Sulfoximine- and sulfilimine-based DAPSON analogues; Syntheses and bioactivities

Article abstract of DOI:10.1055/s-0032-1317493

Sulfoximine- and sulfilimine-based diamino-diphenyl sulfone (DAPSON) analogues have been prepared and their COX-1 and COX-2 inhibition potencies as well as LTBand TNF binding properties were studied. Furthermore, their antiproliferative activities on cancer cell growth were investigated. Neither compounds showed significant bioactivities. Copyright

Full text of DOI:10.1055/s-0032-1317493

2808▌
LETTER
lSetuterlfoximine- and Sulfilimine-Based DAPSON Analogues; Syntheses and Bio-
activities
DAPSON Analogues
Xiao Yun Chen,a Helmut Buschmann,b Carsten Bolm*a
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
b
Sperberweg 15, 52076 Aachen, Germany
Received: 27.08.2012; Accepted after revision: 27.09.2012
O
O
Abstract: Sulfoximine- and sulfilimine-based diamino-diphenyl
sulfone (DAPSON) analogues have been prepared and their COX-
1 and COX-2 inhibition potencies as well as LTB4 and TNF binding
properties were studied. Furthermore, their antiproliferative activi-
ties on cancer cell growth were investigated. Neither compounds
showed significant bioactivities.
S
H2N
NH
NH2
DAPSON (1)
CN
N
S
O
Key words: drug discovery, cancer, oxidation, sulfoximine, sulfil-
S
imine
H2N
NH2
H2N
NH2
sulfoximine 2
sulfilimine 3
Diamino-diphenyl sulfone (DAPSON; 1) was first syn-
thesized in 1908 by Fromm and Wittmann, who were in-
terested in the dying properties of this rather simple diaryl
sulfone.1 In 1937, when medicinal chemists entered the
field, two groups concurrently reported on the anti-
inflammatory potencies of DAPSON in induced infec-
tions in mice.2 Today, it is in clinical use for the treatment
of various infections and chronic inflammatory diseases,3
and, in particular, in dermatology, DAPSON is often re-
garded as the drug of choice.4 For example, in combina-
tion with other antibiotic agents it has proved useful for
treating mutibacillary and paucibacillary leprosy5 as well
as a variety of neutrophilic, eosinophilic, and autoimmune
dermatoses. Despite many investigations, the precise
mode of action of DAPSON is still unknown. Further-
more, it often shows adverse events including hematolog-
ic, nervous system, and gastrointestinal/hepatic effects.4
Consequently, the development of DAPSON variants that
exhibit the positive therapeutic properties of the original
drug but lack unwanted side effects is clearly desirable. In
the light of our recent findings on COX-blocking proper-
ties of sulfoximines,6 we wanted to investigate the biolog-
ical impact of formal oxygen-to-nitrogen exchanges at the
central sulfonyl core of DAPSON.7 Here, we report on the
syntheses and biological properties, with respect to in-
flammatory events, of sulfoximine 2, being the mono-aza
analogue of diaryl sulfone DAPSON (1), and N-cyano
sulfilimine 3, which represents a new related structural
variant (Figure 1).
Figure 1 DAPSON and structural analogues prepared here
direct imination of 5 with PhI(AcO)2 and NH2CN to form
the corresponding sulfilimine (not shown) was unsuccess-
ful, presumably due to the presence of the strong electron-
withdrawing nitro groups on the two arenes. Consequent-
ly, bis-aniline 6 became a preferred target. Its synthesis
proceeded well (83% yield) by treatment of 5 with iron
powder and concentrated HCl in ethanol–water (4:1).8
However, both 6 and N,N′-di(Boc)-protected 7 proved to
be unstable under the reaction conditions of the imination,
thus, an alternative protected derivative had to be found.
To our delight, easily accessible N,N′-[4,4′-thiobis(4,1-
phenylene)]diacetamide (8) proved suitable. It was pre-
pared by double acetylation of 6 and allowed sulfur imi-
nation using the metal-free method with cyanamide as
nitrogen source under conditions reported by us earlier.9
In this manner, N-cyano sulfilimine 9 was obtained in
47% yield.10
To obtain N-cyano sulfoximine 10, sulfilimine 9 was oxi-
dized with a combination of MCPBA and K2CO3 in meth-
anol (78% yield). Finally, both the cyano and the acetyl
group were cleaved upon treatment with concentrated
HCl in methanol to give NH-sulfoximine 2 in 85% yield.
Initially, we expected to prepare N-cyano sulfilimine 3 in
a similar manner to that of 2. However, the use of diacetyl-
protected 8 was excluded because the anilide bonds could
not be cleaved without affecting the N-cyano moiety at the
sulfilimine core. Finally, 6 was treated with phthalic anhy-
dride to give diprotected intermediate 11 in 79% yield
(Scheme 2). Its imination under standard conditions10
