Sulfenic acid -derived glycoconjugated disulfides and sulfoxides: A biological evaluation on human red blood cells

Article abstract of DOI:10.1080/17415993.2013.778259

This article examines the effects of some glycoconjugated disulfides and sulfoxides on red blood cells (RBCs). Compounds under study show sugar units connected directly or through a benzene platform, and have been obtained following synthetic pathways based on the sulfenic acid chemistry. In order to evaluate the relationship between the structural features of the thioglycoconjugates under investigation and their potential biological activity, we were interested in assessing both the cytotoxicity and hemolytic activity produced on human RBCs by overnight exposition to the thioglycoconjugates. The absence of both cytotoxic effect and hemolysis produced by the tested compounds on erythrocytes supports the rational design of hemocompatible molecules for biomedical applications.

Full text of DOI:10.1080/17415993.2013.778259

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Sulfenic acid – derived glycoconjugated
disulfides and sulfoxides: a biological
evaluation on human red blood cells
Paola Bonaccorsi a , Maria Chiara Aversa a , Anna Barattucci a
,
Teresa Papalia b , Agata Torre c , Francesca Trischitta c & Caterina
Faggio c
a Dipartimento di Scienze Chimiche, Università degli Studi di
Messina, Messina, Italy
b Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute,
Università degli Studi di Messina, Messina, Italy
c Dipartimento di Scienze Biologiche e Ambientali, Università degli
Studi di Messina, Messina, Italy
Version of record first published: 19 Apr 2013.
To cite this article: Paola Bonaccorsi , Maria Chiara Aversa , Anna Barattucci , Teresa Papalia ,
Agata Torre , Francesca Trischitta & Caterina Faggio (2013): Sulfenic acid – derived glycoconjugated
disulfides and sulfoxides: a biological evaluation on human red blood cells, Journal of Sulfur
Chemistry, DOI:10.1080/17415993.2013.778259
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Journal of Sulfur Chemistry, 2013
http://dx.doi.org/10.1080/17415993.2013.778259
Sulfenic acid – derived glycoconjugated disulfides and
sulfoxides: a biological evaluation on human red blood cells
Paola Bonaccorsia*, Maria Chiara Aversaa, Anna Barattuccia, Teresa Papaliab, Agata Torrec,
Francesca Trischittac and Caterina Faggioc∗
aDipartimento di Scienze Chimiche, Università degli Studi di Messina, Messina, Italy; bDipartimento
di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Messina, Italy;
cDipartimento di Scienze Biologiche e Ambientali, Università degli Studi di Messina, Messina, Italy
(Received 31 January 2013; final version received 17 February 2013)
This article examines the effects of some glycoconjugated disulfides and sulfoxides on red blood cells
(RBCs). Compounds under study show sugar units connected directly or through a benzene platform,
and have been obtained following synthetic pathways based on the sulfenic acid chemistry. In order to
evaluate the relationship between the structural features of the thioglycoconjugates under investigation
and their potential biological activity, we were interested in assessing both the cytotoxicity and hemolytic
activity produced on human RBCs by overnight exposition to the thioglycoconjugates. The absence of both
cytotoxic effect and hemolysis produced by the tested compounds on erythrocytes supports the rational
design of hemocompatible molecules for biomedical applications.
Keywords: sulfenic acids; disulfides; sulfoxides; cytotoxicity; hemolytic activity
*Corresponding author. Email: pbonaccorsi@unime.it
© 2013 Taylor & Francis

