New heteroarylbenzenesulphonamides as matrix metalloproteinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2003.12.076

A series of derivatives of 2,4- and 2,5-thiazolyl- or oxazolylbenzenesulphonamides has been prepared and evaluated as potential MMP inhibitors. The thiazole 15b have been found to exhibit MMP-2 and MMP-9 inhibitions higher than reference compounds GI 129471 and CGS 27023A.

Full text of DOI:10.1016/j.bmcl.2003.12.076

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1119–1121
New heteroarylbenzenesulphonamides as matrix
metalloproteinase inhibitors
Frederic Delbecq,a Guy Cordonnier,a Nicole Pommery,b Didier Barbrya,*
and Jean-Pierre Henichartb
a
´
Groupe de Recherches sur l’Inhibition de la Proliferation Cellulaire UPRES EA 2692, Equipe de Chimie Organique,
´
Universite des Sciences et Technologies de Lille, F-59655 Villeneuve d’Ascq, France
´
b
Groupe de Recherches sur l’Inhibition de la Proliferation Cellulaire UPRES EA 2692, Institut de Chimie Pharmaceutique
Albert Lespagnol, 3 rue du Professeur Laguesse BP 83, F-59006 Lille, France
Received 23 July 2003; revised 17 December 2003; accepted 22 December 2003
Abstract—A series of derivatives of 2,4- and 2,5-thiazolyl- or oxazolylbenzenesulphonamides has been prepared and evaluated as
potential MMP inhibitors. The thiazole 15b have been found to exhibit MMP-2and MMP-9 inhibitions higher than reference
compounds GI 129471 and CGS 27023A.
# 2004 Elsevier Ltd. All rights reserved.
Degradation of extracellular matrix is crucial for
malignant tumour growth, invasion, metastatis and
angiogenesis.1,2 Matrix metalloproteinases (MMPs) are
a family of zinc-dependent neutral endopeptidases
which regulate many biologic processes3 and have
long been associated with cancer-cell invasion and
metastasis.4
Then, design of new compounds more efficient, for
therapeutic intervention either on their own or in con-
junction with cytotoxic treatments, is still needed, since
it was observed that targeting and inactivating MMPs
may enhance the apoptotic activity of DNA-damaging
anticancer drugs via regulation of Fas/FasL system.16
Among the compounds whose MMP inhibition has
been evaluated, benzenesulphonamides constitute a
main family.17,18 In this view, we have prepared a series
of thiazolyl and oxazolylbenzenesulphonamides which
seem to be good candidates against MMPs in compar-
ison with computational studies. Recent publication of
patents prompts us to report our results.19À21
For at least 30 years, MMPs and specially gelatinases5,6
have been heralded as promising targets for cancer
therapy on the basis of their massive up regulation in
malignant tissues and their unique ability to degrade all
components of the extracellular matrix.7 Synthetic
metalloproteinase inhibitors (MPIs) were rapidly devel-
oped and routed into human clinical trials8À12 but the
results of these trials have been disappointing.
The 2,4-diarylthiazoles were prepared as shown in
Scheme 1. We used the Stille coupling reaction22
between the iodide 1 and the organostannane 4 to
obtain compounds 5 in good yields (50% for 5a; 75%
for 5b). Commercially available 4-iodobenzenesulfonyl
chloride was condensed with the amino group of the
aminoesters derived from Val or Glu to afford 1. 4-
Methoxy-a-bromoacetophenone 2 was converted23 to 1-
(4-methoxyphenyl)-2-thiocyanatoethanone 3 which was
cyclized24 with hydrobromic acid to 2-bromo-4-meth-
oxyphenylthiazole. Lithiation of the later with n-butyl-
lithium and quenching with tributylstannyl chloride
gave compounds 4. Alternatively the derivatives 5 could
be obtained by reaction of methoxy-a-bromoaceto-
phenone 2 with the thiobenzamide 7a (50% for 1a).
However, recent studies6,13,14 showed that the MMPs
have functions other than promotion of invasion, sub-
strates other than components of the extracellular
matrix, and that they function before invasion in the
development of cancer. Use of MPIs in the clinic can
therefore be rethinked: new knowledges on how and
where MMPs effect occurs, can have an impact on the
management of patients affected by malignancies.15
Keywords: MMP inhibitors; Benzenesulphonamides; Thiazoles; Oxa-
zoles.
* Corresponding author. Tel.: +33-3204-34974; fax: +33-3204-34974;
e-mail: didier.barbry@univ-lille1.fr
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.076

