Tetrahydroisoquinoline based sulfonamide hydroxamates as potent matrix metalloproteinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2003.10.026

The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.

Full text of DOI:10.1016/j.bmcl.2003.10.026

Bioorganic & Medicinal Chemistry Letters 14 (2004) 47–50
Tetrahydroisoquinoline based sulfonamide hydroxamates as potent
matrix metalloproteinase inhibitors
Dawei Ma,a,* Wengen Wu,a Guoxin Yang,a Jingya Li,b Jia Lib and Qizhuang Yeb,*
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354Fenglin Lu, Shanghai 200032, China
bChinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences,
Chinese Academy of Sciences, 189 Guo-Shou-Jing Road, Shanghai 201203, China
Received 30 July 2003;revised 11 October 2003;accepted 14 October 2003
Abstract—The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are
described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme
selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
conformationally constrained heterocycle as the back-
bone.3,5,8 The goal was to explore if this modification
would improve the potency, selectivity toward different
MMP isozymes, as well as the pharmacological proper-
ties. Considered 1,2,3,4-tetrahydroisoquinoline-1-car-
boxylates were a class of conveniently available amino
acids,9 we began to use them to synthesize a class of
tetrahydroisoquinoline embodied sulfonamide hydrox-
amates 1. Logically, these compounds possessed neces-
sary elements as the MMP inhibitors like AG-3340,
while their conformational rigidity resulted from their
fused ring, as well as the additional space at the aro-
matic part of the tetrahydroisoquinoline unit, might
result in different selectivity for MMPs.10
The matrix metalloproteinases (MMPs) are an increas-
ing family of zinc-dependent enzymes that degrade the
major components of the extracelluar matrix. This
family of enzymes includes the collagenases, stromely-
sins, and gelatinases. MMPs are necessary for tissue
remodeling and the healing cascade under normal physi-
ological conditions.1 However overactivation of MMPs
has been linked to the accelerated breakdown of con-
nective tissues associated with pathological disease
states including arthritis, tumor invasion and meta-
stasis, periodontal disease, and multiple sclerosis.2 Con-
sequently much attention has been directed to discovery
of orally active MMP inhibitors with understanding
their abilities to treat a number of disease states.2
2. Chemical synthesis
Representative by AG-3340,3 CGS-27023A,4 PGE-
44101865 and WAY-170523,6 many amino acids derived
sulfonamide hydroxamates have been discovered as
potent MMP inhibitors.3ꢀ8 These compounds contain a
hydroxamic acid group that is capable of chelating the
active-site Zn(II) ion of MMPs thereby expressing their
inhibition activities. Although several acyclic amino
acids derived inhibitors has reached low nM range
potency,4,6,7 a considerable amount of effort has been
invested in designing the inhibitors possessing a central,
As outlined in Scheme 1, synthesis of the designed
compounds 1 started from protection of 3-hydroxy-
benzaldehyde or isovanillin with benzyl bromide and
subsequent condensation with nitromethane to afford
the olefins 2. Reduction of 2 with LAH followed by
hydrogenation catalyzed by Pd/C provided the amines
3. Pictet–Spengler reaction of 3 with glyoxylic acid in
ethanol gave the cyclized product, which was esterified
with methanolic hydrogen chloride to produce amino
esters 4.9 Treatment of 4 with a suitable sulfonyl chlo-
ride provided the sulfonamides 5. Direct conversion of
esters 5 to the corresponding hydroxamates was reached
with hydroxylamine hydrochloride under basic condi-
Keywords: MMP inhibitors;Synthesis.
* Corresponding author. Tel.:+86-216-416-3300;fax:+86-216-416-
6128;e-mail: madw@mail.sioc.ac.cn
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.10.026

