Redox regulation of protein tyrosine phosphatase 1B (PTP1B): Importance of steric and electronic effects on the unusual cyclization of the sulfenic acid intermediate to a sulfenyl amide

Article abstract of DOI:10.1016/j.molstruc.2013.05.044

The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its sulfenic acid (PTP1B-SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule chemical models. These studies suggest that the sulfenic acids derived from the H₂O ₂-mediated reactions o-amido thiophenols do not efficiently cyclize to sulfenyl amides and the sulfenic acids produced in situ can be trapped by using methyl iodide. Theoretical calculations suggest that the most stable conformer of such sulfenic acids are stabilized by n _O→σ* _S-OH orbital interactions, which force the -OH group to adopt a position trans to the S· · ·O interaction, leading to an almost linear arrangement of the O· · ·S-O moiety and this may be the reason for the slow cyclization of such sulfenic acids to their corresponding sulfenyl amides. On the other hand, additional substituents at the 6-position of o-amido phenylsulfenic acids that can induce steric environment and alter the electronic properties around the sulfenic acid moiety by S· · ·N or S· · ·O nonbonded interactions destabilize the sulfenic acids by inducing strain in the molecule. This may lead to efficient the cyclization of such sulfenic acids. This model study suggests that the amino acid residues in the close proximity of the sulfenic acid moiety in PTP1B may play an important role in the cyclization of PTP1B-SOH to produce the corresponding sulfenyl amide.

Full text of DOI:10.1016/j.molstruc.2013.05.044

Journal of Molecular Structure 1048 (2013) 410–419
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Journal of Molecular Structure
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Redox regulation of protein tyrosine phosphatase 1B (PTP1B):
Importance of steric and electronic effects on the unusual cyclization
of the sulfenic acid intermediate to a sulfenyl amide
⇑
Bani Kanta Sarma
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its
sulfenic acid (PTP1B–SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule
chemical models. These studies show that the substituents that can induce steric environment and alter
the electronic properties around the sulfenic acid moiety by SÁ Á ÁN or SÁ Á ÁO nonbonded interactions can
influence the cyclization process. The amino acid residues in the close proximity of the sulfenic acid moi-
ety in PTP1B may play important roles via such interactions in the cyclization of PTP1B–SOH to produce
the corresponding sulfenyl amide.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
A small molecule chemical model for
the redox regultion of PTP1B is
described.
X-ray crystal structure of a sulfoxide
obtained by trapping sulfenic acids
with CH3I is reported.
SÁ Á ÁO/N nonbonded interactions play
important roles in the cyclization of
sulfenic acids.
Electronic effects may play more
important role than steric effects in
efficient cyclization of sulfenic acids.
Other amino acid residues near the
active site of PTP1B may assist
cyclization of protein sulfenic acid.
a r t i c l e i n f o
a b s t r a c t
Article history:
The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its
sulfenic acid (PTP1B–SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule
chemical models. These studies suggest that the sulfenic acids derived from the H2O2-mediated reactions
o-amido thiophenols do not efficiently cyclize to sulfenyl amides and the sulfenic acids produced in situ
can be trapped by using methyl iodide. Theoretical calculations suggest that the most stable conformer of
Received 7 January 2013
Received in revised form 23 April 2013
Accepted 21 May 2013
Available online 30 May 2013
such sulfenic acids are stabilized by nO
?
rÃS–OH orbital interactions, which force the –OH group to adopt
Keywords:
a position trans to the SÁ Á ÁO interaction, leading to an almost linear arrangement of the OÁ Á ÁS–O moiety
and this may be the reason for the slow cyclization of such sulfenic acids to their corresponding sulfenyl
amides. On the other hand, additional substituents at the 6-position of o-amido phenylsulfenic acids that
can induce steric environment and alter the electronic properties around the sulfenic acid moiety by
SÁ Á ÁN or SÁ Á ÁO nonbonded interactions destabilize the sulfenic acids by inducing strain in the molecule.
This may lead to efficient the cyclization of such sulfenic acids. This model study suggests that the amino
AIM analysis
DFT calculations
NBO analysis
Redox regulation
Sulfenic acid
Sufenyl amide
⇑
Current address: Department of Chemistry, Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. Fax: 561-228-3050/2360 0683.
E-mail address: capsbani@gmail.com
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.05.044

B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
411
acid residues in the close proximity of the sulfenic acid moiety in PTP1B may play an important role in the
cyclization of PTP1B–SOH to produce the corresponding sulfenyl amide.
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
Protein tyrosine phosphatases (PTPs) are cysteine-containing
enzymes, which regulate cellular processes in response to extra-
cellular signals [1]. These enzymes regulate signal transduction
pathways involving tyrosine phosphorylation and have been
implicated in the development of cancer, diabetes, rheumatoid
arthritis and hypertension [2]. PTPs catalyze the dephosphoryla-
tion of phosphotyrosine (pTyr) to tyrosine via a phosphocysteine
intermediate and together with protein tyrosine kinase modulate
the level of protein tyrosine phosphorylation [3]. In particular, the
structure and function of the mammalian protein tyrosine phos-
phatase 1B (PTP1B) have attracted significant interest in recent
years due to the importance of this enzyme in insulin signaling
and metabolism [4]. Recent studies suggest that the cellular redox
state is involved in regulating tyrosine phosphatase activity
through the reversible oxidation of the catalytic cysteine to the
corresponding sulfenic acid (Cys–SOH) [5]. The sulfenic acid re-
acts with thiols such as glutathione (GSH) to regenerate the thiol,
and this process maintains the redox state of the protein (Fig. 1A)
[6]. However, the sulfenic acid can undergo further reaction with
H2O2 to produce overoxidized species such as sulfinic (E-SO2H) or
sulfonic (E-SO3H) acids. Recently, it has been shown that the sul-
fenic acid intermediate produced in response to PTP1B oxidation
by H2O2, is rapidly converted into a sulfenyl amide species, in
which the sulfur atom of the catalytic cysteine (Cys215) is cova-
lently bonded to the main chain nitrogen of a serine residue
(Ser216) (Fig. 1B) [7]. This novel and unusual protein modification
has been shown to protect the active site cysteine from irrevers-
ible oxidation to sulfinic (E-SO2H) or sulfonic (E-SO3H) acids [7].