2
P. Bonaccorsi et al.
1. Introduction
Sulfenicacidsarefrequentlyoccurringintermediatesinbiologicalandsyntheticchemistry.Among
the numerous examples, cysteine-derived sulfenic acids are recognized as key intermediates in sig-
nal transduction (1), transcriptional regulation events (2), oxidative stress response (3). They also
play catalytic and structural roles in enzymes (4). Furthermore, the sulfenic function is involved in
the biosynthesis of thiosulfinates that give the characteristic odor and flavor to the Allium species,
and in the lachrymatory process of cut onion (5). Recent studies have been addressed to the com-
prehension of the redox chemistry of sulfenic acids, not yet understood exhaustively, and model
systems have been used to mimic the destiny of these transient species in nature (6). On the other
−
hand, the electronic nature of their S O bond and its involvement in various, often stereospecific,
reactions, has prompted many applications of sulfenic acids in organic synthesis, such as their
use as key intermediates in the preparation of peculiar sulfoxides (7) and disulfides.
One of the straightforward ways of generation of transient sulfenic acids is represented by
their syn-elimination from proper sulfoxide precursors, in neutral conditions, through thermolysis
(8), as shown in Scheme 1. The intermolecular syn-addition of sulfenic acids to triple bonds
(pathway a) gives vinyl sulfoxides, while their condensation with thiols (pathway b) leads to the
formation of unsymmetrically substituted disulfides.
The reaction of sulfenic acid/unsaturated moiety is a stereospecific and, in most of the cases,
highly regioselective process that offers significant chances of modulating the synthesis of unsat-
urated sulfoxides due to the possibility of changing both the nature of the unsaturated acceptors
and the sulfenic acid skeleton (9).
The condensation process that involves sulfenic acids and thiols allows an easy entry into the
chemistry of the disulfide bond. This reaction can be regarded as an efficient and smooth general
process for the construction of libraries of unsymmetrically substituted disulfides. It allows the
presence of base/acid and/or thermolabile functional groups in both the sulfenic acid and the
thiol on the basis of the choice of suitable precursors of the sulfenic acids, and offers wide
chances of building the disulfide bond between different structural skeletons such as homo- and
hetero-aromatic, amino acidic and sugar residues (10).
As a part of a program centered on the study of sulfenic acid reactivity in both the directions
above mentioned, thioglycoconjugates with two or three sugar moieties separated by arene spacers
have been synthesized (10a,c). The relationship between their molecular structure and biological
activity was investigated with respect to their ability to induce apoptotic cell death, taking into
account the pivotal role of apoptosis regulation in both the controlled expansion and removal of
immune cells and cancer progression and therapy (11).
O
X
X
S
R
X
a
X
O
S
D
-
R
H
S
H
S
R
R''
R
O
R' R'
H
2O
=
R'
HR''
2C C
,
b
=
=
e
H M
R'
R''
R'''
R'''
S
s
EW
G
H
S
R
S
Scheme 1. In situ generation of sulfenic acids and correlated reactions.

Journal of Sulfur Chemistry
3
Herein, a collection of thioglycoconjugated sulfoxides and disulfides is presented that was
exposed to human red blood cells (RBCs). The aim of this study was the evaluation of the
cytotoxic effects and hemolytic activity of such thioglycoconjugates on human erythrocytes and
comparison of the collected results with those already present in the literature (12). The predictive
value of in vitro cytotoxicity tests is based on the idea of ‘basal’ cytotoxicity, namely that toxic
molecules or pharmaceutical preparations affect basic functions of cells which are common to
all cells, and that the toxicity can be measured by assessing cellular damage (13). Before any
investigation on mechanisms of action of different molecules or pharmaceutical preparations, it
is important to perform cytotoxicity assays. The development of in vitro cytotoxicity assays has
been driven by the need of rapidly evaluating the potential toxicity of large numbers of molecules,
limiting animal experimentation whenever possible, and carrying out tests with small quantities
of each compound.
2. Results and discussion
Polythiols 1–4 and 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetate (5; Figure 1) were used as start-
ingproductsforthepreparationofsuitablesulfoxideprecursorsofthecorrespondingsulfenicacids
(Scheme 1), (9j, 10a–c) that are generated in situ and represent the key intermediates in the syn-
theses of glycoconjugated sulfoxides and disulfides 8–15 (Figure 2). 1-Thio-β-d-glucopyranose
2,3,4,6-tetraacetate (5) was also employed as partner (Rꢀꢀꢀ-SH of pathway b in Scheme 1) in the
condensation reaction of sulfenic acids with thiols, leading to the formation of compounds 9–14
(10a,b). 1-Thio-β-d-galactopyranose 2,3,4,6-tetraacetate (6) was used as sulfenic acid trapper
for obtaining compound 15 (10a) and, finally, the commercially available 2-thiocytosine (7) was
involved in the sulfenic acid/thiol condensation reaction for preparing compound 16 (10b).
Noteworthy, the arene framework of compound 10 is functionalized with two different arms,
one showing a disulfide function linked to the monosaccharide moiety and the other showing a
2-(methoxycarbonyl)ethylsulfinyl function that possesses the structural characteristics for gener-
ating the corresponding sulfenic function by thermolysis. The isolation of compound 10 opened
a new scenery in the way of thinking the reaction pathway of the sulfenic acid/thiol condensation
when bis-functionalized substrates are involved. The synthetic route to compound 11 is outlined in
Scheme 2, with a stepwise formation of the two sulfenic functions and therefore a more complex
pathway than expected before (10c).
H
S
H
S
H
S
H
S
H
S
H
S
n
n
H
S
=
=
n
n
1
2
0
1
3
4
NH2
N
c
A
O
c
A
O
c
A
O
O
O
O
c
N
A
O
=
c
u
l H
S
A
OG
c
H
S
A
O
c
A
H
S
O
c
A
O
c
A
H
S
5
6
7
Figure 1. Thiols involved in the synthesis of bioinvestigated disulfides and sulfoxides.

