Syntheses and biological activities of sulfoximine-based acyclic triaryl olefins

Article abstract of DOI:10.1016/j.bmcl.2012.05.018

Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfoximines 8 and 9 show low COX inhibitory activity.

Full text of DOI:10.1016/j.bmcl.2012.05.018

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4307–4309
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Syntheses and biological activities of sulfoximine-based acyclic triaryl olefins
Xiao Yun Chen a, Seong Jun Park a, Helmut Buschmann b, Maria De Rosa a, , Carsten Bolm a,
⇑
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany
b Sperberweg 15, D-52076 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been
performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfox-
imines 8 and 9 show low COX inhibitory activity. All compounds affect the estrogen receptors. While sul-
fone 2 interacts exclusively with ER b, sulfoximines 8 and 9 reveal almost equal blocking potencies for
Received 17 April 2012
Revised 3 May 2012
Accepted 7 May 2012
Available online 11 May 2012
both estrogen receptors, ER
activities with 91% and 80%, respectively (at 10
a
and ER b. In the tested series, triaryl olefin 9a shows the highest inhibitory
M).
l
Keywords:
Sulfoximine
Ó 2012 Elsevier Ltd. All rights reserved.
Acyclic triaryl olefin
COX-2 selective inhibitor (COXIB)
Estrogen receptor
Nonsteroidal anti-inflammatory drugs (NSAIDs) are amongst
the most widely used pharmaceutical agents for the treatment of
inflammatory conditions. They exert their effect by inhibiting the
biosynthesis of prostaglandins (PGs), which are formed from ara-
chidonic acid. A key enzyme in this process is cyclooxygenase
(COX), which appears in two isoforms (COX-1 and COX-2). Com-
prehensive studies led to the conclusion that selective COX-2
inhibitors (COXIBs) would be potent anti-inflammatory agents
lacking the toxicities and negative effects associated with the inhi-
bition of COX-1 (e.g., gastrointestinal ulceration, perforation and
hemorrhage).1 Although the reports of cardiovascular risk and
the subsequent withdrawal of rofecoxib and valdecoxib have called
COX-2 selective inhibitors into question,2 recent findings revived
interest in such compounds because long-term use of COXIBs led
to a decrease in death rate from several cancers such as colorectal,
stomach, breast, prostate, bladder, and ovarian cancer.3 Further-
more, COX-2 over-expression was related to critical components
of breast cancer including mutagenesis, angiogenesis, inhibition
of apoptosis and aromatase-catalyzed estrogen biosynthesis. Based
on the hypothesis that COX-2 and COX-2-derived PGE2 play a role
in breast tumor initiation and progression, COXIBs became attrac-
tive target for breast cancer prevention.4 More recently, additional
clinical applications of COX-2 inhibitors have been considered, but
they have yet to be confirmed.5
para position (as, for example, in VIOXXÒ (1), Fig. 1). Those polar
molecular units insert into the pocket of the COX-2 active site
and result in the formation of hydrogen bonds with several chain
residues.6,7 The hypothesis that such binding would be affected
by the nature of the sulfur substituent stimulated our recent work
on COXIBs with sulfoximidoyl substituents.8 As shown by Knaus
and co-workers the required cis arrangement of the two arenes
can also be affected by an olefinic bridge as in triaryl alkene 2,
which revealed high COX inhibitory activity with significant
COX-2 selectivity as well.9
The structure of alkene 2 is reminiscent of other tetrasubstitut-
ed olefins, which have the potential for broad medicinal applica-
tions. For example, Tamoxifen (3) is a well-established selective
estrogen receptor modulator (SERM) used for the prevention and
treatment of diseases such as osteoporosis and breast cancer.10,11
Sulfoximines 5 are monoaza analogs of sulfones 4 with sev-
eral appealing features for drug development.12 For example,
their core represents a small hydrophilic functional group with
a potential diversity point at the imine nitrogen, hydrogen bond
acceptors at the sulfur-bound heteroatoms, and, in the case of
NH-sulfoximines (R00 = H), a hydrogen bond donor. Consequently,
sulfoximines have already found various bio-relevant applica-
tions,13 and recent interest is best illustrated by the significant
number of contributions reporting the use of this so far under-
represented molecular scaffold in medicinal and crop protection
chemistry.14,15
A common structural feature of COXIBs is a cis orientation of
two aromatic substituents fixed by a hetero- or carbocyclic core
with one of the arenes having a sulfonyl or sulfonamido group in
In our previous study on sulfoximine-based VioxxÒ analogs, we
showed that the O/NH-exchange (from the sulfone to the corre-
sponding sulfoximine) had a beneficial effect resulting in a moder-
ately COX-inhibiting compound with reduced hERG inhibitory
activity.8,16 Encouraged by these results, we aimed to explore an
extension of this concept using sulfonyl-substituted triaryl olefin
⇑
Corresponding author.