Most importantly, the formation of sulfenyl amide is reversible
and the cleavage of S–N bond by cellular thiols such as glutathi-
one (GSH) converts the inactivated protein back to its catalyti-
cally active form. Furthermore, the inactivated PTP1B can also
be reactivated enzymatically by cysteine-containing redox pro-
teins such as thioredoxin or glutaredoxin [6].
Scheme 1. Cyclization of in situ generated sulfenic acid to their corresponding
sulfenyl amides.
the in situ generated sulfenic acids (3–4) with unreacted thiols
(1–2) (Scheme 2) [9]. Therefore, thiols such as 1 and 2 are not suit-
able chemical models to mimic the cyclization reaction that takes
place at the active site of PTP1B. We have also shown that o-amido
thiophenol with an additional chelating oxazoline substituent at
the 6-position of the phenyl ring (compound 9) is more efficient
and undergoes rapid H2O2-mediated cyclization even in the pres-
ence of external thiols to form the corresponding sulfenyl amide
(11) in quantitative yield (Scheme 3) [9]. Therefore, we proposed
that it may be important to consider the steric and electronic ef-
fects around sulfur [10] for designing suitable chemical models
to mimic the cyclization reaction that takes place at the active site
of PTP1B.
However, several important questions remained unanswered.
For example, (i) how does the in situ formed o-amido phen-
ylsulfenic acids such as 3 react under different conditions? (ii)
Why are the cyclization reactions of o-amido phenylsulfenic
acids to form sulfenyl amides slow and is it possible to detect
or trap such sulfenic acids? (iii) What is the origin of the intra-
molecular nonbonded SÁ Á ÁO interactions in o-amido phenylsulfe-
nic acids and what roles do they play in the cyclization reaction?
(iv) What role do the substituents on the nitrogen atom of o-
amido phenylsulfenic acids have in the cyclization reaction? (v)
What role do the additional groups such as the oxazoline ring
in sulfenic acids 10 play in the cyclization reaction? Is it steric
or electronic? (vi) Can the amide groups in the close proximity
of protein sulfenic acid (PTP1B–SOH) enhance the cyclization
efficiency?
In a recent study, Gates and co-workers have shown that the
cyclization of the o-amido phenylsulfenic acids to their corre-
sponding 3-isothiazolidinones acts as a suitable chemical model
for the H2O2 mediated cyclization reaction that takes place at the
active site of PTP1B (Scheme 1) [8]. We have recently shown that
the H2O2-mediated cyclization of o-amido-thiophenols (1–2) to
form sulfenyl amides (7–8) occurs due to the disproportionation
of the disulfides (5 and 6) that are formed from the reaction of
In this paper we studied the following noteworthy features of
the cyclization reaction of sulfenic acid to sulfenyl amides:
(i) To determine the fate of the in situ produced sulfenic acids,
the reaction of thiol 1 with H2O2 is studied in detail under
different conditions. We observed that the cyclization of
the in situ produced sulfenic acid 3 is a very slow process
and the sulfenic acid 3 can be trapped by using CH3I. The
identity of the sulfoxide (14) produced from the reaction
of 3 with CH3I is confirmed by NMR, ESI mass and X-ray
crystallographic studies.
(ii) In our previous study, [9] based on the computed dis-
tances between the S and the amide O atoms in sulfenic
acids 3 and 4, we predicted that the S and O atoms are
involved in intramolecular SÁ Á ÁO interactions. We also pro-
posed that due to the intramolecular SÁ Á ÁO interaction, the
–NH– and –OH functionalities are positioned in opposite
directions, which hamper the efficient cyclization reaction
of these sulfenic acids to the corresponding sulfenyl
amides. We have now studied the nature of this
Fig. 1. (A) Redox regulation cycle of PTP1B. (B) Participation of the unexpectedly
formed sulfenyl amide in the reversible redox control of PTP1B.

412
B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
Scheme 2. Conversion of thiols to the corresponding sulfenyl amides in the presence of H2O2.
Scheme 3. Proposed mechanism for the formation of sulfenyl amide 11 from thiol 9.
interaction and its influence in the cyclization reaction by
2. Results and discussions
using Natural Bond Orbital (NBO) [11] and Atoms in Mol-
ecules (AIM) [12] analyses using sulfenic acids 3, 4, 20 and
21 as models.
2.1. Reaction of thiol 1 with H2O2
(iii) Recently, we showed that sulfenic acid 10 having an oxaz-
oline ring in the ortho-position of the sulfur atom cyclizes
efficiently and with the help of computational studies we
showed that the heterocyclic ring plays an important role
in this process by neighboring group participation [9].
