Synthesis and activity of fluorinated derivatives of sulindac sulphide and sulindac sulphone

Article abstract of DOI:10.1211/146080800128735926

The synthesis of fluorinated derivatives of the sulphide and sulphone metabolites of sulindac, a non-steroidal anti-inflammatory agent with chemopreventative activity, is reported. The key step in the synthesis is a Pummerer-rearrangement of the parent su

Full text of DOI:10.1211/146080800128735926

Pharm. Pharmacol. Commun. 2000, 6: 217±221
Received November 2, 1999
Accepted November 8, 1999
# 2000 Pharm. Pharmacol. Commun.
Synthesis and Activity of Fluorinated Derivatives of Sulindac
Sulphide and Sulindac Sulphone
MANFRED JUNG, ALAN F. WAHL*, WERNER NEUPERT{, GERD GEISSLINGER{
AND PETER D. SENTER*
È
Westfalische Wilhelms-Universitat Munster, Department of Pharmaceutical Chemistry, Hittorfstr. 58-62,
D-48149 Munster, Germany; *Seattle Genetics, Inc., 22215 26th Avenue SE, Bothell, WA 98021, USA and
È
È
È
È
{Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt, Germany
Abstract
The synthesis of ¯uorinated derivatives of the sulphide and sulphone metabolites of sulindac,
a non-steroidal anti-in¯ammatory agent with chemopreventative activity, is reported.
The key step in the synthesis is a Pummerer-rearrangement of the parent sulindac
sulphoxide using (diethylamino)sulphur tri¯uoride as an activating agent and as a source of
the ¯uoride nucleophile. The reaction leads to the formation of the 4-¯uoromethylthio and
4-¯uoromethylsulphonyl derivatives of sulindac (4a and 4b, respectively). Sulindac sul-
phide is 2Á5 times more potent as a COX-1 inhibitor compared with its ¯uorinated coun-
terpart 4a. The sulphones were inactive as COX-1 inhibitors, and none of the compounds
inhibited COX-2 concentrations up to 0Á1 mM. Cytotoxicity assays showed that 4a and 4b
were as cytotoxic as sulindac sulphide and sulindac sulphone on 3719 colorectal carcinoma
cell lines. Compound 4b was the most potent compound on RCA cells with an IC50 of
95 mM (sulindac sulphide 140 mM, sulindac sulphone 175 mM).
Fluorinated sulindac derivatives warrant further investigation since we have shown that
cytotoxic activity can be retained or even increased independently from COX-inhibitory
properties. This could help minimize the undesired side-effects associated with chronic
sulindac administration.
Inhibition of arachidonic acid pathways is one way
to interfere with carcinogenesis. This has been
studied extensively in numerous in-vitro and in-
vivo models, and in the case of acetylsalicylic acid,
activity has been documented in man (Kahn &
Morrison 1997). One particularly interesting com-
pound from the class of non-steroidal anti-in¯am-
matory agents with respect to cancer prevention is
sulindac (1a) (Kelloff et al 1985; Wattenberg 1997;
Hakama 1998). This agent suppresses familial
adenomatous polyposis (FAP), a premalignant
disease that can lead to colon cancer (Giardiello et
al 1993). The active form of sulindac in terms of
anti-in¯ammatory activity is the sulphide 1b, which
is formed in the gastrointestinal tract. Sulphone 1c
accounts for a large percentage of the sulindac
species in the blood (Duggan et al 1977; Elder &
Paraskeva 1997). In contrast, 1b is a cyclooxy-
genases (COX) inhibitor. Both agents are active in
suppressing chemically induced rat mammary car-
cinogenesis (Thompson et al 1995). Recent studies
suggest that COX inhibition is not necessary for the
anticancer activity of sulindac. The mechanisms by
which these agents exert anticancer activity are not
well understood. Some of the suggested mechan-
isms include increased production of ceramide
(Chan et al 1998), induction of apoptosis (Piazza et
al 1995; Shiff et al 1995), PPAR-a and -g agonistic
activity (Lehmann et al 1997), suppression of
PPAR-d dependent processes (He et al 1999),
alterations on mitochondrial membranes (Waddell
1998), inhibition of growth factor induced angio-
genesis (Verheul et al 1999), and interaction with
the ras=raf-pathway (Herrmann et al 1998).
