The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors

DOI: 10.1016/j.bmcl.2013.07.039

Source and publish data:

Bioorganic and Medicinal Chemistry Letters p. 5061 - 5065 (2013)

Update date:2022-08-04

Topics: Synthesis Inhibitors Derivatives Scaffold Biological Evaluation Disulfide PTP1B

Authors:

Chen, Jing

Jiang, Cheng-Shi

Ma, Wen-Quan

Gao, Li-Xin

Gong, Jing-Xu

Li, Jing-Ya

Li, Jia Li, Jia

Guo, Yue-Wei

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Article abstract of DOI:10.1016/j.bmcl.2013.07.039

Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC ₅₀ value of 4.54 μM.

Full text of DOI:10.1016/j.bmcl.2013.07.039

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5061–5065

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: w ww.elsevier.com/locate/bmcl

The ﬁrst synthesis of natural disulﬁde bruguiesulfurol and biological

evaluation of its derivatives as a novel scaffold for PTP1B inhibitors

Jing Chen ^a,, Cheng-Shi Jiang ^a,, Wen-Quan Ma ^b, Li-Xin Gao ^a, Jing-Xu Gong ^a, Jing-Ya Li ^a, Jia Li ^a,

Yue-Wei Guo ^a,

⇑

^aState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zi Road, Zhangjiang Hi-Tech Park,

Shanghai 201203, PR China

^bBiomedical Science Park of Weifang, Weifang National High-Tech Industrial Development Zone, Weifang, Shandong 261205, PR China

a r t i c l e i n f o

a b s t r a c t

Article history:

Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymno-

rrhiza, was concisely synthesized for the ﬁrst time in four steps, and a series of its synthetic derivatives

were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to

have improved pharmacological proﬁle compared with hit 1. Among them, 5a showed the potent selec-

tivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory

Received 7 May 2013

Revised 8 June 2013

Accepted 17 July 2013

Available online 25 July 2013

activity with an IC₅₀value of 4.54 lM.

Keywords:

Bruguiesulfurol

Derivative

PTP1B inhibitor

Type 2 diabetes

Selectivity

According to the World Health Organization (WHO), about 346

million people worldwide suffer from diabetes and its prevalence

is projected to roughly double by 2030.¹Type 2 diabetes, resulting

from the body’s ineffective use of insulin, makes up 90% of diabetes

cases.²Protein tyrosine phosphatase 1B (PTP1B), the ﬁrst mamma-

lian PTP to be puriﬁed and characterized, has been demonstrated

to play a key role in the insulin-dependent signaling cascade.³Tre-

mendous experimental data have validated PTP1B as one of the

best therapeutical targets for the treatment of type 2 diabetes

and obesity.⁴For example, PTP1B-deﬁcient mice have remarkably

low adiposity, and are protected from diet-induced obesity by

increasing basal metabolic rate and total energy expenditure. This

result is consistent with the inference that PTP1B is a major regu-

lator of energy balance insulin sensitivity and body fat stores

in vivo.⁵In addition, accumulating evidence also indicates that

PTP1B is involved in cancer.⁶The positive physiological role of

PTP1B attracts great interest of medicinal chemists, and in the past

decades numerous drug-like PTP1B inhibitors, mostly involving

phosphotyroine (pTyr) mimetics, have been developed.^7,8How-

ever, discovery of anti-type 2 diabetes drugs targeting PTP1B is still

a big challenging task because of the fundamental nature of highly

conserved and positively charged active-site pocket.⁹The current

pTyr mimetics usually have undesirable cell permeability and oral

bioavailability due to the presence of highly negative charged polar

residues in their structures, or show poor PTP1B selectivity versus

TCPTP (T-cell protein tyrosine phosphatase) due to their highly

homologous catalytic domain and identical active sites.¹⁰There-

fore, there is an urgent need to develop novel potential drug scaf-

folds targeting PTP1B.