4
P. Bonaccorsi et al.
Y
O
O
AcOGlu
S
S
GluOAc
O
O
S
S
S
S
X
S
S
u
c
l A
O
AcOGlu
G
=
=
=
=
=
=
c
c
u
u
u
e
M
8
9
10 X
A
A
l
l
Y
Y
Y
H
)
H
OG
OG
l
S O C 2C 2CO2
(
-
-
u
l
c
A
O
11
X
X
S S G
-
-
u
l H
O
12
H
OG
S S G
X
N
S
S
N
S
NH2
S
S
S
X
S
NH2
N
c
A
O
O
O
c
A
O
c
A
O
c
A
S
O
c
A
O
c
S
A
S
S
S
N
S
O
c
A
O
S
N
X
c
O
A
13 X = AcOGlu
14 X = HOGlu
15
16
N
H2N
Figure 2. Bioinvestigated disulfides and sulfoxides.
e
M
O2C
.
,
re
H
H
S
f 10
SO
H
l
80°
C
e
M
O2C
C
2C 2
SO
S
SO
e
H
c
SO
M
CO2
3
17
18
5
e
M
O2C
H
OS
SO
c
,
A
O
H
l
80°
C
2C 2
C
c
A
O
S
c
A
O
S
S
A
O
c
A
O
S
c
A
O
O
c
A
O
O
c
A
O
19
10
5
c
A
O
O
c
A
O
c
A
S
O
S
.
c
A
O
re
c
c
f 10
A
O
S
c
A
O
S
c
A
O
11
O
c
A
O
H
O
O
O
H
O
12
H
S
O
S
H
H
O
S
H
O
S
H
O
O
H
O
Scheme 2. The synthetic route to compounds 11 and 12.
It appears that the symmetrical bis(sulfoxide) 17 (10c) allows the generation in situ of just one
sulfenic function that, in turn, condenses with the monosaccharide 5.A second syn-elimination and
a second condensation with thiol 5 is necessary to obtain the bis(disulfide) 11 from 10, through the
sulfenic acid 19. The final deprotection converts 11 into the water-soluble bis(disulfide) 12 (10c).
We did not isolate any analogous intermediate in the synthesis of compounds 13 and 16, (10b)
starting from thiol 4 and following pathway b of Scheme 1. However, the appearance and disap-
pearance of spots on theTLC plates, before ending of the reactions for preparing the tris(disulfides)
13 and 16, support the stepwise formation of the sulfenic functions and condensation with thiols.