As part of a programme for the development of
new cancer chemoprevention drugs, we synthesized
new derivatives and analogues of sulindac (1a).
Since the total synthesis of 1a is lengthy (Shuman
et al 1977), we chose to modify the commercially
available material, with a focus on alterations of the
sulphoxide group. This molecular site apparently
in¯uences biological activity, given the differences
È
Correspondence: M. Jung, Westfalische Wilhelms-Univer-
È
È
sitat Munster, Department of Pharmaceutical Chemistry,
Hittorfstr. 58-62, D-48149 MuÈnster, Germany.
E-Mail: jungm@uni-muenster.de

218
MANFRED JUNG ET AL
in activity between sulphide 1b and sulphone 1c. It
was thought that slight modi®cations at the sulph-
oxide position would be synthetically practical and
would lead to new molecules of biological interest.
The Pummerer rearrangement is a powerful tool
for the modi®cation of sulphoxide groups, leading
to a-substituted sulphides that can subsequently be
oxidized to form substituted sulphoxides and sul-
phones (De Lucchi et al 1991). We applied the
Pummerer rearrangement reaction to 1a using
(diethylamino)sulphur tri¯uoride (DAST) (McCar-
thy et al 1985). This leads to the formation of a-
¯uoro-substituted sulphoxides that can be further
modi®ed to form substituted sulphides and sul-
phones. It has been previously shown that sub-
stitution of hydrogen by ¯uorine can in¯uence the
biological activity of drugs without affecting the
overall molecular size (Welch & Eswarakrishnan
1991; Filler et al 1993). In this study we describe
the synthesis and biological properties of a-¯uoro-
substituted derivatives of sulindac (1a).
(34 mg, 0Á15 mmol) were added. After stirring at
room temperature for 24 h, 20 mL 5 % aqueous
NaHCO3 was added. The organic phase was sepa-
rated, dried over Na2SO4 and evaporated. The
desired product (3a) was obtained as yellow crys-
tals after ¯ash chromatography (ethyl acetate=
hexane 1 : 3) and recrystallization from hexane=
CH2Cl2 (1Á34 g, 72%): mp 102ꢀC; 1H NMR
(CDCl3): d ˆ 2Á18(s, 3H, 2-CH ), 3Á56 (s, 2H,
3
CH2COOR), 3Á70 (s, 3H, OCH3), 5Á80 (d,
2JH,F ˆ 52Á6 Hz, CH2F), 6Á52 (ddd, 3J ˆ 9Á3 Hz, 3J ˆ
4
3
9Á1 Hz, JH,H ˆ 2Á3 Hz, 1H, 6-H), 6Á88 (dd, JH,F
ˆ
4
8Á9 Hz, JH,H ˆ 2Á3 Hz, 1H, 4-H), 7Á13 (s, 1H,
ArÀCH ˆ C), 7Á23±7Á31 (m, 1H, 7-H), 7Á47±7Á55
(m, 4H, CH3SOArÀH); 13C NMR (CDCl3):
d ˆ 10Á54 (2-CH3), 31Á58( CH2COO), 52Á22
1
(OCH3), 87Á98(d, JH,F ˆ 216Á6 Hz,CH2F),105Á91(d,
2JC,F ˆ 23Á8Hz, C-4), 110Á66 (2JC,F ˆ 22Á7 Hz, C-6),
123Á68(d, 3JC,F ˆ 9Á0 Hz,C-7),129Á12(ArÀCHˆ C),
129Á66(d,4JC,F ˆ 3Á1 Hz,C-7a),129Á95and130Á25(C-
20=C-60,C-30=C-50),131Á16(C-3),134Á58(C-2),135Á89
(C-10),138Á32(C-1),140Á80(C-40),146Á58(d, 3UC,F
ˆ
1
9Á1 Hz, C-3a), 163Á24 (d, JC,F ˆ 246Á1 Hz, CÀF),
‡
170Á80 (CO); MS: m=z ˆ 372, [M ], 233 (100); IR
(KBr): n ˆ 1720 (CO), 1590 (C ˆ C) cmÀ1; Anal.
(C21H18F2O2S) 372Á44; calc. C 67Á72 H 4Á88; found
C67Á62 H 5Á04.
