Bioactive sulfoximines: Syntheses and properties of Vioxx analogs

Article abstract of DOI:10.1016/j.bmcl.2011.06.029

The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).

Full text of DOI:10.1016/j.bmcl.2011.06.029

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4888–4890
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Bioactive sulfoximines: Syntheses and properties of VioxxÒ analogs
Seong Jun Park a, Helmut Buschmann b, 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
The syntheses and biological profiles of sulfoximine-based VioxxÒ analogs 2 are described. Interesting
data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as VioxxÒ
itself) exhibiting reduced hERG activity compare to the parent sulfone VioxxÒ (1).
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 13 April 2011
Revised 6 June 2011
Accepted 8 June 2011
Available online 22 June 2011
Keywords:
Sulfoximine
VioxxÒ (Rofecoxib)
hERG activity
COX-2-selective inhibitor (COXIB)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly
used medications for the treatment of both acute and chronic pain.
The discovery of cyclooxygenase (COX) as the target of NSAIDs, the
subsequent identification of two isozymes of COX (COX-1 and
COX-2), and studies of their regulation and expression sites sug-
gested COX-2 as prime molecular target for new drugs. Selective
COX-2 inhibitors (COXIBs) were expected to retain the desirable
anti-inflammatory and analgesic effects of the NSAIDs without
exhibiting frequently observed side effects such as gastrointestinal
toxicity (as described for COX-1 inhibitors). Consequently, a num-
ber of selective COX-2 inhibitors were developed, and some of
those have found wide acceptance on the market.1 However, the
long-term use of both traditional NSAIDs and COXIBs has been re-
ported to cause significant cardiovascular side effects, which finally
led to withdrawals of compounds such as rofecoxib (VioxxÒ, Fig. 1)
and valdecoxib (BextraÒ).2 For the currently still available NSAIDs
the risk increase of cardiovascular diseases is often uncertain.3
New COX-2 inhibitors are therefore needed, which challenged us
to approach and test structurally distinct chemical entities related
to known COXIBs.
tions of sulfoximines in crop protection8 and medicinal chemis-
try.9–11 A few examples related to the latter area are shown in
Fig. 2.
One particular report caught our attention. Researchers at Pfizer
described that in their studies of proline-rich tyrosine kinase 2
inhibitors the switch of a sulfone to the corresponding N-alkylsul-
foximines (such as 3) resulted in active compounds with promising
biological profiles. Of particular importance was the unexpected
finding that those products showed a lower dofetilide binding,
which translated to a significant improvement in a hERG assay.11,12
Realizing that VioxxÒ (1) was an aryl methyl sulfone we wondered
about the biological profiles of the analogous sulfoximine deriva-
tives 2. Here, we describe the syntheses of NH- and N-methyl sul-
foximines 2a and 2b, respectively, and report results of initial
enzyme inhibition studies with them.
For the preparation of sulfoximines 2 the original strategy for
the synthesis of VioxxÒ13 was combined with chemistry developed
in our laboratories.14 As illustrated in Scheme 1, acetophenone 5
was prepared by Friedel–Crafts acylation of thioanisole 4. Imina-
tion of 5 with a combination of cyanogen amine and PhI(OAc)2
Since the discovery of methionine sulfoximine as the toxic fac-
tor for canine hysteria by Bentley et al. at the end of 1940s,4 sulfox-
imines have played various roles in organic and medicinal
chemistry. As monoaza analogs of sulfones they were applied as
chiral auxiliaries in asymmetric synthesis,5 used as ligands in
enantioselective metal catalysis6 and introduced as enzyme inhib-
itors.7 Recently, additional biological activities have been found,
which led to a significant number of patents describing applica-
N R
CH3
O
O
O
S
S
CH3
O
O
O
O
a: R = H
b: R = CH3
1
2
⇑
Corresponding author. Tel.: +49 241 8094675; fax: +49 241 8092391.
E-mail address: Carsten.Bolm@oc.rwth-aachen.de (C. Bolm).