Journal of Sulfur Chemistry
5
These mechanistic considerations, in relation to the isolation of intermediates such as 10, can also
provide new explanations for stereochemical outcomes previously observed (9i).
Compound 8 is the result of the generation in situ of the corresponding sulfenic functions
from 3,3ꢀ-[1,3-phenylenebis(sulfinyl)]bispropanoic acid 1,1ꢀ-dimethyl ester and their com-
pletely regioselective syn-addition to the triple bond of 2-propyn-1-yl β-d-glucopyranoside
2,3,4,6-tetraacetate (9j).
Some of the compounds reported in this paper have been subjected to biological studies proving
that they induce detectable levels of cell death toward several cancer cell lines (9j,10c). In the
aim of finding additional therapeutic value to our preliminary results and examining the level
of toxicity on human cells, for instance RBCs, we have performed with compounds 8–15, a
common cytotoxicity test, the trypan blue assay that measures cytotoxicity based on alterations
in plasma membrane permeability and consequent dye uptake, normally excluded by viable cells.
This method involves direct counting of viable cells (13). Analogous biotests were performed
on 2-thiocytosine derivative 16 owing to the presence of the biorelevant pyrimidine residues.
Human whole blood samples collected from four healthy donors were used within 24 h after
bleeding. Each of compounds 8–16 was dissolved (0.1%) in dimethyl sulfoxide (DMSO) or
dichloromethane (DCM). Stock solutions were diluted in a saline solution at pH 7.4. As a control,
the same cells were exposed to the vehicle alone (DMSO or DCM), in amounts corresponding
to those employed for dissolving the compounds under study. In order to define cell viability,
the samples were incubated in the saline solution for 1, 3 h, and overnight. Trypan blue stock
solution was then added to the RBCs, hence they were loaded on a hemocytometer and examined
immediately under a microscope at low magnification. The numbers of blue staining and total
cells were counted. The trypan blue assay showed a viability of 92–100% in all experiments (data
not shown). There were no statistical differences in the viability depending on exposure durations
at 10−4 M concentrations of each compound.
Furthermore, we decided to subject compounds 8–16 to the hemolysis assay, a sensitive and
accurate tool used as a guide to assess the safety and utility of a molecule or pharmaceutical
preparations (14). This test evaluates hemoglobin (Hb) release in the plasma (as an indicator of
RBC lysis) following molecule exposure (12). Human whole blood samples collected from four
healthy donors were used within 24 h after bleeding and were incubated in a saline solution. After
overnight incubation at 37◦C, the samples were centrifuged and the supernatants were harvested.
As a measure of hemolysis, Hb concentration of the supernatants was determined photometrically.
The absorption of the supernatant of erythrocytes lysed in distilled water was defined as 100%
hemolysis. In the treatment of RBCs with each of compounds 8–16, hemolysis did not occur
at 300 and 200 mOsm/kg, while became clearly visible at 100 mOsm/kg to accomplish itself
Table 1. Percentage of hemolysis by compounds 8–16 (10−4 M).
Osmolarity (mOsm/kg)
Compounds
300
200
150
100
0
Control
8
9
10
11
12
13
14
15
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
4%
4%
4%
4%
4%
4%
4%
4%
4%
4%
100%
98%
97%
95%
98%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
98%
100%
100%
100%
96%
16