Herein, we have studied the role of the oxazoline ring in
the cyclization process by isosteric replacement of the ring
heteroatoms. We have also evaluated the role of steric
effect alone by substituting the oxazoline ring by other
bulky groups such as t-Bu that lacks heteroatoms. Along
with 10, we have now included sulfenic acids 24, 26, 28
and 30 and studied the effect of the additional substituent
at the 6- position of o-amido sulfenic acids. These studies
show that the steric and electronic effects of heteroatoms
near the sulfur center of sulfenic acids may play significant
roles in the cyclization process.
(iv) Finally, we have done theoretical calculations on sulfenic
acid 32, as a model, to mimic the possible role of an
amide carbonyl group near the sulfenic acid moiety of
PTP1B. We propose that the nearby amide oxygen atom
can involve in SÁ Á ÁO non bonded interactions, sulfenic acid
32 may cyclize more efficiently and, therefore, amido
groups near to the sulfenic acid moiety of PTP1B may
influence the cyclization process.
Recently, we have shown that the cyclization reaction of the o-
amido thiophenols 1 and 2 in presence of H2O2 via sulfenic acids 3
and 4 is a very slow process and it is the disproportionation reac-
tion of the disulfides 5 and 6 formed in the reaction that leads to
the formation of sulfenyl amides 7 and 8 (Scheme 2) [9]. Further,
it was observed that the disproportion reaction of the disulfides
5 and 6 are highly solvent dependent and much slower in CH3CN
compared to protic solvents [9]. Therefore, a detailed analysis of
the products formed in the reaction of the o-amido thiophenols
in presence of H2O2 is considered to be of interest to have a better
understanding of the cyclization process. Accordingly, we have
undertaken a detailed analysis of the products that are formed
from the reaction of thiol 1 with H2O2 under different conditions.
We have observed that the reaction of thiol 1 with H2O2 in CH3
CN produced disulfide 5 in quantitative yield. The yield of disulfide
5 was unaffected when the reaction was carried out in CH3CN in
the presence of an excess amount methyl iodide (CH3I), (final con-
centrations: 1, 17.0 mM; H2O2, 20.5 mM; CH3I, 7.97 M; acetonitrile,
ꢁ50% by volume). It is to be noted that the formation of disulfide 5
in the H2O2-mediated oxidation of 1 is mainly due to the reaction
between the unreacted thiol 1 and the sulfenic acid 3 produced
in situ and not due to the dimerization of the sulfenic acid as
CH3I is known to block the dimerization of sulfenic acids [8]
(Scheme 4). On the other hand, when the reaction of thiol 1 with

B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
413
H2O2 in the presence of an excess amount of CH3I was carried out
in a 1:1 mixture of acetonitrile and phosphate buffer (pH = 7.5)
(final concentrations: 1, 11.9 mM; H2O2, 12.0 mM; buffer,
174.6 mM, pH 7.5; CH3I, 5.58 M; acetonitrile, 30% by volume),
we obtained compound 13 (ꢁ90%) along with small amounts of
sulfoxide 14 (ꢁ10%) (Scheme 4) and no disulfide (5) formation
was observed.
The sulfide 13 is formed due to the fast methylation of thiol 1 in
phosphate buffer. This was confirmed by independent reaction of
thiol 1 with CH3I in phosphate buffer, which produced 13 in quan-
titative yield in 1 h. However, the reaction of thiol 1 with CH3I was
found to be very slow in acetonitrile and 13 was obtained in ꢁ10%
yield along with ꢁ30% disulfide 5 (Scheme 5). In this particular
case, most of the thiol 1 remained unreacted even after 15 h.
Therefore, it is clear that due to the slow reaction between thiol
1 and CH3I in CH3CN, the reaction of thiol 1 with H2O2 in presence
of excess CH3I produces the disulfide 5 in quantitative yield.
strongly depends on the amount of disulfide (5) impurity present
in the reaction mixture.
The unusual disproportionation of disulfides 5 and 6 may be be-
cause of the presence of SÁ Á ÁO interaction as evidenced from the
crystal structure of 6, where both the sulfur atoms are involved
in SÁ Á ÁO interactions [9]. In contrast to the disulfide 5 and 6, the
unsymmetrical disulfides 15–17 (Scheme 6) were found to be sta-
ble in solution and did not produce any sulfenyl amide species.
This may be because both the sulfur atoms are not involved in
SÁ Á ÁO interaction in 15–17. DFT calculations using B3LYP/6-
31G(d) level of theory [13] reveal the presence of SÁ Á ÁO interactions
of the sulfur atoms with the ortho-amide oxygen atoms in 15 and
17 to form five-membered rings [15: rSÁ Á ÁO = 2.69 Å; ESÁ Á ÁO = 5.29 -
kcal molÀ1; 17: rSÁ Á ÁO = 2.71 Å; ESÁ Á ÁO = 4.71 kcal molÀ1] (ESÁ Á ÁO = NBO
second-order perturbation energy [11]) (see Scheme 6).
2.3. Formation of sulfoxide 14 via methylation of sulfenic acid 3
2.2. Disproportionation of the disulfide 5
The formation of sulfoxide 14 in the reaction of thiol 1 with
H2O2 in a 1:1 mixture of acetonitrile and phosphate buffer even
in the presence of an excess amount of CH3I may occur via two dif-
ferent pathways: (i) methylation of the sulfenic acid 3 or (ii) oxida-
tion of 13 in presence of H2O2. To find out whether the oxidation of
13 by H2O2 under the conditions described above can produce 14,
we synthesized compound 13, purified and treated it with H2O2 in
CH3CN/buffer (1:1) (Scheme 7). This reaction, however, did not
produce 14 even after 24 h. Similarly, sulfides 18 and 19 that are
structurally similar to 13, did not undergo oxidation in presence
of H2O2 in CH3CN/buffer (1:1) even after 24 h. These observations
indicate that sulfides such as 13, 18 and 19 are not reactive to
H2O2 in CH3CN/buffer (1:1) under the conditions discussed above.