Materials and Methods
Chemistry
Chloroform was dried using molecular sieves (3A).
Ê
Compound 1a is commercially available from
Sigma. Melting points are uncorrected. The fol-
lowing instruments were used: Perkin Elmer CHN-
Analyser 240 for elemental analyses, Shimadzu
470 for infrared spectroscopy, Varian Gemini 200
(200 MHz) for 1H NMR, Varian Gemini 200
(50Á29 MHz) for 13C NMR, Varian MAT 44S and
Finnigan MAT 312 for mass spectrometry. Silica
gel 60, 230±400 mesh (Merck), was used for ¯ash
chromatography.
Methyl 5-¯uoro-1-Z-(4-¯uoromethylsulphonyl-
benzylidene)-2-methyl-3-indenylacetate (3b)
Compound 3a (740 mg, 2 mmol) and meta-
chlorobenzoic acid (MCPBA) (990 mg, 4 mmol)
were dissolved in 10 mL THF and stirred for 3 h at
room temperature. After evaporation, ¯ash chro-
matography (ethyl acetate=hexane 2 : 3) and
recrystallization (hexane=CH2Cl2), yellow crystals
of 3b were obtained (610 mg, 75%): mp 141ꢀC; 1H
NMR (CDCl3): d ˆ 2Á21 (s, 3H, 2-CH3), 3Á57 (s,
2H, CH2COOR), 3Á72 (s, 3H, OCH3), 5Á21 (d,
3
2JH,F ˆ 47Á1 Hz, CH2F), 6Á58(ddd, JH,F ˆ 8Á9 Hz,
Methyl 5-¯uoro-2-methyl-1-Z-(4-methylsulphinyl-
benzylidene)-3-indenylacetate (2)
3JH,H ˆ 8Á5 Hz,4JH,H ˆ 2Á4 Hz, 1H, 6-H), 6Á88 (dd,
4
Compound 1a (5 g) was dissolved in 200 mL
methanol and 1 mL concentrated H2SO4 was added.
The mixture was heated to re¯ux for 6 h. After
cooling to room temperature the mixture was eva-
porated and the resulting solid was recrystallized
from CH2Cl2=hexane. The identity and purity of 2
as previously described by Jones (1975) was
3JH,F ˆ 8Á9 Hz, JH,H ˆ 2Á4 Hz, 1H, 4-H), 7Á28(dd,
3
3JH,F ˆ 5Á1 Hz, JH,H ˆ 8Á5 Hz, 1H, 7-H), 7Á13
(s, 1H, ArÀCH ˆ C), 7Á72±8Á05 (m, 4H,
CH3SOArÀH); 13C NMR (CDCl3): d ˆ 10Á46 (2-
CH3), 31Á61 (CH2COO), 52Á23 (OCH3), 92Á07 (d,
1JH,F ˆ 220Á4 Hz, CH2F),106Á42(d,2JC,F ˆ 24Á0Hz,C-
3
4), 110Á01 (2JC,F ˆ 22Á8Hz, C-6), 123Á71 (d, JC,F
ˆ
1
determined using IR, MS, H and 13C NMR.
9Á1 Hz, C-7), 126Á78(Ar À CH ˆ C), 129Á23 (C-7a),
129Á29 and 130Á35 (C-20=C-60, C-30=C-50), 132Á63
(C-3), 135Á31 (C-2), 138Á05 (C-10), 142Á77 (C-1),
Methyl5-¯uoro-1-Z-(4-¯uoromethylthio-benzylidene)-
2-methyl-3-indenylacetate (3a)
To a solution of 2 (1Á85 g, 5 mmol) in 25 mL of
CHCl3 in an oven dried ¯ask purged with N2,
DAST (1Á32 mL, 1Á61 g, 10 mmol) and ZnBr2
3
143Á83 (C-40), 146Á94 (d, JC,F ˆ 9Á1 Hz, C-3a),
1
163Á64 (d, JC,F ˆ 247Á4 Hz, CÀF), 170Á49 (CO);
‡
MS (70 eV); m=z (%) ˆ 404 [M ], 233 (100 %); IR
(KBr): n ˆ 1720 (CO), 1590 (C ˆ C), 1310s (SO2),

FLUORINATED DERIVATIVES OF SULINDAC METABOLITES
4
219
3
1150s (SO2); Anal. (C21H18F2O4S) 404Á44; calc. C
8Á8Hz, JH,H ˆ 2Á4 Hz, 1H, 4-H), 7Á07 (dd, JH,F ˆ
62Á36 H 4Á45; found C 62Á20 H 4Á43.