6
P. Bonaccorsi et al.
at 0 mOsm/kg, as in the control conditions (Table 1). The maintenance of integrity of RBC
membrane up to 150 mOsm/kg and the hemolysis occurrence at identical concentrations of the
control conditions suggest that none of the compounds under study shows toxicity effects in
human erythrocytes at the concentration tested and overnight.
3. Conclusions
The collection of compounds 8–16, all showing sulfoxide and/or disulfide functions connected
to biorelevant residues, have been obtained by the stepwise generation in situ of more than
one sulfenic function from suitable precursors and the reactions of such transient species with
substituted propynyl derivatives or thiols. Some of the mechanistic features of such reactions
have been discussed. Human erythrocytes from various subjects were used to assess both the
cytotoxicity and hemolytic activities of compounds 8–16. Results obtained in vitro demonstrated
that all the molecules under study show neither cytotoxicity nor hemolytic effect. On the basis of
previouslyreportedbiologicalresults(10)andtheactualperformedtests, thisfamilyofcompounds
could represent a new frontier in biomedical applications.
4. Experimental
4.1. Chemistry
Solvents were purified according to standard procedures. Reactions were monitored by TLC on
commercially available precoated plates (Aldrich silica gel 60 F254) eluted with EtOAc/MeOH,
and the products were visualized with vanillin [1 g dissolved in MeOH (60 mL) and conc. H2SO4
(0.6 mL)]. Silica gel used for column chromatography was Aldrich 60. 1H and 13C NMR spectra
were recorded with aVarian Mercury 300 spectrometer at 300 and 75 MHz, respectively, in CDCl3
solutions; the assignments are supported by Attached Proton Test and COrrelation SpectroscopY
and Heteronuclear Single Quantum Coherence experiments; proton and carbon nuclei identified
by apex pertain to the glucose residue of compound 10. Glycoconjugated disulfides and sulfoxides
8, 9, 11–16 have been already described (9j, 10a–c).
1-{[(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)dithio]methyl}-4-{[(2-methoxycarbonylethyl)
sulfinyl]methyl}benzene (10)
A solution of bis(sulfoxide) 17 (0.37 g, 1 mmol) and 1.46 g (4 mmol) of 2,3,4,6-tetra-O-acetyl-
1-thio-β-d-glucopyranose (2 mmol for each sulfinyl function) in 20 mL of 1,2-dichloroethane
was maintained at reflux temperature (83◦C) under stirring. The reaction, monitored via TLC
1
and H NMR, was stopped when the starting compound 17 disappeared. The reaction mix-
ture was purified by flash chromatography. The excess of glucosylthiol was recovered from
the column, together with 10% maximum of bis(disulfide) 11. 1-{[(2,3,4,6-Tetra-O-acetyl-β-d-
glucopyranosyl)dithio]methyl}-4-{[(2-methoxycarbonylethyl)sulfinyl]methyl}benzene (10) was
obtained as a 1:1 diastereomeric mixture in 52 % yield. TLC: Rf 0.35 (eluant EtOAc/MeOH
90:10). Low melting solid. 1H NMR: δ7.30 (m, 4H, ArH), 5.4–5.0 (m, 3H, H-2ꢀ, 3ꢀ, 4ꢀ), 4.54 (d,
J1 ,2 = 10.0 Hz, 0.5H, H-1ꢀ) of one diastereoisomer, 4.50 (d, J1 ,2 = 10.0 Hz, 0.5H, H-1ꢀ) of the
other diastereoisomer, 4.3–4.1 (m, 2H, H2-6ꢀ), 4.0–3.9 (m, 4H, 2×ArCH2), 3.8–3.7 (m, 1H, H-5ꢀ),
3.71 (s, 3H, OCH3), 3.0–2.8 (m, 4H, CH2CH2), 2.09, 2.05, 2.04, and 2.02 (4s, 12H, 4×COCH3).
13C NMR: δ 171.73, 170.47, 170.18, 169.38, and 169.10 (5 x CO), 137.23 (C-4), 130.37, 130.23,
130.13, and 129.84 (C-2,3,5,6), 128.80 (C-1), 87.68 (C-1ꢀ), 76.13, 73.77, 69.07, and 68.02 (C-
2ꢀ-5ꢀ), 62.05 (C-6ꢀ), 61.86 (ArCH2SO), 52.18 (OCH3), 43.84 (CH2SS and CH2CH2CO2CH3),
ꢀ
ꢀ
ꢀ
ꢀ

Journal of Sulfur Chemistry
7
26.73 (CH2CO2CH3), 20.74, 20.69, 20.64, and 20.55 (4×COCH3). Anal. Calcd for C26H34O12S3
(634.74): C, 49.20; H, 5.40. Found: C, 49.37; H, 5.47.
4.2. Biology
Molecules were dissolved (0.1%) in DMSO or DCM. Stock solutions were diluted in saline
solution having the following composition (mM): 125 NaCl, 5 KCl, 1 MgSO4, 32 4-(2-
hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 5 d-glucose, 1 CaCl2; pH 7.4. As
a control, the same cells were exposed to the vehicle alone (DMSO or DCM), in amounts
corresponding to those employed for dissolving the compounds.
4.2.1. Trypan blue assay
Human whole blood samples collected from four healthy donors were used within 24 h after
bleeding. In order to define cell viability, the samples were incubated in the saline solution
described above containing each molecule under study at 10−4 M concentration for 1, 3 h, and
overnight. Afterward, 0.1 mL of trypan blue stock solution was added to 0.1 mL of RBCs, hence
they were loaded on a hemocytometer and examined immediately under a microscope at low
magnification. The numbers of blue staining and total cells were counted. The percentage cell
viability was calculated by the formula:
Number of viable cells (unstained cells) × 100
Cell viability (%) =
.
Total number of cells (stained and unstained)
4.2.2. Hemolysis test
Human whole blood samples collected from four healthy donors were used within 24 h after
bleeding and were incubated in saline solution containing each molecule under study at 10−4 M
concentration. After overnight incubation at 37◦C, the samples were centrifuged (5 min at
1500 rpm), and the supernatants were harvested. As a measure of hemolysis, hemoglobin (Hb)
concentration of the supernatants was determined photometrically at 540 nm. The absorption of
the supernatant of erythrocytes lysed in distilled water was defined as 100% hemolysis.
Acknowledgements
Financial support by the Italian Ministry for the University and Research (MIUR) within PON01_01499 and PRIN
20109Z2XRJ_010 is gratefully acknowledged.
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