Therefore, the formation of compound 14 must take place via the
methylation of the sulfenic acid 3. The identity of sulfoxide 14
was unambiguously confirmed by NMR, mass and X-ray crystallo-
graphic studies (Fig. 2). The crystal structure of 14 shows an unu-
sual SÁ Á ÁO interaction between the tetravalent sulfur atom and the
amide carbonyl moiety. The SÁ Á ÁO distance of 2.75 Å is much short-
er than the sum of the van der Waal’s radii of sulfur and oxygen
atoms (3.25 Å).
We have observed that the disulfide 5 disproportionates to give
thiol 1 and sulfenyl amide 7. Therefore, the yield of sulfenyl amide
7 may depend on the amount of disulfide (5) impurity present with
thiol 1. To verify this, we have designed experiments where the
disulfide 5 was mixed in different amounts along with a fixed
amount of thiol 1. We observed that the yield of sulfenyl amide
7 increases with an increase in the amount of disulfide 5 added
to thiol 1. In a typical experiment, thiol 1 was mixed with one
equivalent of the disulfide 5 and treated with H2O2 and CH3I (ex-
cess) in 1:1 a mixture of CH3CN and phosphate buffer (final con-
centrations: 1, 3.97 mM; 5, 3.98 mM; H2O2, 13.23 mM; buffer,
174.6 mM, pH 7.5; CH3I, 5.58 M; acetonitrile, ꢁ35.0% by volume).
As expected, we have obtained compounds 7 (35%) and 13 (45%)
as major species in the reaction along with sulfoxide 14 in ꢁ10%
yield. As discussed above, when a similar reaction of thiol 1 with
H2O2 in presence of excess of CH3I was carried out in CH3CN and
phosphate buffer mixture, we only observed the formation of com-
pound 13 and 14 and no sulfenyl amide (7) formation was ob-
served. This indicates that the formation of cyclic compound 7
Scheme 4. The reaction of thiol 1 with H2O2 in presence of excess of CH3I produces disulfide 5 in acetonitrile. But the same reaction produces sulfide 13 and sulfoxide 14 in
1:1 acetonitrile:phosphate buffer.

414
B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
Scheme 5. Reaction of thiol 1 with CH3I in acetonitrile and 1:1 acetonitrile:phosphate buffer.
Scheme 6. Chemical structures of mixed disulfides 15–17.
Fig. 2. Crystal structure of 14 shows the presence of SÁ Á ÁO nonbonded interaction. A
water molecule was found to be hydrogen bonded to the amide –NH– group.
2.4. Theoretical studies
2.4.1. Intramolecular SÁ Á ÁO nonbonded interactions in o-amido
phenylsulfenic acids
The experimental observations discussed above clearly indicate
that the cyclization of sulfenic acid 3 to sulfenyl amide 7 is a slow
process and the o-amido thiophenols may not be suitable models
to study the redox regulation that takes place at the active site of
PTP1B. To find out the reason for the slow cyclization of the such
sulfenic acids, we carried out density functional theory (DFT) cal-
culations on sulfenic acids 3, 4, 20 and 21 (Schemes 2 and 8) using
B3LYP/6-31G(d) level of theory [13]. We used hybrid B3LYP func-
tional with 6-31G(d) basis set calculations as they have recently
been used successfully by us [9] and Boyd and co-workers [15]
to study the cyclization of sulfenic acids. Recently, Bayse and co-
workers [16] have used solvent-assisted proton exchange (SAPE)
to study the cyclization of such selenium system.
Scheme 7. Reaction of sulfenic acid 3 with CH3I produces sulfoxide 14. Sulfides 13
and 18–19 do not react with H2O2.
To predict the most stable conformation of o-amido sulfenic
acids, a conformational search on sulfenic acid 20 was performed.
It has been observed that the conformer of 20 with an intramolec-
ular SÁ Á ÁO interaction is at least 1.3 kcal molÀ1 more stable than
other conformers (Fig. S1, Supporting information). This geometri-
Interestingly, 14 may lead to the formation of cyclic sulfenyl
amide 5 in CH3CN/buffer because such a transformation is known
in the literature for the selenium analogue of 14 [14]. Therefore, we
treated 14 with a 1:1 mixture of acetonitrile and phosphate buffer
but no sulfenyl amide formation was observed even after 15 h. This
indicates that sulfoxide 14 is not involved in the cyclization of 1–7
in presence of H2O2. These studies suggest that although the oxy-
gen atoms of sulfenic acids are considered as very weak nucleo-
philes, the nucleophilic attack of oxygen atom of sulfenic acid 3
on CH3I produces 14. Therefore, the cyclization of sulfenic acid 3
to sulfenyl amide 7 must be a very slow process and the o-amido
thiophenols may not be suitable models to study the redox regula-
tion that takes place at the active site of PTP1B.
Scheme 8. Cyclization reaction of sulfenic acids 20 and 21 to sulfenyl amides 22
and 23.