E-mail address: Carsten.Bolm@oc.rwth-aachen.de (C. Bolm).
Present address: Department of Medicinal Chemistry, Uppsala University, Box
574, SE-751 23 Uppsala, Sweden.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.018

4308
X. Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4307–4309
Table 1
COX-1, COX-2, ER
SO2Me
SO2Me
a and ER b inhibitory data
Entry Compd N subst.
R
% Inhibition (at 10
lM)
COX-1 COX-2 estrogen ER
a
estrogen ER b
a
a
1
2
3
4
2
8a
9a
9b
n-Bu
n-Bu
—
—
ꢀ6
54
91
77
77
60
80
53
O
O
CN
H
H
5
10
17
ꢀ13
Me
n-Bu 12
Me 23
Vioxx® (1)
2
a
In vitro IC50 values reported in Ref. 9: COX-1 = >100 lM, COX-2 = 0.014 lM.
O
O
O
Me2N
S
R
R'
ER
a
and ER b. Indomethacin (for COX-1), VioxxÒ (for COX-2) and
4
diethylstilbestrol (for ER
a and ER b) were used as reference
Me
compounds in those biological tests.20
O
N R''
S
Based on the excellent results by Knaus and co-workers, who
found a remarkable COX-2 inhibitory potency in combination with
an extraordinary COX-2 selectivity for sulfonyl-substituted triaryl
R
R'
5
Tamoxifen (3)
olefin 2 (COX-1: IC50 >100 lM; COX-2: IC50 0.014 lM), we pre-
Figure 1. Bioactive compounds containing tetrasubstituted double bonds; sulfone
and sulfoximine core structures.
sumed sulfoximines 8 and 9 to provide results in a comparable
range. However, to our disappointment all three compounds were
essentially inactive. Neither N-cyano sulfoximine 8a nor NH-sul-
foximines 9a and 9b showed a significant COX inhibition (5–23%;
Table 1). Although this outcome was dissatisfying, the comparison
of the binding behavior of the two direct analogs sulfone 2 and sul-
foximine 9a led to an interesting conclusion. Apparently, the sub-
stitution of a single oxygen atom (as in sulfone 2) by a NH unit
(as in the corresponding sulfoximines 9a) led to a significant activ-
ity change. On the molecular level this was surprising because the
docking studies by Knaus and co-workers had suggested the sulfo-
nyl unit to be doubly hydrogen-bonded in the COX-2 active site
(through the NH of Phe518 and a NH2 of Arg513),9 and we expected
the sulfoximine nitrogen to be a better H-bond acceptor than the
two oxygens of the sulfone. In this particular case, however, the
data appear to indicate that the binding mode of the two analogs
(2 and 9a) was very different and that, perhaps, the sulfoximine
NH was even a H-donor.
S
Me
O
R
i
ii, iii
H
MeS
R
6a,b
7a 86%
7b 66%
N
CN
N
O
O
S
S
Me
Me
iv
R
R
The estrogen binding affinities of sulfoximines 8 and 9 were eval-
uated using human recombinant enzymes.20 In this case, sulfone 2
was employed as reference compound. The data are summarized
in Table 1. While compound 2 was a good ER b selective agent with
8a ii: 80%; iii: 75%
8b ii: 79%; iii: 91%
9a 88%
9b 79%
6a-9a: R = n-Bu 6b-9b: R = Me
no affinity to ER
ent behavior (entries 2–4). For all of them moderate to high blocking
potencies for both estrogen receptors with essentially no ER
selectivity were found. NH-Sulfoximine 9a was the most active com-
pound with 91% and 80% inhibition for ER and ER b, respectively, at
10 M. In line with the observations made in the COX inhibition
a
(entry 1)21 the three sulfoximines showed a differ-
Scheme 1. Reagents and conditions: (i) Benzophenone, TiCl4 (1 M solution in DCM),
Zn, dry THF, reflux 4.5 h; (ii) PhI(OAc)2, NH2CN, CH3CN, 0 °C, 1.5 h; (iii) K2CO3,
m-CPBA, MeOH, 0 °C to rt, 1.5 h; (iv) aqueous H2SO4 (50%), 110 °C, 4 h.
