from
compound 1 to compound 13.
Introduction of additional various allyl substituents at the C-30
position of compound 1 led to compounds 32–34 with two- to
three-fold increases in activity compared to compound 1. Among
them, prenyl-substituted compound 33 had the best activity with
a
Results are expressed as IC50 values (lM) and as mean SD of three replicates.
pounds 9 and 18, dose-dependently inhibited PTP1B with IC50 val-
ues ranging from 1.9 to 26.4 M, and most of them showed better
IC50 of 4.4 l
M. Meanwhile methylation of the C-40 hydroxyl group
l
activity than licochalcone A.5 Introduction of bromine at the C-5 po-
sition, instead of allyl groups, gave compound 1, which had moder-
ate PTP1B inhibitory activity. But compounds without any
substituent at the C-5 position of retrochalcone displayed no PTP1B
inhibitory activities.5 This result indicates that substitution at the
C-5 position of retrochalcone is important for the activity and that
bromine is a better substituent than 3,3-dimethylallyl or 2,3-
dimethylallyl at this position. This finding led us to conduct a quan-
titative structure–activity relationship study of bromo-retrochal-
cones such as compound 1. Methylation of compound 1 at the 40-
hydroxy position gave compound 2, which had better activity than
compound 1, and this observation was in accord with our previous
result.5 In contrast, bromo-retrochalcones bearing a meta-methoxy
group, such as compound 3, showed lower potency than compound
2. Incorporation of various alkyl groups at the 40-hydroxy position
yielded compounds that were much more potent. For example,
introduction of butyl or prenyl group at the 40-hydroxy position
of compounds 32–34 led to compounds 35–37 with the best results.
The most active compound 37 with 2,3-dimethylallyl substitution
at the C-30 position had an IC50 of 1.9
lM, about two-fold better than
that of the positive control, ursolic acid. But introduction of 2,3-
dimethylallyl group at the C-30 position of compound 5 provided
compound 38, which had reduced activity (IC50 = 7.0 lM). Com-
pound 39 with a hydroxyl group at the C-2 position exhibited the
same potency as compound 36 and the positive control, ursolic acid.
Introduction of a tetrahydropyran group at the 4-hydroxy position
in compound 34 produced compound 40, which had decreased
activity (IC50 = 10.3
group at the 4-hydroxy group in compound 39 gave compound
41, which had potent inhibitory activity (IC50 = 2.9 M).
lM), but introduction of a tetrahydropyran
l
On the basis of these results, it appeared that the PTP1B inhib-
itory activities of the bromo-retrochalcones may provide valuable
information regarding structure–activity relationships for the
development of novel PTP1B inhibitors.
gave compounds 4 (IC50 = 4.2
tively, which displayed two- and three-fold increases in activity
compared to compound 2 (IC50 = 9.9 M). However, benzylation
at the 40-hydroxy position gave the most active compound 6
l
M) and 5 (IC50 = 3.5
l
M), respec-
In conclusion, we designed, synthesized, and developed a novel
series of retrochalcones with bromine at position 5 in the B ring as
potential PTP1B inhibitors. Of the bromo-retrochalcone deriva-
tives, compounds 6, 12, 13, 14, 25, 36, 37, 39, and 41 showed po-
tent inhibitory activities with IC50 values ranging from 1.9 to
l
(IC50 = 2.9 lM). This indicates that a hydrophobic group at this po-
sition is preferred for the activity. Alkylation at the 40-hydroxy po-
sition with ethyl bromo-acetate or ethyl bromo-butanoate
2.9
at the C-30 position and methoxy group at the C-40 position, the
most potent among the series, had an IC50 of 1.9 M, about two-
lM. In particular, compound 37 with 1,2-dimethylallyl group
furnished compound 7 (IC50 = 15.2
lM) and 8 (IC50 = 10.8
l
M),
l
respectively. But hydrolysis of the ester in 7 and 8 provided acidic
compounds 9 and 10 with no activity. This result further proved
that hydrophobicity is critical for the activity. Benzoylation of the
40-hydroxy group greatly increased the potency compared to com-
fold better than that of the positive control, ursolic acid. The bro-
mo-retrochalcones with a substituted amine on ring A also showed
promising PTP1B inhibitory properties. These results provide a
starting point for further optimization of substituted retrochal-
cones with bromine at position C-5 as a PTP1B inhibitor. Further
SAR studies of substituted bromo-retrochalcones in PTP1B inhibi-
tion are currently ongoing and the results will be published in
due course.
pound 1 as shown in compound 11 (IC50 = 4.9
lM). Introduction of
para-bromo or para-t-butyl group to the benzoyl moiety provided
strongly active compound 12 (IC50 = 2.3 lM) and 13 (IC50 = 2.4 lM),
respectively. p-Toluenesulfonylation of the 40-hydroxy group also
greatly increased the potency as shown in compound 14
(IC50 = 2.7
(IC50 = 18.4
Replacement of the hydroxyl group at the C-40 position with an
amine led to compound 16 (IC50 = 6.2 M), which exhibited a two-
fold gain in the PTP1B inhibitory activity compared to compound 1.
Compound with meta-oriented amine such as 17 also displayed the
same activity as compound 16. Dimethylation of the amine in
compound 16 gave compound 18, which surprisingly had no activ-
ity. A compound with ortho-dimethylamine on ring A such as 19
showed better activity than a compound with meta-dimethyl-
amine on ring A such as 20. Compound 21, which had a methylene-
dioxy group in addition to the ortho-dimethylamine on ring A,
l
l
M), but methanesulfonylation provided compound 15
M), which had lower activity than compound 1.
Acknowledgments
This work was supported by National Research Foundation of
Korea Grant funded by the Korean Government 2010-0016417.
We thank the Korea Basic Science Institute (KBSI), Gwangju branch,
for performing the NMR and HRMS experiments.
l
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.057.

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Z. Liu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3755–3758
5. Yoon, G.; Lee, W.; Kim, S.; Cheon, S. H. Bioorg. Med. Chem. Lett. 2009, 19, 5155.
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8. PTP1B assay: Recombinant human PTP1B was purchased from BIOMOL
1. (a) Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A. L.;
Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C.-C.; Ramachandran, C.;
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International LP. For the inhibition assay, a sample (3
to a reaction mixture containing enzyme (2 L), reaction buffer [10
citrate (pH 6.0), 0.1 M NaCl, 1 mM EDTA and 1 mM dithiothreitol], water (35
and 50 of 4 mM p-nitrophenyl phosphate (pNPP). The reaction mixture
(100 L) was incubated at 37 °C for 30 min and then quenched by addition of
10 L of 10 N NaOH. The hydrolysis of pNPP was determined by measuring the
absorbance at 405 nm.
l
L in DMSO) was added
L, 50 mM
L)
l
l
l
l
L
l
l
4. Montalibet, J.; Kennedy, B. P. Drug Discovery Today Ther. Strategic 2005, 2, 129.