Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B

Article abstract of DOI:10.1016/j.bmcl.2012.09.040

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC₅₀ = 12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.

Full text of DOI:10.1016/j.bmcl.2012.09.040

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7237–7242
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid
derivatives as novel inhibitors of protein tyrosine phosphatase 1B
Hai-Bing He a,b, , Li-Xin Gao c, , Qi-Feng Deng b, Wei-Ping Ma c, Chun-Lan Tang c, Wen-Wei Qiu b,
c,
a,b,
Jie Tang a,b, Jing-Ya Li c, , Jia Li , Fan Yang
⇑
⇑
⇑
a Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, Shanghai 200062, China
b Institute of Medicinal Chemistry and Department of Chemistry, East China Normal University, Shanghai 200062, China
c National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2012
Revised 1 September 2012
Accepted 12 September 2012
Available online 21 September 2012
Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals.
For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2
diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B
(IC50 = 12.74 lM) by a vertical screen for the first time. Further SAR research was carried out by synthe-
sizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle
to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and
a 14-fold selectivity over the homogenous enzyme TCPTP.
Keywords:
4,4-Dimethyl lithocholic acids
Protein tyrosine phosphatase 1B
Ó 2012 Elsevier Ltd. All rights reserved.
Inhibitor
SAR
Diabetes
14–16
Type 2 diabetes and obesity are characterized by insulin and
leptin resistance. Studies suggest that these may be due to defects
in the insulin and leptin signalling pathways.1 The control of insu-
lin signaling is involving the coordinated action of both positive
and negative regulatory proteins. Among the negative regulatory
factors, the protein tyrosine phosphatases (PTPs) play an important
role to blunt or terminate insulin signals by dephosphorylation of
tyrosyl residues.2–5 Protein tyrosine phosphatase 1B (PTP1B), one
of the PTPs, was the first protein-tyrosine phosphatase to be iden-
tified and characterized.6–8 A large body of experimental data
acquired from in vivo studies on humans and PTP1B-knockout
mice has identified PTP1B as a major negative regulator of both
insulin and leptin signals.9–12 Consequently, inhibiting of PTP1B
was considered to be a potential therapeutics for treating Type 2
diabetes and obesity by enhance insulin sensitivity and resistance
to obesity.13
Thereinto, a number of pentacyclic triterpenoids, obtained
by modifying ursolic acid and oleanolic acid at C-3 and C-28 with
long hydrophobic chains was reported with good PTP1B inhibitory
activity.17,18 However, due to the long hydrophobic chains, all the
compounds showed poor water solubility. Thereafter, our group
disclosed a new series of PTP1B inhibitors synthesized by introduc-
ing various fused heterocyclic rings at C-2 and C-3 positions of
maslinic acid (MA, 1) and oleanolic acid (OA, 2) respectively.19,20
Nevertheless, comparing with their inhibition activities to PTP1B,
the selectivity over other homologous enzymes of those pentacy-
clic triterpenoids was unsatisfactory, especially T-cell protein
tyrosine phosphatase (TCPTP). TCPTP is the most closed intracellu-
lar enzyme to PTP1B. Although they have a sequence identity of
about 74% in the catalytic domains, TCPTP and PTP1B clearly fulfill
different biological functions.21
In order to searching for new compounds with better PTP1B/
TCPTP inhibitory selectivity and potential bioavailability, we still
tried to find a new skeleton from natural products. Based on liter-
ature and our previous research, it is evident that a monoacid
based fragment binding with the catalytic site of PTP1B and a
hydrophobic framework or chain are both essential for the activity.
From this point, steroids with a monoacid fragment were taken
into account for screen on our mature PTP1B assay model. As a
result, lithocholic acid (LCA, 3), a steroid acid with the PTP1B inhib-
In the past decades, substantial efforts were made to develop
kinds of PTP1B inhibitors. Modification and evaluation of small
molecular compounds extracted from natural products was widely
adopted as an effective way due to their potential druggability.
⇑
Corresponding authors. Tel.: +86 21 50801313x132; fax: +86 21 50801552
(J.L.); tel.: +86 21 62232764; fax: +86 21 62232100 (F.Y.).
E-mail addresses: jyli@mail.shcnc.ac.cn (J.-Y. Li), jli@mail.shcnc.ac.cn (J. Li),
fyang@chem.ecnu.edu.cn (F. Yang).
itory activity of 12.7 lM was found by a vertical screen.
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.040