ab
a
2
as starting point. Here, we report on the syntheses of
sulfoximine-based analogs 8 and 9, their COX-1/2 inhibitory activ-
ities and blocking potencies of both estrogen receptors, ER
l
studies described above, the replacement of a single oxygen atom
by a NH unit had a majorimpact. This can best be seen when compar-
ing the results of sulfone 2 with those of NH-sulfoximine 9a (Table 1,
entry 1 vs entry 3). While the former is a good, highly selective ER b
binder, the latter shows significantly better receptor inhibition but
a and
ER b.
Sulfoximines 8 and 9 were prepared by a combination of
published procedure9 and methods developed in our laboratories
(Scheme 1).17,18 Accordingly, compounds 7 were prepared by
McMurry olefinations starting from ketones 6 and benzophenone.
Metal-free oxidative imination with NH2CN and PhI(OAc)2 followed
by oxidation of the intermediately formed N-cyano sulfilimines (not
shown) with m-CPBA combined with K2CO3 in methanol afforded N-
cyano sulfoximines 8 in high yields. The corresponding NH-sulfoxi-
mines 9 were then generated using 50% aqueous H2SO4 for the re-
moval of the cyano group.19
lacks the ER
and to speculate on potential arrangements of the molecules in
the binding sites of ER and ER b is difficult, because, to the best
ab selectivity. To draw conclusions on molecular level
a
of our knowledge, docking studies with neither sulfone 2 nor any
sulfoximines on estrogen receptors have yet been performed. If
the hydrogen bonding scheme is relevant in this case as well, as sug-
gested above for the alternation of the COX binding behavior of sul-
fone 2 and the sulfoximines, remains to be established.
The inhibition studies involved N-cyano sulfoximine 8a and
NH-sulfoximines 9a and 9b. Those compounds were evaluated
in vitro on their inhibitory activities against the two COX isoen-
zymes (from human platelets and human recombinant insect Sf21
cells for COX-1 and COX-2, respectively, with arachidonic acid as
substrate) and their binding affinities for the two estrogen receptors,
In conclusion, we prepared sulfoximine-based acyclic triaryl
olefins and investigated their inhibitory effects against COX-1
and COX-2 as well as their binding affinities to both estrogen
receptors, ER
a and ER b. Those results were compared with the
ones obtained in studies of a sulfonyl-substituted analog. Interest-
ingly, the sulfonimidoyl group had a major impact on the enzyme

X. Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4307–4309
4309
13. For example, see the inhibition of the glutathione biosynthesis by buthionine
sulfoximine (BSO): (a) Takahashi, K.; Tatsunami, R.; Oba, T.; Tampo, Y. Biol.
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S.; Dolan, P. M.; Kensler, T. W.; Peleg, S.; Saha, U.; Chuang, S. S.; Bernstein, G.;
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Perez, A. Bioorg. Med. Chem. Lett. 2009, 19, 3253; (d) Takahashi, K.; Tatsunami,
R.; Oba, T.; Tampo, Y. Biol. Pharm. Bull. 2010, 33, 556.
15. For selected examples in crop-protection chemistry, see: (a) GarcíaMancheño,
O.; Dallimore, J.; Plant, A.; Bolm, C. Adv. Synth. Catal. 2010, 352, 309; (b) Zhu, Y.;
Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang, J. X.; Gerwick, B.
C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent, B. M.; Renga, J. M.; Denholm,
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http://dx.doi.org/10.1016/j/j.bmcl.2012.03.106.
inhibition and receptor binding. In contrast to the sulfone-based
analog, all sulfoximines showed low COX inhibitory potency. Also
their binding to the estrogen receptors differed. While the sulfone
was selective and moderately active for ER b, the sulfoximines
were essentially ER
ab unselective with remarkable inhibitions of
up to 91% and 80% for ER
a
and ER b, respectively. Subsequent
studies shall focus on testing these and other sulfoximine-based
molecules in additional enzyme inhibitory assays and confirm
the opportunities on modifying biological profiles by replacing sin-
gle atoms by other molecular units in core fragments of drug-like
molecules.22
Acknowledgments
Support by the Fonds der Chemischen Industrie is greatly
appreciated. X.Y.C. thanks the China Scholarship Council for a doc-
toral stipend, and M.D.R. acknowledges support by the University
of Siena for a pre-doctoral fellowship allowing her to perform re-
search at RWTH Aachen University.