5Á1Hz,3JH,H ˆ 8Á4 Hz,1H,7-H),7Á14(s,1H,ArÀCH ˆ
C), 7Á71±7Á77 (m, 4H, CH3SOArÀH); 13C NMR
(CH3OH-d4): d ˆ 10Á37 (2-CH3), 32Á12 (CH2COO),
24Á4 Hz, C-4), 111Á48( 2JC,F ˆ 23Á9 Hz, C-6), 124Á72
93Á52 (d, 1JH,F ˆ 215Á6 Hz, CH2F), 107Á13 (d, 2JC,F
ˆ
General procedure for ester cleavage
The ester was dissolved in tetrahydrofuran (THF)
and two equivalents of LiOH were added as a 1 M
aqueous solution. After stirring for 5 h at room
temperature, 20 mL diethyl ether and 20 mL H2O
were added. The aqueous phase was separated and
acidi®ed with 2 M HCl (pH 2±3). The acidic solution
was extracted with 3 6 30 mL ethyl acetate. The
organic layer was dried over Na2SO4 and evapo-
rated.
3
(d, JC,F ˆ 9Á2 Hz, C-7), 128Á55 (ArÀCH ˆ C),
129Á82 (C-7a), 130Á32 and 131Á45 (C-20=C-60, C-
30=C-50), 136Á93 (C-2), 139Á31 (C-10), 143Á69 (C-1),
3
145Á16 (C-40), 148Á65 (d, JC,F ˆ 8Á0 Hz, C-3a),
1
164Á84 (d, JC,F ˆ 245Á4 Hz, CÀF), 174Á00 (CO);
‡
MS: m=z ˆ 390 [M ], 233 (100); IR (KBr): n ˆ
1690 (CO), 1590 (C ˆ C), 1310 (SO2), 1150 (SO2)
cmÀ1; Anal. (C20H16F2O4S) 390Á41; Calc. C 61Á52
H 4Á14; Found C 61Á79 H 4Á47.
5-Fluoro-1-Z-(4-¯uoromethylthio-benzylidene)-2-
methyl-3-indenylacetic acid (4a)
Inhibition of cyclooxygenases
Ester cleavage as described above was performed
on 3a (370 mg, 1 mmol). The crude product was
puri®ed by ¯ash chromatography (ethyl acetate=
CH3OH 50 : 1, 0Á5% HOAc). Recrystallization from
CH2CH3OH=H2O gave the desired product 4a as
yellow-orange powder (80 mg, 22%): mp 148ꢀC;
1H NMR (DMSO-d6): d ˆ 2Á20 (s, 3H, 2-CH3), 3Á58
Inhibition of cyclooxygenase activity was studied
using a whole blood assay as described previously
(Panara et al 1995; Neupert et al 1997). COX-1
inhibition was analysed by measuring immuno-
reactive thromboxan B2 (irTXB2) and COX-2 (after
induction with LPS) by monitoring immuno-
reactive protaglandin E2 (irPGE2), both via enzyme
immunoassay. For COX-2 assessment aspirin was
added to suppress COX-1 contribution.
2
(s, 2H, CH2COOR), 5Á80 (d, JH,F ˆ 52Á8Hz,
3
CH2F), 6Á58(ddd, 3JH,F ˆ 9Á2 Hz, JH,H ˆ 8Á7 Hz,
3
4JH,H ˆ 2Á4 Hz, 1H, 6-H), 6Á88 (dd, JH,F
ˆ
4
9Á1 Hz, JH,H ˆ 2Á5 Hz, 1H, 4-H), 7Á26 (s, 1H,
3
3
ArÀCH ˆ C), 7Á28(dd, JH,F ˆ 5Á2 Hz, JH,H ˆ 8Á7
Hz, 1H, 7-H), 7Á45±7Á56 (m, 4H, CH3SOArÀH);
13C NMR (DMSO-d6): d ˆ 10Á53 (2-CH3), 31Á28
Growth inhibition of RCA colon cancer cells
The RCA (Ricinus communis agglutinin) human
colon cancer cells was provided by M. Brattain,
University of Texas, San Antonio. The 3719 human
colorectal carcinoma cell line was established from
a freshly surgically removed colorectal carcinoma
tumour. The cell lines were plated at approximately
5000 cells=well into 96 well tissue culture plates in
150 mL of RPMI medium containing 10% foetal
bovine serum, 60 mg mLÀ1 penicillin and
0Á1 mg mLÀ1 streptomycin. After adhering over-
night at 37ꢀC, the cells were exposed to varying
concentrations of the drugs for 72 h. XTT tetra-
zolium dye was added to the wells, and after 6 h,
dye reduction was measured in a plate reader.