Marine natural products are a proliﬁc source of lead molecules

for discovering clinically drugs for human diseases.¹¹As a special

and important member, marine disulﬁde- and multisulﬁde-con-

taining metabolites possess varying bioactivities and fantastic

molecular skeletons, which have been paid more and more

attentions by pharmacologists and chemists recently.^12–16Our

group has focused on this ﬁeld for many years, and in our research

project for ﬁnding promising anti-type 2 diabetes drug candidates

a series of unique marine cyclic disulﬁdes and multisulﬁdes with

PTP1B inhibitory activity had been isolated and synthesized.¹⁷Bru-

guiesulfurol (1, Fig. 1), a cyclic 4-hydroxy-dithiosulfonate isolated

for the ﬁrst time from the ﬂowers of mangrove plant Bruguiera

gymnorrhiza,¹⁸was found to exhibit PTP1B inhibitory activity

(IC₅₀= 17.5

icant bioactivity, and low natural yield of 1 stimulated our interest

to synthesize and perform more-in-depth pharmacological

M) by our group.^17bThe uncommon structure, signif-

evaluation. Herein, the present letter describes the ﬁrst concise

synthesis of 1 and biological evaluation of its synthetic derivatives

as selective PTP1B inhibitors.

⇑

Corresponding author. Tel.: +86 21 50805813; fax: +86 21 50807088.

E-mail address: ywguo@mail.shcnc.ac.cn (Y.-W. Guo).

These authors contributed equally to the study.

http://dx.doi.org/10.1016/j.bmcl.2013.07.039

5062

J. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5061–5065

bond. In addition, it is also vital to select a suitable and practical

hydroxyl protecting group. 4-Bromobenzoyl as a common hydro-

xyl protecting group was used since it makes small-molecule com-

pound easy to crystallize, which is helpful for puriﬁcation and

structural identiﬁcation. The initial approach to synthesize 1

(shown in Scheme 1) started from commercially available epi-

bromohydrin (2). Treatment of 2 with 40% aqueous HBr gave 1,3-

dibromo-2-propano (3). The esteriﬁcation between bromide 3

and 4-bromobenzene carboxylic acid yielded ester 4a. Then, ester

4a was reacted with Na₂S₂(prepared from Na₂S and S)²²to form

the key intermediate 5a with the assistance of tetrabutyl ammo-

nium bromide (TBAB) as phase transfer catalyst, following oxidiza-

tion by treatment with oxone to give oxidative product 6a. The

structures of 5a and 6a were conﬁrmed through X-ray diffraction

analysis (Fig. 2).²³Disappointingly, no expected compound 1 was

Figure 1. Structure of bruguiesulfurol (1).

The construction of sulfur–sulfur bond is the decisive step for

the synthesis of 1. Many methods for the formation of disulﬁdes

have been reported, such as oxidative coupling of thiols or Bunte

salts,¹⁹reductive formation from sulfenyl, sulﬁnyl, sulfonyl or thio-

cyanate derivatives,²⁰or the reaction of alkyl halide with sodium

disulﬁde (Na₂S₂).²¹Based on our previous study and analysis of

structural features of 1, the last method was used to form disulﬁde

Scheme 1. Reagents and conditions: (a) 40% aqueous HBr, CH₂Cl₂, 0 °C, 5 h, 85%; (b) 4-bromobenzene carboxylic acid, EDCI, DMAP, CH₂Cl₂, rt, 12 h, 88%; (c) Na₂S₂, cat. TBAB,

CHCl₃, rt, 5 h, 60%; (d) Oxone, NaHCO₃, acetone, 2 h, 81%.

Figure 2. Single-crystal X-ray structures of 5a and 6a.

Scheme 2. Reagents and conditions: (a) pyridinium-p-toluene sulfonate, 2,3-dihydropyran, THF, rt, 2 h, 85%; (b) Na₂S₂, cat. TBAB, CHCl₃, rt, 5 h, 58%; (c) mCPBA, CH₂Cl₂, rt,

4 h, 30%.

Scheme 3. Reagents and conditions: (a) RCO₂H, EDCI, DMAP, CH₂Cl₂, rt, 12 h; (b) Na₂S₂, cat. TBAB, CHCl₃, rt, 5 h; (c) mCPBA, CH₂Cl₂, rt, 4 h.

J. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5061–5065

5063

Table 1

Inhibitory activity of 5a–t against PTP1B and other PTPs presented as IC₅₀

(lM)

Compd

PTP1B

17.5

TCPTP

SHP-1

SHP-2

LAR

11.01 1.31

NA^a

33.97 3.47

ND^b

34.57 4.55

33.42 2.02

48.18 4.91

25.62 4.53

34.10 3.63

42.08 7.86

20.43 3.15

20.36 4.12

10.91 2.47

24.88 2.68

40.67 0.46

14.05 3.63

13.36 2.98

NH₂

22.56 2.95

37.37 5.86

O₂N

14.83 2.31

27.28 7.43

24.37 7.74

13.81 2.72

NO₂

OCH₃

H₃CO

H₃C

78.19 6.98

17.94 1.71

21.45 2.13

35.23 2.82

75.41 4.21

15.77 0.79

22.29 3.01

24.08 4.48

3.02 0.20

35.84 4.29

Oleanolic acid

NA, not active.

ND, not determined.

obtained upon subjection of 6a to a variety of deprotection condi-

tions.²⁴Furthermore, 6a is very stable in acidic conditions resulting

in no reaction occurring. However, it rapidly decomposed in basic

conditions, which suggested the disulﬁde bond might be unstable

in basic condition, but stably exist in acidic condition.

Based on the experimental results above, using hydroxyl pro-

tection group that can be deprotected in acidic conditions seems

available for access to 1. Therefore, the 2-tetrahydropyranyl group

was used as protecting group. The synthetic route to 1 was carried

out as shown in Scheme 2. The hydroxyl group of 3 was protected

5064

J. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5061–5065

Table 2

Inhibitory activity of series of 6 and 7 against PTP1B and other PTPs presented as IC₅₀(lM)

Compd

PTP1B

NA^a

TCPTP

ND^b

SHP-1

SHP-2

LAR

29.00 3.38

Lone pair

27.96 3.83

Lone pair

22.38 1.85

29.68 2.66

4.54 0.47

32.97 2.33

36.80 0.89

11.12 1.14

Lone pair

31.42 2.42

44.98 5.10

52.64 2.87

NA, not active.

ND, not determined.

by 2,3-dihydropyran to yield 3a, which was reacted smoothly with

Na₂S₂to give the desired disulﬁde 3b in 49% overall yield over two

steps. In order to oxidize the disulﬁde bond in 3b, several oxidants

were tried.²⁵Finally, 3-chloroperoxybenzoic acid (mCPBA) was

found to be an efﬁcient oxidant, and target compound 1 was pro-

duced by oxidation and deprotection in one pot with an overall

yield of 30%. The physical and spectral data of 1 were in agreement

with the literature data.^17b,18

original natural product 1, with an IC₅₀value of 11.01

M, and also

showed signiﬁcant selectivity toward PTP1B versus other PTPs,

especially the most homologous PTPCP by threefold. These positive

results encouraged us to prepare a series of derivatives of 1, and to

conduct a preliminary structure–activity relationship (SAR) study

on these compounds.

The syntheses of three series of 5, 6 and 7 were carried out as

shown in Scheme 3. Esteriﬁcation of bromide 3 with various car-

boxylic acids, and following nucleophilic substitution reaction be-

tween ester 4 and Na₂S₂provided disulﬁde 5. Compounds 6 and 7

During the process for synthesizing 1, the key intermediate 5a

was found to exhibit stronger PTP1B inhibitory activity than the

J. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5061–5065

5065

were ﬁnished by oxidative reaction of 5 with mCPBA. The synthetic

derivatives were evaluated in the enzyme inhibition assay against

PTP1B and other four PTPs (TCPTP, SHP-1, SHP-2 and LAR).

Foundation Grant (No. 2012M520956), and was partially funded

by the EU 7th Framework Programme-IRSES Project (No. 246987).

The results of the ﬁrst series of analogs (5a–t) are shown in Ta-

ble 1. Among 5a–h with halo-substituted group in benzene ring,

para-bromo substituted compound 5a was the most active towards

PTP1B, and showed highest selectivity over other PTPs (about

threefold selectivity over TCPTP and LAR; inactive toward to SHP-

1 and SHP-2). Compounds 5f–h were active towards PTP1B with

A. Supplementary data

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.