16. This observation was in line with data reported by Pfizer on inhibition studies
of proline-rich tyrosine kinase 2. For details see Ref. 14c.
17. (a) Mancheño, O. G.; Bolm, C. Org. Lett. 2007, 9, 2951; (b) Mancheño, O. G.;
Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809; (c) Pandey, A.; Bolm, C. Synthesis
2010, 2922.
Supplementary data
18. Selected data for product characterization: Compound 8a 1H NMR (400 MHz,
CDCl3): d 7.72–7.65 (m, 2H), 7.37–7.13 (m, 7H), 7.04–6.89 (m, 3H), 6.82–6.74
(m, 2H), 3.23 (s, 3H), 2.42 (t, 2H, J = 7.8 Hz), 1.44–1.08 (m, 4H), 0.73 (t, 3H,
J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 151.3, 142.44, 142.39, 141.9, 138.8,
133.2, 131.5, 130.7, 129.3, 128.4, 128.0, 127.5, 127.4, 126.9, 111.9, 45.0, 35.42,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.
018.
31.2, 22.8, 13.9; IR (KBr):
t
= 2195, 1249, 1090, 967 cmꢀ1; MS (EI), m/z (relative
intensity) 414 [M+, 100], 373 [31], 315 [58], 267 [14], 167 [15], 91 [17]; 8b 1H
NMR (300 MHz, CDCl3): d 7.76 (d, 2H, J = 8.6 Hz), 7.44 (d, 2H, J = 8.6 Hz), 7.38–
7.22 (m, 7 H), 7.10–7.04 (m, 2H), 6.90–6.84 (m, H), 3.29 (s, 3 H), 2.18 (s, 3 H);
13C NMR (75 MHz, CDCl3): d 152.2, 142.7, 142.3, 141.8, 133.1, 133.0, 131.1,
130.7, 129.7, 128.7, 128.3, 127.9, 127.5, 127.3, 125.9, 44.8, 22.8; IR (KBr):
References and notes
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t
= 2195, 1097, 965 cmꢀ1; 9a 1H NMR (400 MHz, CDCl3): d 7.75–7.65 (m, 2H),
7.34–7.13 (m, 7H), 7.01–6.88 (m, 3H), 6.84–6.75 (m, 2H), 3.01 (s, 3H), 2.40 (t,
2H, J = 7.8 Hz), 1.45–1.09 (m, 4H), 0.72 (t, 3H, J = 7.1 Hz); 13C NMR (100 MHz,
CDCl3): d 148.4, 142.8, 142.3, 141.3, 140.9, 139.5, 130.74, 130.6, 129.4, 128.4,
127. 8, 127.4, 127.1, 126.5, 46.4, 35.6, 31.2 22.9, 14.0; IR (KBr):
t = 3180, 1261,
1214, 1090, 1006 cmꢀ1; Anal. Calcd for C25H27NOS: C 77.08, H 6.99, N 3.60,
found: C 76.89, H 7.158, N 3.52; HRMS (ESI), m/z: [M+H] Calcd for C25H27NOS
390.1886, found 390.1891; 9b 1H NMR (300 MHz, CDCl3): d 7.76 (d, 2H,
J = 8.4 Hz), 7.40–7.23 (m, 9H), 7.06–7.02 (m, 2H), 6.93–6.80 (m, 1H), 3.06 (s,
3H), 2.31 (bs, 1H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3): d 149.6, 142.7, 142.2,
141.5, 140.7, 133.8, 130.7, 130.2, 129.8, 128.2, 127.7, 127.3, 127.0, 126.5, 46.2,
23.0; IR (KBr):
t
= 3274, 1220, 1069, 969 cmꢀ1; Anal. Calcd for C22H21NOS: C
76.04, H 6.09, N 4.03, found: C 75.17, H 5.67, N 3.86; HRMS (ESI), m/z: [M+H]
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