Figure 1. VioxxÒ (1) and sulfoximine-based VioxxÒ analogs (2).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.029

S. J. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4888–4890
4889
Me
Me
HN
S
60
O
Vioxx® (1)
sulfoximine 2a
H
Me
Ph
N
OH
50
40
30
20
O
NH
H
N
N
S
H
N
CONHtBu
O
HO
OH
HIV-1 protease inhibitor
O
CYP24 hydroxylase inhibitor
N
Br
HN
H
N
Me N
Me
N
S
CF3
N
HO
N
H
N
N
H
10
0
O
N
N
S
Me
Me
Me Me
3
PYK2 inhibitor
CDK inhibitor
0
25
50
75
100
concentration (µM)
Figure 2. Examples of sulfoximines studied in medicinal chemistry.10,11
Figure 3. Blocking potencies of VioxxÒ (1, d) and sulfoximine 2a (4) on the hERG
ion channel (for details see text and Ref. 19).
CN
N
S
S
CH3
S
a
b
CH3
CH3
H3C
VioxxÒ as reference compounds.18 To our delight, inhibitory activ-
ities were found for both sulfoximines albeit compared to the one
of (the sulfone) VioxxÒ they were only moderate. Most interesting
was that sulfoximine 2a showed a COX-1/2 selectivity with no
binding to the COX-1 receptor and 26% inhibition of the COX-2 en-
zyme. Methylated derivative 2b, in contrast, was unselective
exhibiting COX-1 and COX-2 inhibitory activities of +10% and
+11%, respectively.
H3C
87%
81%
O
O
4
5
6
c
86%
O
N CN
S
O
CN
CN
N
N
S
O
CH3
S
e
d
CH3
CH3
O
O
H3C
49%
54%
Br
The hERG blocking potencies of sulfoximine 2a and (sulfone)
VioxxÒ (1) were determined in whole-cell patch clamp recordings
using HEK293 cell stably expressing the hERG ion channel.19 The
O
O
9
8
7
compounds were tested at 1.0, 3.16, 10, 31.6 and 100 lM concen-
trations with each on two individual cells. Fig. 3 shows a summary
of the data. Both compounds showed only a weak inhibitory effect
on the hERG ion channel at concentrations up to 100 lM, and for
both the IC50 values were estimated to be higher than this concen-
tration. A more detailed analysis, however, revealed for sulfoxim-
f
62%
O
N CH3
O
NH
S
S
CH3
CH3
g
O
O
O
75%
ine 2a a clear channel inhibition at concentrations of 31.6
and higher, whereas for VioxxÒ the respective concentration was
10 M. Hence, as in previously mentioned PYK2 inhibitor study
lM
O
2a
2b
l
by Pfizer, the switch from a sulfone to the corresponding sulfoxim-
ine appears to have a positive impact leading to compounds with
reduced hERG inhibitory activity. Although the effect reported here
is only moderate, we see relevance for the search of new bioactives
and potential drug entities taking into account the close link be-
tween hERG activity and cardiovascular side effects.20
In conclusion, we synthesized sulfoximines, which are structur-
ally analogous to VioxxÒ and investigated their COX-1/2 inhibitory
activity and the hERG blocking potencies. The most interesting
compound was NH-sulfoximine 2a, which showed COX-2 selectiv-
ity, albeit being less active than VioxxÒ (1), and lower hERG activ-
ity compared to 1. Currently, we conceive that this beneficial effect
is related to the sulfonimidoyl unit of the sulfoximine, and in sub-
sequent research we hope to consolidate our hypothesis that an O/
NH-exchange (from a sulfone to the corresponding sulfoximine)
could also improve the properties of other drug-like molecules. Fu-
ture results along these lines will be reported in due time.