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H.-B. He et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7237–7242
hepatic toxicity during cholestasis.22,23 The physiological and bio-
logical functions of LCA and its derivatives have been widely stud-
ied, such as antibacterial, antifungal,24 membrane probe,25 tumor
promotion or inhibition,26,27 and vitamin D receptor modula-
tion.28–30 Compared with a pentacyclic triterpenoid, LCA contains
four fused rings, which means a smaller molecular weight beneficial
to membrane permeability. Furthermore, as a metabolic product,
derivatives of LCA may afford better bioavailability. The screen re-
COOH
COOH
H
H
HO
2
2
H
H
A
A
HO
HO 3
3
H
H
Oleanolic acid (2)
Maslinic acid (1)
sult showed that LCA endows
a
moderate PTP1B inhibitory
M).
(IC50 = 12.7 M) and a slight selectivity over TCPTP (IC50 = 20.5
l
l
It was noted that there is a couple of methyls at C-4 position for 1
and 2, which was considered contributive to activity and selectivity.
Accordingly, we attempt to double-methylate C-4 position of LCA
(Scheme 1). Before oxidated the 3-hydroxyl group by Jones reagent
to obtain 3-ketone (5), the carboxyl group at C-24 position of LCA
was protected with methyl esterification. Reacting 5 with bromine
in DCM and HOAc resulted in a mixture of 2-bromide (6a), 2,4-
dibromide (6b) and 4-bromide (6c) intermediates.31 The mixture
was not separated and refluxed directly in DMF with LiBr and
COOH
2
A
HO
3
H
Lithocholic acid (3)
Li2CO3 to give the corresponding a
,b-unsaturated ketones31,32 with
LCA is a monohydroxy secondary bile acid, formed by bacterial
7-dehydroxylation of the primary bile acid chenodeoxycholic acid
(CDCA) and of the secondary bile acid ursodeoxycholic acid (UDCA),
and is recognized as an endogenous compound associated with
7c as a major product. Compound 8 was obtained by reacting 7c
with methyliodide and potassium tert-butoxide accompanied by
the rearrangement of olefinic bond.32 Hydrolysis of 8 with NaOH
COOH
i
COOCH3
ii
COOCH3
HO
HO
O
H
H
H
3
COOCH3
COOCH3
Br
O
O
H
H
7a
Br
Br
6a
6b
COOCH3
COOCH3
iv
iii
Br
O
O
7b
COOCH3
COOCH3
O
O
H
Br
6c
7c
v
COOCH3
COOH
vi
O
O
8
9
Scheme 1. Reagents and conditions: (i) MeOH,SOCl2, (99%); (ii) Jones reagent, (92%); (iii) HOAc, DCM, Br2; (iv) Li2CO3, LiBr, DMF (48%); (v) t-BuOK, MeI; (vi) (1) NaOH, (2) HCl,
(95%).