B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
415
cal arrangement is further supported by the crystal structures of 8
[9] and 14, which also contain SÁ Á ÁO nonbonded interactions. DFT
calculations indicated the presence of intramolecular SÁ Á ÁO interac-
tions in the sulfenic acids 3, 4, 20 and 21 (Fig. 3) due to the involve-
amide. Further, theoretical studies suggested a neighboring group
participation of the oxazoline ring in the transition state of 10
[9]. Herein, we studied the role of the additional substituent at
the 6-position of the phenyl ring of sulfenic acids such as 10 on
the cyclization reaction by using NBO and AIM analyses. Interest-
ingly, because of the steric hindrence of the additional substituents
at the 6-position of the phenyl ring, the ortho-amide oxygen atom
of sulfenic acid 10 cannot involve in a noncovalent interaction and
unlike sulfenic acids 3, 4, 20 and 21 the linear arrangement of
OÁ Á ÁS–OH is not possible in 10. In contrast, the additional oxazoline
ring in 10 forces the OH group towards the NH group. In addition to
that, the oxazoline nitrogen atom forms a nonbonded SÁ Á ÁN inter-
ment of nO
?
rÃ
orbital interactions and the SÁ Á ÁO distances
S–OH
are found to be much shorter than the sum of the van der Waal’s
radii of sulfur and oxygen atoms (3.25 Å) (Table 1). The SÁ Á ÁO non-
bonded interaction between a divalent sulfur and an oxygen atom
attracts considerable current interest [17] Tomoda and co-workers
recently suggested that the SÁ Á ÁO nonbonded interactions not only
regulate enzymatic functions, but also may stabilize folded protein
structures [18] The NBO analysis [11] at B3LYP/6-31G(d) level of
theory on 3, 4, 20 and 21, suggests that the stabilization energy
action (SÁ Á ÁN = 2.83 Å; ESÁ Á ÁN = 2.95 kcal molÀ1
; qbcp = 0.019 au)
due to nO
?
rÃ
orbital interaction (ESÁ Á ÁO) (NBO second order
due to nN
?
rÃ
orbital interaction. DFT calculations and AIM
S–OH
S–OH
perturbation energy) is about 13 kcal molÀ1 (Table 1). Further,
the generation of a bond critical point (bcp) between the oxygen
and sulfur atom and a ring critical point (rcp) for the resulting 5-
membered ring clearly indicates the presence of SÁ Á ÁO nonbonded
interaction in 3, 4, 20 and 21 (Table 1). Due to these interactions,
the –OH group adopts a position trans to the SÁ Á ÁO interaction,
leading to an almost linear arrangement of the OÁ Á ÁS–O moiety (Ta-
ble 1). Thus the cyclization partners –OH and –NH stay far away
from each other and this may be the reason for the slow cyclization
of such sulfenic acids to their corresponding sulfenyl amides. As
SÁ Á ÁO nonbonded interaction energies and electron densities at
analysis also suggested the presence of such stabilizing SÁ Á ÁN inter-
action (SÁ Á ÁN = 2.76 Å; ESÁ Á ÁN = 6.03 kcal molÀ1
; qbcp = 0.020 au) be-
tween the oxazoline nitrogen and the sulfur atom [nN
?
rÃ
S–N
orbital interaction] in the sulfenyl amide 11. The crystal structure
of 11 also confirms the presence of strong SÁ Á ÁN interactions [9].
Similarly, in sulfenic 24 where the alcoholic moiety in 10 has been
replaced by a hydrogen atom, a similar geometrical arrangement
and SÁ Á ÁN nonbonded interaction were observed by NBO and AIM
analyses. Therefore, the oxazoline rings in 10 and 24 not only pre-
vent the SÁ Á ÁO interaction by steric hindrance to force the –OH
moiety closer to the –NH– group and but also form additional non-
bonded SÁ Á ÁN interactions, which may facilitate the cyclization
process.
the bond critical point (qSÁ Á ÁO) do not change much with the change
in the substituent on the nitrogen atom, we assume that the cycli-
zation efficiency will not depend on the substituent on the nitro-
gen atom.
2.4.3. Isosteric replacement and importance of steric effect
One way to evaluate the importance of steric and electronic ef-
fects in the cyclization reaction is the isosteric replacement of het-
eroatoms of the oxazoline ring in sulfenic acids 10 and 24. The
isosteric replacement of the nitrogen and oxygen atoms with –
CH– and –CH2– groups, respectively, are expected to retain the ste-
ric hindrance at the 6-postion of the phenyl ring, but would alter
the electronic properties around the sulfenic acid moiety (ÀSOH).
As expected, DFT calculations suggest that the introduction of the
5-membered ring having no heteroatoms does maintain the steric
bulkiness of the 6-substituent in the sulfenic acids and this steric
hindrance is sufficient to prevent any nonbonded SÁ Á ÁO interac-
tions between the sulfur and the carbonyl oxygen atom in
2.4.2. Role of addition groups near the sulfenic acid (–SOH) moiety
We have previously shown that the sterically hindered thiol 9,
in which the 6-H in compound 2 has been replaced by an oxazoline
moiety (Scheme 3), reacts with H2O2 to produce the sulfenyl amide
11 in a quantitative yield [9]. We proposed that the introduction of
the oxazoline ring in the 6-position provides steric hindrance in
the thiol 9 to prevent the oxidation of thiol to the corresponding
disulfide 12 [9] and the SÁ Á ÁN interactions [19] between the sulfur
atom and the 5-membered heterocyclic nitrogen atom in the sulfe-
nic acid may force the –OH moiety to approach the –NH– group
facilitating the cyclization reaction to form expected sulfenyl
Fig. 3. B3LYP/6-31G(d) level optimized geometries and AIM structures of sulfenic acids 3, 4, 20 and 21.

416
B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
Table 1
Structural parameters and NBO second order perturbation energy and AIM parameters for the sulfenic acids 3, 4, 20 and 21 calculated at B3LYP/6-31G(d) level of theory.