Scheme 1. Reagents and conditions: (a) acetylchloride, AlCl3, CH2Cl2, rt, 30 min; (b)
NH2CN, PhI(OAc)2, CH3CN, rt, 1 h; (c) K2CO3, m-CPBA, MeOH, rt, 30 min; (d) AlCl3,
Br2, CH2Cl2, 45 °C, 24 h; (e) Et3N, phenylacetic acid, DBU, CH3CN, 90 °C, 24 h; (f)
aqueous H2SO4 (50%), 110 °C, 4 h; (g) CH2O, HCO2H, 150 °C, 72 h.
led to N-cyano sulfilimine 6, which was subsequently oxidized
with a combination of m-CPBA and K2CO3 in methanol affording
the desired sulfoximine 7. In this reaction sequence all transforma-
tions proceeded with yields above 80%. Sulfoximine 7 was then re-
acted with bromine in CH2Cl2 in the presence of a trace amount of
AlCl3 to give bromoketone 8. For the following two steps (coupling
and cyclization) a one-pot procedure was applied. First, a mixture
of 8 and phenylacetic acid in acetonitrile was treated with triethyl-
amine at room temperature providing an ester intermediate (no
shown), which cyclized upon addition of DBU at 0 °C leading to lac-
tone 9. Finally, NH-sulfoximine 2a was obtained by cleavage of the
N-cyano group of 9 using aqueous H2SO4 (50%).15 Mono-methyla-
tion of the sulfoximine nitrogen of 2a under Eschweiler–Clarke
conditions16 concluded the synthesis of N-methylsulfoximine 2b.17
Next, the COX-1/2 inhibitory activity and the hERG blocking
potencies were evaluated. In the COX-1/2 assays samples of sulfox-
imines 2a and 2b were tested concurrently to indomethacin and
Acknowledgment
Support by the Fonds der Chemischen Industrie is greatly
appreciated.

4890
S. J. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4888–4890
16. (a) Swigert, J.; Taylor, K. G. J. Am. Chem. Soc. 1971, 93, 7338; (b) Johnson, C. R.;
Supplementary data
Schroeck, C. W.; Schanklin, J. R. J. Am. Chem. Soc. 1973, 95, 7424; (c) Shiner, C. S.;
Berks, A. H. J. Org. Chem. 1988, 53, 5542.
17. Selected data for product characterization: 6: mp 140.0–140.9 °C; 1H NMR
(300 MHz, CDCl3) d 8.16 (t, 1H, J = 2.0 Hz, Ph), 8.13 (t, 1H, J = 1.9 Hz, Ph), 7.90 (t,
1H, J = 2.0 Hz, Ph), 7.87 (t, 1H, J = 2.0 Hz, Ph), 3.05 (s, 3H, -Ph-S(NCN)-CH3), 2.65
(s, 3H, CH3–CO–Ph–); 13C NMR (75 MHz, CDCl3) d 196.4 (CO), 140.7 (C), 140.4
(C), 129.9 (2 ꢀ CH), 126.1 (2 ꢀ CH), 119.9 (CN), 36.7 (CH3), 26,8 (CH3); IR (KBr)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.06.029.
References and notes
m
2148, 1678, 1178, 978 cmꢁ1. 7: 1H NMR (300 MHz, CDCl3) d 8.17 (t, 1H,
J = 2.0 Hz, Ph), 8.14 (t, J = 1.9 Hz, Ph), 8.06 (t, 1H, J = 2.0 Hz, Ph), 8.03 (J = 1.9 Hz,
Ph), 3.32 (s, 3H, –Ph–S(O)(NCN)–CH3), 2.63 (s, 3H, CH3–CO–Ph–); 13C NMR
(75 MHz, CDCl3) d 196.1 (CO), 142.2 (C), 139.8 (C), 129.8 (2 ꢀ CH), 128.4
1. Marnett, L. J. Annu. Rev. Pharmacol. Toxicol. 2009, 49, 265.
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1619; (c) McGettigan, P.; Henry, D. JAMA 2006, 296, 1633.
(2 ꢀ CH), 44.5 (CH3), 27.0 (CH3); IR (KBr)
m .