H.-B. He et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7237–7242
7239
COOEt
COOCH3
COOCH3
H
O
ii (a or b or c)
i
N
O
R
O
11
11a
11b
11c
R= NH
8
10
R=
R=
NPh
O
iii
COOH
COOCH3
N
O
N
X
14
14a
14b
14c
R= NH
12
R=
R=
NPh
O
11a
11b
13a
13b
13c
14a
14b
15a
15b
15c
v
iv (a or b or c)
COOH
COOEt
vi
11c
14c
N
N
R
N
R
N
15
13
15a
15b
13a
13b
R= H
R= H
R=
R=
Me
Me
15c R=
13c R=
NH2
NH2
Scheme 2. Reagents and conditions: (i) HCOOEt, NaOMe; (ii) (a) NH2NH2Á2HCl, EtOH, reflux, (80%); (b) NH2OHÁHCl, EtOH, reflux, (56%); (c) PhNHNH2ÁHCl, EtOH, reflux, (58%);
(iii) piperidine, EtOH, reflux; (iv) (a) guanidine hydrochloride, NaOMe, EtOH, reflux, (78%); (b) acetamidine hydrochloride, NaOMe, EtOH, reflux, (45%); (c) formamidine
acetate, NaOMe, EtOH, reflux, (25%); (v) LiOH, EtOH/H2O, rt, (78–85%); (vi) 6 M HCl, Dioxane/H2O, rt, (69%).
diazole 22.39 Compound 8 and diethyl oxalate produced 24 via Cla-
solution produced the 4,4-dimethyl derivative of LCA (9).
Compound
(IC50 = 13.2
(IC50 >50
9
l
presented
M) to LCA while a weak inhibition against TCPTP
lM). In spite of the moderate activity, the increased selec-
a similar PTP1B inhibitory activity
isen condensation with sodium hydrogen as the base. Subsequently,
pyrazole-3-carboxylate 25 was prepared from 24 and hydrazine
hydrochloride in a yield of 81%.40,41 Almost all the 23-carboxylic es-
ter intermediates were smoothly hydrolyzed in the condition of
LiOH in the mixed solution of alcohol and water with the exception
of 11c. Treatment of 11c with LiOH or NaOH resulted in the open of
imidazole ring. Finally, the hydrolysis was successfully carried out
in the mixture of hydrochloric acid and methanol. Hydrolysis of
25 gave the double-carboxylic acids derivative 26.
In this Letter we focus on develop a potent PTP1B inhibitor. LCA
was screened as the lead compound for modification and SAR
study. Based on our previous work, to increase inhibitory activity
and selectivity between PTP1B and other homogenous enzymes,
a fused heterocycle was introduced at C-2 and C-3 positions to a
4,4-dimethylated LCA derivative (9). All the synthetic derivatives
were evaluated in the enzyme inhibition assay against PTP1B by
the method of p-nitrophenyl phosphate using compound 27 as ref-
erence compound.42 Homogeneous TCPTP inhibitory activities
were investigated simultaneously by the same method for the
selectivity studying (Table 1).
tivity between the two enzymes inspired us to modify the structure
of 9 to get more potent compounds.
Based on our previous work,19,20 a fused heterocycle on ring A
would markedly improve the water solubility and activity of 1
and 2. On this conclusion, we could imagine that a fused heterocy-
cle on C-2 and C-3 position of 9 would be effective to a higher
activity. Consequently, a fused substituted pyrazole (14a, 14b,
26), oxazole (14c), substituted pyrimidine (15), 1,2,3-thiadiazole
(23), aminothiazole (20) and pyrazine (17) were introduced to 9
as shown in Scheme 2 and 3. Formylation at C-2 of 8 was con-
ducted in the existence of sodium methoxide and ethyl formate
to give 10.33 Afterwards, reacting 10 with corresponding hydrazine
or hydroxylamine by heating the reacting mixture to reflux in eth-
anol gave 11 in a yield of 56–80% with an ethyl caboxylate group at
C-24 position by an ester exchange reaction.33–35 Similarly, fused
pyrimidine (13) was prepared from 12 with guanidine or amidine
in hot ethanol.36,37 Compound 12, the product of 10 reacted with
piperidine, was used for the next step immediately after prepara-
tion due to its instability.
The assay results indicated a good tolerance of kinds of hetero-
cyles fused to LCA. Almost all of the 24-carboxylic acid derivatives
had exhibited more potent inhibition against PTP1B than that of
lead compound LCA except 23. And there was no obvious
difference for the reason of the size of fused cycles. However,
substituents on each heterocycle made big differences. Unsubsti-
tuted pyrazole derivative (14a) presented a threefold improved
Bromination of 8 with BTMABr3 in DCM and MeOH afforded 18.
Reacting 18 with aminourea formed the 2-amino thiazole 19.38 Pyr-
azine 16 was produced from 8 with morpholine, ethanediamine and
sulfur in one-pot.39 The condensation of 8 with aminourea gave 21,
which was then reacted with thionyl chloride in DCM to obtain thia-