07.039.

IC₅₀values ranging from 25.62 4.53 to 48.18 4.91

did not showed selectivity towards TCPTP with IC₅₀values ranging

from 20.43 3.15 to 42.08 2.77 M. Compounds 5i and 5j, also

lM, but they

References and notes

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noticeable selectivity towards TCPTP as 5a. The results above indi-

cated that the para-bromo substitution might play a key role in the

PTP1B inhibitory activity and selectivity for 5a. Further, another

two analogs (5k and 5l) with para-bromo substitution in benzene

ring were prepared, but it is disappointing that their PTP1B inhibi-

tory activity were lost with increase in the amount of carbon atoms

between benzene ring and carbonyl group. It is worth noting that

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23. Crystallographic data for the structures of 5a and 6a in this Letter have been

deposited with the Cambridge Crystallographic Data Centre as supplementary

publication number CCDC 934510 and 934511 respectively. Copies of the data

can be obtained, free of charge, on application to CCDC, 12 Union Road,

Cambridge CB2 1EZ, UK [Fax: +44 (0) 1223 336033 or E-mail:

deposit@ccdc.cam.ac.uk].

24. Among these attempts were reactions with concd hydrochloric acid, acetic

acid, concd sulfuric acid, sodium bicarbonate, sodium carbonate, and

potassium carbonate in MeOH, respectively.

compound 5m (IC₅₀= 14.83 2.31 lM), bearing two electron-with-

drawing nitro groups at ortho- and meta-position, almost shows

similar level of PTP1B inhibitory activity to that of 5a, however,

5m did not show good PTP1B selectivity as 5a. Among compounds

5q–t with heteroaromatic substitutions, 5q, 5r and 5t showed weak

or moderate PTP1B inhibitory activity, but they also did not have

PTP1B selectivity as good as 5a.

The results of series of oxidative products 6 and 7 are shown in

Table 2. Surprisingly, most of sulfoxides 7 showed higher PTP1B

inhibitory than their precursor 5. Among all the tested sulfoxides,

compound 7j showed the highest PTP1B inhibitory activity with

an IC₅₀value of 4.54 lM (about 2.4-fold selectivity over TCPTP),

and no effect against other PTPs. Interestingly, the PTP1B inhibitory

activity of 7a was lost compared with 5a, so that there seems to be

ambiguous effect about the formation of sulfoxide. Compared with

sulfoxides 7, sulfones 6 nearly did not have PTP1B inhibitory activ-

ity except compound 6c. It was speculated that the introduction of

another oxygen atom change the conﬁguration of 1,2-dithiolane

and/or increase steric hindrance, which might make these sulfones

can not bind to the active site of PTP1B resulting in the loss of

PTP1B inhibitory activity.

In summary, the ﬁrst concise synthesis of bruguiesulfurol (1)

has been achieved in only four steps in 12.6% overall yield, and a

series of its derivatives were developed and evaluated for in vitro

inhibitory activity against a panel of PTPs. Some derivatives were

found to have improved PTP1B inhibitory activity compared with

hit 1, such as 5a and 7j showing high PTP1B inhibitory activity

and relatively good selectivity. The preliminary SAR study provides

a novel potential scaffolds for designing novel class of PTP1B inhib-

itors. Further studies to improve pharmacological proﬁle and clar-

ify action mechanism for this class of disulﬁde PTP1B inhibitors are

in progress and will be reported in due time.

Acknowledgments

This research work was ﬁnancially supported by the

National Marine ‘863’ Projects (Nos. 2011AA09070102 and

2013AA092902), the Natural Science Foundation of China (Nos.

21021063, 81273430, 21072204, and 81072572), the SKLDR/SIMM

Projects (No. SIMM1203ZZ-03), China Postdoctoral Science

25. The oxidants are mCPBA, oxone, and tert-butyl hydroperoxide, respectively.

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The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors

DOI: 10.1016/j.bmcl.2013.07.039

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