1
(CH2COO), 87Á17 (d, JH,F ˆ 216Á9 Hz, CH2F),
2
2
105Á93 (d, JC,F ˆ 24Á0 Hz, C-4), 110Á8 3 (JC,F
ˆ
3
22Á7 Hz, C-6), 123Á83 (d, JC,F ˆ 8Á9 Hz, C-7),
4
129Á32 (ArÀCH ˆ C), 129Á69 (d, JC,F ˆ 3Á1 Hz, C-
7a), 130Á09 and 130Á16 (C-20=C-60, C-30=C-50),
130Á62 (C-3), 134Á70 (C-2), 135Á97 (C-10), 138Á75
3
(C-1), 140Á81 (C-40), 146Á49 (d, JC,F ˆ 9Á0 Hz, C-
1
3a), 163Á33 (d, JC,F ˆ 236Á4 Hz, CÀF), 175Á11
‡
(CO); MS: m=z ˆ 358[M ], 233 (100); IR (KBr):
n ˆ 1690 (CO), 1590 (C ˆ C) cmÀ1; Anal.
(C20H16F2O2S) 358Á42; Calc. C 67Á02 H 4Á51;
Found C 67Á02 H 4Á62.
5-Fluoro-1-Z-(4-¯uoromethysulphonylbenzylidene)-
2-methyl-3-indenylacetic acid (4b)
Results and Discussion
Ester cleavage as described above was performed
on 3b (202 mg, 0Á5 mmol). Recrystallization from
CH2CH3OH=H2O gave the desired product as a
yellow powder (120 mg, 62%): mp 176ꢀC; 1H
NMR (DMSO-d6): d ˆ 2Á21 (s, 3H, 2-CH3), 3Á60 (s,
Sulindac methyl ester 2 was treated with DAST and
catalytic amounts of zinc bromide. The desired a-
¯uoro sulphide 3a was isolated after chromato-
graphy in 72% yield. Oxidation of 3a with meta-
chloroperbenzoic acid led to a 75% yield of the a-
¯uoro sulphone 3b. Hydroxide mediated cleavage
of the esters 3a and 3b gave the respective acids 4a
2
2H, CH2COOR), 5Á21 (d, JH,F ˆ 47Á2 Hz, CH2F),
6Á58(ddd,
3JH,F ˆ 9Á1 Hz,
3JH,H ˆ 8Á4 Hz,
3
4JH,H ˆ 2Á4 Hz, 1H, 6-H), 6Á89 (dd, JH,F
ˆ

220
MANFRED JUNG ET AL
Figure 1. Structure and synthesis of the ¯uorinated derivatives of sulindac metabolites.
and 4b. All compounds were obtained as crystalline
solids that were analytically pure (Figure 1).
The compounds were then investigated for their
ability to inhibit COX-1 and 2 using enzyme
immunoassays for the quanti®cation of respective
metabolites (irTXB2 for COX-1 and irPGE2 for
COX-2) as described previously (Panara et al 1995;
Neupert et al 1997). None of the compounds dis-
played signi®cant inhibition of COX-2. Sulindac
sulphide (1b) and its ¯uorinated derivative 4a were
both active as inhibitors of COX-1, with 1b (IC50
2Á6 mM) being 2Á5 times more potent than 4a (IC50
6Á4 mM). Neither of the sulphones 1c or 4b inhibited
COX-1 at the highest concentrations tested
(Table 1).