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H.-B. He et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7237–7242
COOR
COOR
COOCH3
iv
Br
S
N
S
N
H2N
N
O
18
19 R = Me
20 R = H
22 R = Me
23R = H
ii
ii
iii
vi
COOCH3
COOCH3
i
COOR
N
N
v
H
N
H2N
N
O
O
21
8
16 R = Me
17 R = H
ii
vii
O
COOH
COOR1
COOEt
viii
R2OOC
N
O
OH
O
O
HOOC
O
N
Et
O
H
27
O
24
25 R1 = Et, R2 = Et
26 R1 = H, R2 = H
ii
Scheme 3. Reagents and conditions: (i) morpholine, ethanediamine, S, reflux, (41%); (ii) LiOH, EtOH/H2O, rt, (75–90%); (iii) BTMABr3, DCM/MeOH, rt, (90%); (iv) thiurea, EtOH,
reflux, (20%); (v) aminourea hydrochloride, NaOAC, MeOH, rt, (88%); (vi) SOCl2, DCM, 0 °C, rt, (30%); (vii) diethyl oxalate, NaH, tolune, rt, (81%); (viii) NH2NH2Á2HCl, EtOH,
reflux, (81%).
Table 1
Table 2
Inhibitory activity of LCA derivatives against PTP1B and TCPTP
Inhibitory activity of 14b against SHP-1, SHP-2 and LAR
Compounds
IC50
(
l
M)
TCPTP
TCPTP/PTP1Ba
SHP-1
SHP-2
LAR
PTP1B
Inhibitiona (%)
Inhibition at 40
0.97 5.42
9.36 0.43
26.87 3.68
3
8
12.74 1.41
13.21 2.0
20.45 2.10
>50
>40
19.22 3.30
22.78 4.36
46.6 3.53
10.75 0.87
11.5 1.8
>40
17.09 2.99
>40
23.78 1.24
>40
11.03 1.93
36.58 32.12
9.00 0.95
6.24 0.19
1.6
>3.8
>2.1
4.7
14.1
5.1
0.9
1.2
—
5.0
>1.4
2.8
>4.4
2.0
0.9
0.9
1.6
a
lM.
11a
14a
14b
14c
15a
15b
13c
15c
16
17
19
20
23
19.164 1.66
4.11 0.23
1.62 0.08
9.13 1.20
11.65 1.42
9.11 0.78
>40
in binding to the enzyme. Another amino substituted compound
20 also showed a similar activity to 15c. The comparison between
the three unsubstituted compounds 14c (IC50 = 9.13
(IC50 = 8.62 M) and 15a demonstrated the good tolerance of the
kinds of the fused heterocycles. The only exception to this phe-
nomenon was that the thiadiazole compound 23 (IC50 = 39.44 M)
lM), 17
l
3.61 0.64
28.22 8.51
8.62 2.16
9.04 2.85
5.57 0.98
39.44 8.82
9.27 1.44
3.89 0.08
l
diminished activity dramatically. In order to confirm the impor-
tance of the 24-carboxyl, we chose four pairs of corresponding
ester and acid (11a vs 14a, 13c vs 15c, 16 vs 17, 19 vs 20) for com-
parison. Without any exception, all of the acids showed a more po-
tent inhibitory activity against PTP1B. Among them, 15c has an
activity over 11-fold than 13c. When it comes to the selectivity
between PTP1B and TCPTP, it seemed that there was no specific
regularity to be found, but to our delight, the most potent com-
pound 14b with the best selectivity (TCPTP/PTP1B = 14.1) between
the two homogenous enzymes was obtained. In addition, there are
other three potent compounds (14a, 14c and 15c) showed the
threefold increased selectivities than LCA. Besides TCPTP, the selec-
tivity of the most potent compound 14b between the other three
homogenous enzymes (SHP-1, SHP-2 and LAR) was assessed
sequentially (Table 2). Encouragingly, 14b has no obvious inhibi-
tion against SHP-1, SHP-2 and LAR.
26
27b
a
TCPTP/PTP1B, the ratio of IC50 of TCPTP and PTP1B.
Positive control.
b
PTP1B inhibitory activity than LCA. 1-Phenyl pyrazole (14b,
IC50 = 1.62 M) showed 2.5-fold more potent than 14a, while the
3-carboxyl group on pyrazole (26) reduced the activity to
9.27 M. This may suggest that a hydrophobic group here is more
l
l
beneficial to the affinity to certain enzyme site than a hydrophilic
one. However manipulation of the substituent groups on the 2-po-
sition of pyrimidine presented another case. A more hydrophilic
amino compound (15c, IC50 = 3.61
hydrophobic methyl (15b, IC50 = 9.11
IC50 = 11.65 M). The result indicated that the charge effect of
the sustituents on the fused hetrocycle may also play a key role
l
M) showed better activity than
For evaluating the inhibitory modality of the compound series,
14b was selected for enzymatic kinetic study on PTP1B. The effect
of compound 14b on PTP1B-catalyzed reaction was studied at five
different concentrations (Fig. 1). The results confirmed that 14b is a
l
M) or hydrogen (15a,
l