À3
À3
Compd. (R group on N)
rSÁ Á ÁO (Å)
<O–S–O (°)
ESÁ Á ÁO (kcal molÀ1
)
qSÁ Á ÁO ea0
qrcp ea0
3 (Ph)
4 [C(Me)2CH2OH]
20 (H)
2.457
2.448
2.471
2.462
176.6
176.8
176.7
176.7
14.00
14.75
13.69
14.11
0.0358
0.0354
0.0338
0.0336
0.0202
0.0200
0.0195
0.0201
21 (Me)
compounds 26 and 28 (see Supporting information for optimized
structures). However, as the heteroatom-sulfur nonbonded inter-
action is absent in 26 and 28 their cyclization efficiency to form
sulfenyl amides 27 and 29 is predicted to be lower than that of
the conversion of sulfenic acids 10 and 24 to sulfenyl amides 11
and 25. Further, when a t-butyl group was introduced at the 6-po-
sition of the o-amido phenylsulfenic acid (compound 30, Fig. 4),
similarly to sulfenic acids 26 and 28, the optimized structure of
30 shows that the t-butyl group pushes the –OH group close to
the –NH– group. Therefore, it can be concluded that additional
substituent at the 6-position of o-amido sulfenic acids can facilitate
the cyclization process by steric and electronic effects. The substit-
uents that can contribute both steric and electronic effects simul-
taneously will be more effective in facilitating the cyclization
process.
to each other by steric effect and additionally contribute to the
effective cyclization via SÁ Á ÁO nonbonded interactions. Therefore,
it is likely that the amido groups near the sulfenic acid moiety
may play important roles in the cyclization of the PTP1B sulfenic
acid (PTP1B–SOH) to sulfenyl amides.
3. Conclusions
In summary, we have modelled the unusual transformation of
the PTP1B sulfenic acid to the corresponding cyclic sulfenyl amide
by using small molecule chemical models. It is found that the
cyclization of an o-amido phenylsulfenic acids to sulfenyl amides
is a slow process and the sulfenic acid produced in situ from
H2O2-mediated oxidation of o-amido thiophenols can be trapped
by using trapping agents such as CH3I under suitable conditions.
Theoretical studies suggest that the o-amido phenylsulfenic acids
are stabilized by nonbonded SÁ Á ÁO interactions between the lone
pair of ortho-amido oxygen and antibonding orbital of S–OH bond
2.4.4. Effect of amide groups near the sulfenic acid moiety (-SOH)
In the PTP1B protein, the amide residues nearby the sulfenic
acid moiety can modulate the electronic environments around
the sulfur atom. Such an involvement of Gln residue in the antiox-
idant selenoenzyme glutathione peroxidase [20] has been pro-
posed by Bayse and co-workers with the help of theoretical
calculations [21]. In this regard, we have done theoretical calcula-
tions on sulfenic acid 32, as a model, to mimic the role of amide
carbonyl groups near the sulfenic acid moiety of PTP1B. Similar
to the oxazoline ring discussed above, the SÁ Á ÁO interactions be-
tween the sulfur atom and the amide carbonyl oxygen at the 6-po-
sition of the phenyl ring in the sulfenic acid 32 force the –OH
moiety to approach the –NH– group. The SÁ Á ÁO interaction in 32
(nO
?
rÃ
orbital interactions). Due to this nonbonded interac-
S–OH
tion, the –OH group adopts a position trans to the SÁ Á ÁO interaction,
leading to an almost linear arrangement of the OÁ Á ÁS–O moiety,
which keeps the cyclization partners –OH and –NH groups far
away from each other. This may be the reason for the slow cycliza-
tion of such sulfenic acids to their corresponding sulfenyl amides.
As SÁ Á ÁO nonbonded interaction energies and electron densities at
the bond critical point (qSÁ Á ÁO) do not change much with the change
in the substituent on the nitrogen atom of o-amido phenylsulfenic
acids, it can be concluded that the cyclization efficiency of these
sulfenic acids to their corresponding sulfenyl amides will not
depend on the substituent on the nitrogen atom.
DFT calculations further suggest that the introduction of a
group that can induce steric effect can prevent the SÁ Á ÁO interac-
tion and force the –OH group close to the –NH– group, which
may help in their cyclization to the sulfenyl amides. NBO analysis
suggests that the introduction of groups such as an oxazoline ring
[SÁ Á ÁO = 2.53 Å; ESÁ Á ÁO = 9.72 kcal molÀ1] due to nO
?
rÃ
orbital
S–OH
interation may contribute to the effective cyclization of 32–33.
DFT calculations also suggested the presence of SÁ Á ÁO nonbonded
interaction in the sulfenyl amide 33 [SÁ Á ÁO = 2.57 Å; ESÁ Á ÁO = 9.21 -
kcal molÀ1]. It is interesting that the nearby amide groups can push
cyclization partners –OH and –NH– moieties in sulfenic acids close
Fig. 4. Chemical structures of model sulfenic acids and sulfenyl amides.