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F. Delbecqet al. / Bioorg. Med. Chem. Lett. 14 (2004) 1119–1121
Scheme 2. Reagents and conditions: (a) NaN(CHO)2, CH3CN, 20 ꢀC,
3 h, 96%; (b) HCl 12N, MeOH, 20 ꢀC, 2days, 92%; (c) 9, NaHCO3–
ꢀ
H2O, PhCH3, 2 0C, 1 h, 90%; (d) P2S5, pyridine, 100 ꢀC, 1 h; (e)
POCl3, reflux, 2h; (f) NaOH, MeOH, 20 ꢀC, 5 h, 100%; (g) NH2OH,
MeOH, 50 ꢀC/30 min then 20 ꢀC/2h, 91%.
The inhibitory activity of test compounds against
MMP-2and MMP-9 (purchased from Sigma) was
determined by using semi quantitative zymographic
analysis (Table 1). MMPs were electrophoresed on a
SDS-PAGE separating gel containing 0.1% gelatine.
Gels were then incubated overnight at 37 ꢀC in activa-
tion buffer supplemented with different concentrations
of test compounds, stained with Coomassie blue for 1 h
and destained with methanol:acetic acid:water (40:10:50)
(Scheme 3).
Scheme 1. Reagents and conditions: (a) Et3N, CH2Cl2, reflux, 2h, 50–
70%; (b) KSCN, EtOH, reflux, 2h, 98%; (c) HBr gas, Et O, 20 ꢀC, 2
2
h, 62%; (d) n-BuLi, Et2O–hexane, À78 ꢀC, 1 h then Bu3SnCl, À78 ꢀC/
1 h and 20 ꢀC/2h, 95%; (e) 1, PdCl2(PPh3)2, DMF, 70 ꢀC, 8 h.; (f)
NaOH, MeOH or DMSO, 20 ꢀC, 100%; (g) NaHCO3, H2O, 3 h,
20 ꢀC, 63%; (h) SOCl2, CH2Cl2, reflux, 2h, 86%; (i) NH 4OH, CHCl3,
20 ꢀC, 60%; (j) Lawesson’s reagent, THF, reflux, 2h, 72%; (k) 2,
EtOH, reflux, 3 h.
Table 1. Inhibitory activities of diarylthiazolyl- or diaryloxazolyl-
benzenesulphonamides against MMP-2and MMP-9
Compd
IC50 (mM)a
MMP-2MMP-9
GI 129471b
0.20.2
3
—
CGS 27023 Ab
6a
6b
3
—
—
—
4-Chlorosulfonylbenzoic acid was transformed into the
sulphonamide 8a. The carboxylic acid part of 8a was
converted with thionyl chloride into acyl chloride 9a
which reacted with ammonia to afford the carboxamide
10a. Lawesson’s reagent25 converted 10a into the thio-
amide 7a. Esters 5 were easily saponified to the carb-
oxylic acids 6.
15a
15b
17a
16a
16b
18a
0.20.7
0.05
0.4
1
10
1
0.05
0.9
1
10
1
a Concentration required for 50% inhibition of enzyme activity.
b See Scheme 3.
Another synthetic strategy was used to obtain the 2,5-
diarylthiazoles 11 as described in Scheme 2. The
aminoketone 12 resulted from the action of sodium
diformylamide with the bromoketone 2 followed by an
acid-catalyzed hydrolysis according to Yinglin and
Hongwen.26 Acyl chloride 9 (9a or b) was condensed27
with 12 to afford the b-ketoamide 13 which was cyclized
by phosphorus pentasulfide28 to the thiazole 11 (20% for
11a and 33% for 11b). Similarly, the 2,5-diaryloxazoles
14 arose from the cyclization of 13 with phosphorous
oxychloride (25% for 14a and 39% for 14b). Esters 11
and 14 were easily saponified respectively to the carb-
oxylic acids 15 and 16 or converted respectively to the
hydroxamic acids 17 and 18.
Scheme 3. Reference compounds for evaluation of inhibitory activity
of new heteroarylbenzenesulphonamides.

F. Delbecqet al. / Bioorg. Med. Chem. Lett. 14 (2004) 1119–1121
1121
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This work was supported by the Association pour la
Recherche sur le Cancer.