H.-B. He et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7237–7242
7241
Figure 1. Inhibition of PTP1B catalyzed pNPP hydrolysis by 14b.
Figure 2. Binding conformational comparison of 14b with PTP1B and TCPTP. (a) Binding pose of 14b in the protein surface of PTP1B; (b) binding pose of 14b in the protein
surface of TCPTP; (c) key residues of PTP1B binding site surrounding 14b; (d) key residues of TCPTP binding site surrounding 14b.
competitive PTP1B inhibitor as the Vmax value retained invariable
while the Km value increased with the increasing compound con-
centration. And the Ki value of 14b was calculated to 0.84 lM.
the notion that selectivity between PTP1B and TCPTP can be
achieved by targeting the less homologous second pTyr binding
site.44 Figure 2(d) shows the binding interactions of 14b with
TCPTP. The carboxylic acid group of 14b is also bound into
the active site of TCPTP, the same part of PTP1B. The carbonyl of
the –COOH interacts with Arg222 via a salt bridge, respectively.
The inhibitory modality implied that the binding interactions of
14b with PTP1B might be related to the active site of the enzyme.
In order to further understand the good activity and the best
selectivity of 14b between PTP1B and TCPTP, a molecular docking
analysis of 14b was carried out using LibDock available with Dis-
covery Studio 2.1.43 The preferred coordination modes of 14b with
PTP1B and TCPTP are presented in Figure 2. Figure 2(c) shows the
binding interactions of 14b with PTP1B. The carboxylic acid group
of 14b is bound into the active site. The carbonyl of the –COOH
may interact with Arg221 via a salt bridge and the hydroxyl of
the –COOH shows H-bond interaction with Ser216, while phenyl
group of 14b binds in the second phosphotyrosine (pTyr) binding
While the phenyl group of 14b makes ion–p interaction with gua-
nidine group of Arg114 of TCPTP, not corresponding to the same
part of PTP1B. The docking result demonstrated that 14b extends
the full span of active site and second pTyr binding site of PTP1B.
The inhibitory modality, best activity against PTP1B of 14b and
its good selectivity over TCPCP can be well explained.
In summary, we found LCA with a moderate inhibitory activity
against PTP1B by vertical screen for the first time. By double meth-
ylation at the C-4 position of LCA, we obtained a new lead com-
pound 9 with better selectivity for PTP1B over TCPTP. Thereafter,
a class of compounds with various fused heterocyclic rings on C-
2 and C-3 positions of 9 was synthesized and evaluated. Most of
site of PTP1B by ion–p interaction with guanidine group of
Arg24. Puius and co-workers first identified the site (Asp48,
Val49, Phe52, Ile219, Met258, Arg24, and Arg254) and pioneered

7242
H.-B. He et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7237–7242
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1, SHP-2 and LAR). The 14b as a competitive inhibitor of PTP1B
was confirmed by an enzymatic kinetic study. Moreover, the good
activity of 14b and a 14-fold selectivity over TCPTP were well sup-
ported by the binding interactions with PTP1B and TCPTP respec-
tively on a docking model. This Letter showed an effective way
for discovering specific potentinhibitors of PTP1B by modifying
naturally steroid compounds. Currently we are in the process of
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This work was supported by National Nature Science Founda-
tion of China(81125023) and National Science and Technology Ma-
jor Projects for Major New Drugs Innovation and Development
(2012ZX09304011), Shanghai Science and Technology council
(No. 10142200802 and 11DZ2292200). We also thank ‘Lab of Or-
ganic Functional Molecules, THE SINO-FRENCH INSTITUTE OF ECNU’
for supports.
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