B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
417
that can induce steric effect as well as electronic effects due to the
presence of the heteroatoms that can engage in nonbonded inter-
ation with the sulfenic acid moiety may be more effective in
improving the cyclization efficiency to form sulfenyl amides. Fur-
ther, it was observed that amide groups near the sulfenic acid moi-
ety can induce both steric and electronic effetcs, which can help in
efficient conversion of sulfenic acids to sulfenyl amides. This sug-
gests that amido groups from amino acids other than the cycliza-
tion partners Cys215 and Ser216, that are close to the sulfenic
acid moiety may play important roles in the cyclization of the
PTP1B sulfenic acid (PTP1B–SOH) to sulfenyl amides. Therefore, it
is important to consider both the steric and electronic environ-
ments around sulfenic acid moiety in PTP1B for designing syn-
thetic models for the active site of the enzyme.
the organic layer was washed with water followed by brine. The
organic layer was further dried over anhydrous sodium sulfate
and the solvent was removed under vacuum. The crude reaction
mixture was then purified by flash column chromatography to
yield 14 white solid in ꢁ10% yield. 1H NMR (DMSO-d6) d 10.60
(s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.86 (t,
J = 8.0 and 8.0 Hz, 1H), 7.69–7.72 (m, 3H), 7.37 (t, J = 8.0 and
8.0 Hz, 2H), 7.14 (t, J = 8.0 and 8.0 Hz, 1H), 2.82 (s, 3H); 13C NMR
(DMSO-d6) d 165.1, 148.7, 139.0, 132.7, 130.8, 129.2, 128.4,
124.7, 124.1, 120.9, 45.1; MS (TOF MS ES+) m/z 282.0569 [M+Na]+.
4.1.3. Synthesis of 15
To a stirred solution of 7 (100 mg, 0.44 mmol) in CH2Cl2 (10 mL)
under nitrogen was added thiophenol (46 lL, 0.45 mmol). The
reaction mixture was stirred for 12 h at ambient temperature un-
der nitrogen. The solvent was removed under reduced pressure
to give a yellow oil which was the purified by flash column chro-
matography to give compound 15 in 80% yield (119 mg). 1H NMR
(CDCl3) d 7.88 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.63 (t, J = 4.0 and
4.0 Hz, 3H), 7.49 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 8.0 and 8.0 Hz, 1H),
7.38 (t, J = 8.0 and 8.0 Hz, 3H), 7.28–7.31 (m, 3H), 7.22 (d,
J = 4.0 Hz, 1H), 7.17 (t, J = 8.0 and 8.0 Hz, 1H); 13C NMR (CDCl3) d
165.7, 137.8, 137.5, 136.2, 134.4, 131.5, 129.1, 128.4, 127.6,
127.3, 126.7, 124.9, 120.2. MS (TOF MS ES+) m/z 360.0461 [M+Na]+.
4. Experimental section
4.1. General procedure
All chemicals were of the highest purity available. All experi-
ments were carried out under anaerobic conditions using standard
Schlenk techniques for the synthesis. Due to unpleasant odors of
several of the reaction mixtures involved, most manipulations
were carried out in a well-ventilated fume hood. Mass spectral
(MS) studies were carried out on a Q-TOF Micro mass spectrometer
with electrospray ionization MS mode analysis. In the case of iso-
topic patterns, the value given is for the most intense peak. Liquid
state NMR spectra were recorded in CDCl3 as a solvent. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were obtained on a
Bruker Avance 400 NMR Spectrometer using the solvent as an
internal standard for 1H and 13C. Chemical shifts (1H, 13C) are cited
with respect to tetramethylsilane (TMS). Thin-layer chromatogra-
phy analyses were carried out on pre-coated silica gel plates
(Merck) and spots were visualized by UV irradiation. Column chro-
matography was performed on glass columns loaded with silica gel
or on automated flash chromatography system (Biotage) by using
preloaded silica cartridges.
4.1.4. Synthesis of 16
To a stirred solution of 8 (100 mg, 0.45 mmol) in CH2Cl2 (10 mL)
under nitrogen was added benzenethiol (46 lL, 0.45 mmol). The
reaction mixture was stirred for 12 h at ambient temperature un-
der nitrogen. The solvent was removed under reduced pressure
to give a yellow oil which was the purified by flash column chro-
matography to give compound 16 in 70% yield (104 mg). 1H NMR
(CDCl3) d 7.77 (d, J = 8.0 Hz, 1H), 7.48 (d, 7.6 Hz, 3H), 7.38 (t,
J = 7.6 and 8.0 Hz, 1H), 7.23–7.32 (m, 4H), 6.14 (s, 1H), 3.65 (s,
2H), 3.73 (s, 2H), 1.42 (s, 6H); 13C NMR (CDCl3) d 168.0, 136.2,
135.8, 134.6, 130.7, 128.7, 127.9, 127.3, 127.2, 126.9, 126.3, 69.8,
56.5, 24.2. MS (TOF MS ES+) m/z 356.0738 [M+Na]+.
4.1.5. Synthesis of 17
4.1.1. Synthesis of 2-(2-(methoxycarbonyl)ethylthio)benzoic acid
To a stirred solution of thiosalicylic acid (1 g, 6.4 mmol) in dry
THF (10 mL) under nitrogen was added triethylamine (1.3 g,
1.8 mL, 12.8 mmol) and methyl acrylate (671 mg, 702 mL,
7.8 mmol). The resulting solution was stirred at 25 °C under nitro-
gen for 24 h. The solution was then acidified with 10% H2SO4. The
white precipitate was removed by filtration and the filtrate was ex-
tracted with diethyl ether (3 Â 30 mL). The combined filtrates were
dried over anhydrous Na2SO4 and evaporated to dryness to give a
white solid, which was purified by flash chromatography to give
To a stirred solution of 7 (100 mg, 0.45 mmol) in CH2Cl2 (10 mL)
under nitrogen was added 4-methyl-thiophenol (56 mg,
0.45 mmol). The reaction mixture was stirred for 12 h at ambient
temperature under nitrogen. The solvent was removed under re-
duced pressure to give a yellow oil which was the purified by flash
column chromatography to give compound 17 in 75% yield
(116 mg). 1H NMR (CDCl3) d 7.89 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H),
7.58–7.64 (m, 3H), 7.44 (t, J = 8.0 and 8.0 Hz, 1H), 7.37 (t, J = 8.0
and 8.0 Hz, 4H), 7.30 (t, J = 4.0 and 8.0 Hz, 1H), 7.16 (t, J = 8.0 and
4.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR (CDCl3)
d 165.7, 137.8, 137.7, 137.6, 134.8, 132.8, 131.5, 130.0, 129.1,
129.0, 128.8, 127.9, 126.9, 124.8, 120.2, 21.1. MS (TOF MS ES+)
m/z 374.0762 [M+Na]+.