gave N-cyano sulfilimine 12, which could be converted
into the desired product 3 by reaction with hydrazine
monohydrate in ethanol (32% over two steps). It is note-
The syntheses of sulfoximine 2 and sulfilimine 3 proceed-
ed via bis(4-nitrophenyl)sulfane (5), which was available
from 4-nitrobromobenzene (4) by nucleophilic substitu-
tion with sodium sulfide (Scheme 1). Unfortunately, the
SYNLETT 2012, 23, 2808–2810
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317493; Art ID: ST-2012-B0719-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
DAPSON Analogues
2809
Table 1 Biological Properties of Sulfoximine 2 and Sulfilimine 311
S
Na2S, S8, H2O
O2N
Br
Entry
Assay
Inhibition (%)a
DMF, reflux (79%)
O2N
NO2
Sulfoximine 2
Sulfilimine 3
5
4
S
1
2
3
4
COX-1
COX-2
LTB4
6
4
9
4
Fe powder, concd HCl
5
EtOH–H2O (4:1), reflux
(83%)
RHN
NHR
(7: R = Boc)
–14
– 6
11
–3
6: R = H
Ac2O, CH2Cl2
TNF
r.t. (64%)
8: R = Ac
a Using 10 μM inhibitor concentration. For details see the Supporting
Information.
CN
N
S
NH2CN, PhI(OAc)2
effects in the enzyme or radioligand binding assays. Ap-
parently, even the comparatively minor one-atom modifi-
cation [SO2 versus SO(NH) for 2] of the sulfonyl core had
a major influence on the biological properties. The results
with 3 were less surprising considering the significant
property change associated with the sulfonyl-to-N-cyano
sulfimidoyl switch (sulfone 1 vs. N-cyano sulfilimine 3).
8
9
DMF, 0 °C to r.t.
(47%)
AcHN
AcHN
NHAc
NHAc
9
CN
N
O
S
MCPBA, K2CO3
MeOH, 0 °C to r.t.
(78%)
Being aware of current studies that revealed anticancer ac-
tivities of DAPSON derivatives,12 we decided to submit
compounds 2 and 3 for an anticancer screening within the
Developmental Therapeutics Program of the Division of
Cancer Treatment and Diagnosis of the National Cancer
Institute (NCI) at the National Institutes of Health, USA.13
In the full NCI 60 cell panel representing leukemia, mela-
noma, and cancers of the lung, colon, CNS, ovarian, renal,
prostate, and breast, 2 and 3 were applied at a single dose
(10 μM).14 Unfortunately, the observed antiproliferative
activities on cell growth were not significant enough to
progress the initial study.
10
concd HCl, EtOH
reflux (85%)
2
Scheme 1 Synthesis of sulfoximine 2
S
phthalic anhydride
6
AcOH, reflux
PhthHN
NHPhth
(79%)
11
CN
N
S
Because several effects in DAPSON therapies have been
attributed to the formation and presence of metabolites
(such as N-hydroxylamines of 1),3,4,15 it remains to be seen
if the reported core modifications also affect those activi-
ties due to altered oxidation potentials of the sulfur-
bridged aniline moieties.
NH2CN, PhI(OAc)2
11
DMF, 0 °C to r.t.
PhthHN
NHPhth
12
hydrazine monohydrate (60%)
12
3
In summary, we have prepared two structural analogues
of DAPSON (1) and studied their biological behavior with
respect to COX-1/2 inhibitions, LTB4 and TNF bindings,
and anticancer activities. Neither sulfoximine 2 nor sul-
filimine 3 showed significant blocking or binding poten-
cies. The antiproliferative activities on cancer cell growth
were not significant.
EtOH, r.t
(32% over 2 steps)
Scheme 2 Synthesis of sulfilimine 3
worthy that the sulfilimine core remained intact under
these hydrolysis conditions.
Next, the biological properties of sulfoximine 2 and sul-
filimine 3 were evaluated. Considering the effect of
DAPSON on inflammatory events and to allow a direct
comparison, the following enzyme and radioligand bind-
ing assays were initially selected: cyclooxygenase (COX-
1 and COX-2), leukotriene (BLT; LTB4), and tumor ne-
Acknowledgment
This study was supported by the Fonds der Chemischen Industrie.
We thank Prof. Dr. Reissig (FU Berlin) for alerting us to DAPSON
on January 21, 2011, and Prof. Dr. Wozel (TU Dresden) for a stimu-
lating discussion on October 28, 2011. X.Y.C. is grateful to the Chi-
crose factor (TNF; non-selective); Table 1 summarizes nese Scholarship Council (CSC) for a predoctoral stipend.
the results.11
To our great disappointment, neither sulfoximine 2 nor
sulfilimine 3 (10 μM concentrations) showed significant http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimntgirSatnoIuipfog
Supporting Information for this article is available online at
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2808–2810

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X. Y. Chen et al.
LETTER
the reaction mixture was diluted with H2O (30 mL) and
References
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Synlett 2012, 23, 2808–2810
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