Cytotoxicity assays were performed using the
RCA and 3719 human colorectal carcinoma cell
lines. The cells were exposed to the drugs for 72 h,
and cell viability was determined using the tetra-
zolium stain XTT, which gives a readout of mito-
chondrial membrane integrity. The IC50 values of
the sulindac derivatives 1b, 1c, 4a and 4b were
approximately the same on the 3719 cell line. On
the RCA cells the ¯uoro sulphone 4b (IC50 of
95 mM) was more active than the other agents. The
observed IC50 values are in the range of sulindac
concentrations that have previously been shown to
induce apoptosis in colon cancer cells (120 mM in
HAT-29 cells; Piazza et al 1995) (Table 1).
Several studies have shown that long term
chronic use of NSAIDs can be effective in reducing
the incidence and death rate from colorectal car-
cinoma (Elder & Paraskeva 1997). Sulindac (1a) is
one such agent that has been shown to reduce polyp
formation in patients with familial adenomatous
polyposis (Shiff et al 1995). While many of the
chemopreventive agents actively inhibit COX-1
and=or COX-2, there is now evidence that COX
inhibition is not required for the activity of 1a and
its metabolites. We (Table 1), and others (Thomp-
son et al 1997) have shown that sulindac sulphone
(1c), an agent that is chemopreventive in rat models
of breast and colorectal carcinoma, does not inhibit
either of the COX enzymes. COX-1 inhibition by
sulindac sulphide (1b) may actually be detrimental
for long term administration, since the enzyme is
constitutively expressed, and inhibitors of COX-1
lead to signi®cant gastrointestinal toxicity. While
the use of selective COX-2 inhibitors might be one
possibility to avoid side effects (Oshima et al
1996), we are aiming to establish compounds with
increased proapoptotic properties that are inde-
pendent of inhibition of prostaglandin synthesis.
We have demonstrated that the ¯uoro derivative of
sulindac sulphide 4a retains, or even has slightly
increased cytotoxic activity on colorectal cell lines,
but displays 2Á5-fold less inhibitory activity on
COX-1 than sulindac sulphide 1b. Additionally, the
¯uorinated sulphone 4b shows an increased cyto-
Table 1. Cox-inhibition and cytotoxic activity of sulindac
metabolites and derivatives.
Assay
IC50 (mM)
1c 4a
1b
4b
COX-1 inhibition
COX-2 inhibition
2Á6 > 100a. 6Á4 > 100a.
> 100a. > 100a. > 100a. > 100a.
3719 growth inhibition
RCA growth inhibition
125.
140.
125.
175.
125.
140.
125.
95.
aLess than 20% inhibition at 100 mM.

FLUORINATED DERIVATIVES OF SULINDAC METABOLITES
221
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toxicity on RCA cells and retained activity on the
3719 cells without displaying COX-inhibitory
properties. Therefore, ¯uorinated derivatives of
sulindac metabolites constitute interesting proto-
types for further structure±activity studies. These
may lead to new agents for cancer chemopreven-
tion with reduced undesired side-effects compared
with the clinically approved agent from which they
are derived.
Neupert, W., Brugger, R., Euchenhofer, C., Brune, K., Geis-
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coenzyme A thioesters on human prostaglandin endoper-
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Oshima, M., Dinchuk, J. E., Kargman, S. L., Oshima, H.,
Hancock, B., Kwong, E., Trzaskos, J. M., Evans, J. F.,
Taketo, M. M. (1996) Suppression of intestinal polyposis in
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M. T., Padovano, R., Digiamberardino, M., Cipollone, F.,
Cuccurullo, F., Patrono, C., Patrignani, P. (1995) Effects of
the novel antiin¯ammatory compounds, N-[2-(cyclohexy-
loxy)-4-nitrophenyl] methanesulfonamide (Ns-398) and 5-
methanesulphonamido-6-(2,4-di¯uorothiophenyl)-1-inda-
none (L-745,337), on the cyclooxygenase activity of human
blood prostaglandin endoperoxide synthases. Br. J. Pharma-
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Acknowledgements
Manfred Jung thanks B. Unterhalt for his generous
support and also the Fonds der Chemischen
Industrie and the DPhG-Stiftung fuÈr den Wis-
senschaftlichen Nachwuchs im Stifterverband fuÈr
die Deutsche Wissenschaft for funding. We thank
Dr. G. Winde, Department of General Surgery,
University of MuÈnster, for the generous gift of
compound 1a.
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