a
white powder (1.25 g, 83%). 1H NMR (CDCl3)
d 8.13 (d,
J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 and 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz,
1H), 7.23 (t, J = 7.2 and 7.6 Hz, 1H), 3.73 (s, 3H), 3.25 (t, J = 7.2
and 7.6 Hz, 2H), 2.75 (t, J = 7.6 and 7.6 Hz, 2H); 13C NMR (CDCl3)
d 172.2, 171.0, 141.6, 133.2, 132.6, 126.6, 125.6, 124.4, 52.1, 33.0,
26.9. MS (TOF MS ES+) m/z 263.0415 [M+Na]+.
4.1.6. Synthesis of 18
To a stirred solution of 2-(2-(methoxycarbonyl)ethylthio)ben-
zoic acid (264 mg, 1.1 mmol), DCC (336 mg, 1.64 mmol) and DMAP
(26.8 mg, 20 mol%) in dry THF (12 mL) was added aniline (152 mL,
1.64 mmol) and the mixture allowed to stir at 25 °C for 12 h under
nitrogen. The solvent was removed by rotary evaporation and the
resulting oil taken up in diethyl ether and filtered to remove dicy-
clohexyl urea (DCU). The filtrate was then washed with 5% H2SO4,
followed by water and saturated NaCl solution. The ether layer was
then dried over anhydrous sodium sulfate, filtered, and evaporated
to give a yellow oil, which was then purified by a flash column
chromatography to give 18 as a white powder (205 mg, 65%). 1H
NMR (CDCl3) d 8.65 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.69 (d,
4.1.2. Synthesis of 14
The thiol 1 (10 mg, 0.044 mmol) in acetonitrile (1.1 mL) was
treated with sodium phosphate buffer (1.28 mL, 500 mM, pH 7.5)
and methyl iodide (1.28 mL). To this mixture was added hydrogen
peroxide (5.5 lL, 8.82 M in water) and the reaction was vigorously
stirred (final concentrations: 1, 11.9 mM; H2O2, 12.0 mM; buffer,
174.6 mM, pH 7.5; CH3I, 5.58 M; acetonitrile, 30% by volume).
The excess methyl iodide was removed by passing a stream of
nitrogen over the mixture in a well-ventilated hood after 1.5 h.
The reaction mixture was then extracted with ether twice and

418
B.K. Sarma / Journal of Molecular Structure 1048 (2013) 410–419
J = 8.0 Hz, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.34–7.45 (m, 4H), 7.16 (t,
J = 7.6 and 7.2 Hz, 1H), 3.58 (s, 3H), 3.19 (t, J = 6.8 and 7.2 Hz,
2H), 2.63 (t, J = 6.8 and 7.2 Hz, 2H); 13C NMR (CDCl3) d 172.1,
165.9, 137.9, 132.4, 132.3, 131.0, 130.0, 129.6, 127.6, 124.6,
120.0, 52.0, 34.0, 33.0. MS (TOF MS ES+) m/z 338.0820 [M+Na]+.
G. Mugesh for his useful suggestions, encouragements and help in
the preparation of the manuscript. The author also thanks the
Supercomputer Engineering and Research Centre (SERC), Indian
Institute of Science (IISc) for computing facilities.
Appendix A. Supplementary material
4.1.7. Synthesis of 19
To a stirred solution of 2-(2-(methoxycarbonyl)ethylthio)ben-
zoic acid (382 mg, 1.59 mmol), DCC (485 mg, 2.38 mmol) and
DMAP (38 mg, 20 mol%) in dry THF (20 mL) were added the 2-ami-
no-2-methyl propan-1-ol (213 mg, 230 mL, 2.38 mmol) and the
mixture allowed to stir at 25 °C for 24 h under nitrogen. The sol-
vent was removed by rotary evaporation and the resulting oil ta-
ken up in diethyl ether and filtered to remove dicyclohexyl urea
(DCU). The filtrate was then washed with 5% H2SO4, followed by
water and saturated NaCl solution. The ether layer was then dried
over anhydrous sodium sulfate, filtered, and evaporated to give a
yellow oil, which was then purified by a flash column chromatog-
raphy to give 19 as a white powder (270 mg, 60%). 1H NMR (CDCl3)
d 7.47 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 and
7.6 Hz, 1H), 7.22 (t, J = 7.2 and 8.0 Hz, 1H), 6.52 (s, 1H), 4.52 (s, brd,
1H), 3.65 (s, 2H), 3.56 (s, 3H), 3.10 (t, J = 7.2 and 6.8 Hz, 2H), 2.55 (t,
J = 6.8 and 7.2 Hz, 2H), 1.34 (s, 6H); 13C NMR (CDCl3) d 171.1, 167.8,
137.7, 130.9, 129.5, 127.7, 126.4, 69.0, 55.9, 33.0, 28.9, 23.5. MS
(TOF MS ES+) m/z 334.1091 [M+Na]+.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.
2013.05.044.
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