2192, 1687, 1398, 1192, 973 cm–1
8: mp 99.2–99.9 °C; 1H NMR (300 MHz, CDCl3) d 8.21 (t, 1H, J = 2.0 Hz, Ph), 8.18
(t, J = 1.9 Hz, Ph), 8.09 (t, 1H, J = 2.0 Hz, Ph), 8.06 (J = 2.0 Hz, Ph), 4.40 (s, 2H, Br–
CH2–CO–Ph–), 3.33 (s, 3H, –Ph–S(O)(NCN)–CH3); 13C NMR (75 MHz, CDCl3) d
189.8 (CO), 140.5 (C), 139.2 (C), 130.6 (2 ꢀ CH), 128.6 (2 ꢀ CH), 44.5 (CH3), 30.0
3. (a) Solomon, S. D.; McMurray, J. J. V.; Pfeffer, M. A.; Wittes, J.; Fowler, R.; Finn,
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(CH2); IR (KBr)
m
2188, 1690, 1396, 1192, 980 cmꢁ1. 9: 1H NMR (400 MHz,
CDCl3) d 7.90 (d, 2H, J = 8.6 Hz, Ph), 7.54 (d, 2H, J = 8.6 Hz, Ph), 7.37–7.31 (m,
5H, Ph), 5.14 (s, 2H, –CO–O–CH2–C–Ph–), 3.28 (s, 3H, CH3–S(O)(NH)–Ph–); 13C
NMR (100 MHz, CDCl3) d 172.2 (CO), 152.4 (C), 138.0 (C), 137.4 (C), 130.0 (C),
129.8 (CH), 129.7 (CH), 129.2 (2 ꢀ CH), 129.1 (4 ꢀ CH), 128.9 (C), 128.6
(2 ꢀ CH), 70.2 (CH2), 44.6 (CH3); IR (KBr)
m H
2197, 1748, 1196, 964 cmꢁ1. 2a: 1
NMR (400 MHz, CDCl3) d 7.93 (d, 2H, J = 8.5 Hz, Ph), 7.44 (d, 2H, J = 8.5 Hz, Ph),
7.33 (s, 5H, Ph), 5.13 (s, 2H, –CO–O–CH2–C–Ph–), 3.10 (s, 3H, CH3–S(O)(NH)–
Ph–), 2.88 (br, 1H, CH3–S(O)(NH)–Ph–); 13C NMR (100 MHz, CDCl3) d 172.5
(CO), 153.5 (C), 144.3 (C), 135.8 (C), 129.4 (CH), 129.2 (C), 129.1 (2 ꢀ CH), 128.9
(2 ꢀ CH), 128.8 (C), 128.4 (4 ꢀ CH), 70.4 (CH2), 45.9 (CH3); IR (KBr)
m 3344,
1747, 1116, 958 cmꢁ1; MS (EI), m/z (relative intensity) 313 [M+, 21], 250 [M+-
S(O)(NH)CH3, 100], 192 [66], 178 [61], 165 [43], 152 [23]; HRMS (EI), m/z: Anal.
Calcd for C17H16O3NS 314.0845. Found: 314.0845. 2b: 1H NMR (400 MHz,
CDCl3) d 7.82 (d, 2H, J = 8.5 Hz, Ph), 7.45 (d, 2H, J = 8.8 Hz, Ph), 7.35 (s, 5H, Ph),
5.14 (s, 2H, –CO–O–CH2–C–Ph–), 3.05 (s, 3H, CH3–S(O)(NH)–Ph–), 2.59 (s, 3H,
CH3–S(O)(NCH3)–Ph–); 13C NMR (100 MHz, CDCl3) d 172.5 (CO), 153.5 (C),
140.5 (C), 135.4 (C), 129.4 (CH), 129.4 (2 ꢀ CH), 129.3 (C), 129.1 (2 ꢀ CH), 128.9
(2 ꢀ CH), 128.8 (C), 128.5 (2 ꢀ CH), 70.4 (CH2), 44.7 (CH3), 29.5 (CH3); HRMS
(EI), m/z: Anal. Calcd for C18H18O3NS 328.1002. Found: 328.1002.
18. The biochemical assays for the COX-1/2 inhibitions were performed by Ricerca
Biosciences, Chicago, USA. In the analysis of sulfoximine 2a (at 10
concentration) concurrently tested samples of indomethacin (for COX-1) and
VioxxÒ (for COX-2) showed IC50 values of 0.0338 and 0.156
M, respectively. In
the studies of 2b those IC50 values were 0.0424 and 0.156 M, respectively.
lM
that BSO blocks the GSH synthesis by inhibiting the
synthetase, see: (b) Meister, A. Science 1983, 220, 472.
c-glutamylcysteine
l
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l
Details are given in the Supplementary data. The following references were
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