48
D. Ma et al. / Bioorg. Med. Chem. Lett. 14 (2004) 47–50
Scheme 1.
Scheme 2.
4. Biological results and discussion
tion furnished the target molecules bearing a 6-hydroxyl
group. Alternatively, alkylation of the 6-hydroxyl group
of 5 with benzyl bromide yielded the esters 6, which
were treated with hydroxylamine hydrochloride medi-
ated by potassium hydroxide afforded the target mole-
cules with 6-benzoxyl groups (Scheme 2).
As summarized in Table 1, most compounds displayed
potent inhibition activities for selected MMPs but
marked difference in potency and selectivity was
observed for analogues with the different substituents at
the 6 and 7 positions and arylsulfonyl groups. For 6-
hydroxy substituted analogues, compound 1b was much
potent than 1a or 1c (compare entries 1–3), which indi-
cated that a critical space at the 40-position of 1 might
be necessary for interaction of inhibitors with enzymes.
A different selectivity pattern was seen for different
substituents at the aromatic ring of the sulfonyl group.
For example, analogues with 40-amino group or 20,50-
dichloro groups showed selectivity preferred to MMP-2
and MMP-12 but less potent for MMP-1, while 40-nitro
substituted derivative was very potent inhibitor for
MMP-1 (compare entries 4–6). For compounds bearing
a 6-benzoxyl group, although 1g and 1i displayed better
activity in comparison with the corresponding com-
pounds with 6-hydroxyl group 1a and 1c, the fact that
1h and 1j were less potent than 1b and 1f, respectively,
illustrated that switch hydroxyl to benzyloxy group at
the 6-position can either increase or decrease the activity
of 1. Similar results were noticed when a 7-methoxy
group was introduced (compare entries 1,7 and 11;3, 9
and 12). These results demonstrated that the space at
the 6- and 7-positions of these inhibitors may play some
role for activity. Noteworthy is that 1i showed highest
3. Preparation of MMPs and inhibition assay
The encoded catalytic MMP sequence was amplified
from the full-length gene and cloned into the pGEMEX-
1 plasmid, individually. After sequence confirmation, the
recombinant plasmid was transformed into the BL21
(DE3) strain for expression. The target catalytic domains
of MMPs (MMP-1, 2, 7, 9, 12, 14, 15, 16 and 26) were
purified and refolded as previous described.11ꢀ17
The typical inhibition assay was carried out in 100 mL
reaction system containing 50 mM Tris–HCl, pH 7.5, 10
mM CaCl2, 10 mM ZnCl2, 100 mM TPL, 1 mM DTNB,
2% DMSO and MMPs (5 nM for MMP-1, 10 nM for
MMP-2, 1 mM for MMP-7, 15 nM for MMP-9, 5 nM
for MMP-12, 300 nM for MMP-14, 10 nM for MMP-
15, 10 nM for MMP-16, 10 nM for MMP-26) with dif-
ferent concentration of compounds. The enzymatic rate
was recorded at 412 nm for 2 min. Each measurement
was done in triplicate to ensure statistically significant
results. For comparison, a known potent MMP inhib-
itor, galardin18 was used for standard drug.

D. Ma et al. / Bioorg. Med. Chem. Lett. 14 (2004) 47–50
Table 1. IC50 values for inhibition of MMPs by compounds 1 (mM)
49
Entry
Compd
MMP-1 MMP-2 MMP-7 MMP-9 MMP-12 MMP-14 MMP-15 MMP-16 MMP-26
1
2
3
4
5
6
7
8
1a (R0¼R¼Y¼H)
1b (R0¼R¼H, Y=40-Me)
1c (R0¼R¼H, Y=40-OMe)
1d (R0¼R¼H, Y=40-NH2)
1e (R0¼R¼H, Y=40-NO2)
1f (R0¼R¼H, Y¼20-Cl, 50-Cl)
1g (R0¼Bn, R¼Y¼H)
6.319
0.152
15.02
13.19
0.041
N.A.
0.452
0.462
0.088
N.A.
0.595
0.123
0.006
0.430
0.018
0.724
0.150
0.076
0.853
0.024
0.033
0.016
1.099
0.027
0.026
0.007
N.A.a
10.50
N.A.
N.A.
21.42
21.38
7.136
12.04
2.424
N.A.
10.69
3.192
—
0.335
0.040
4.10
0.248
0.258
1.882
0.035
0.130
0.03
3.118
0.10
0.046
0.015
0.421
0.029
7.689
0.191
0.059
0.170
0.057
0.072
0.057
0.931
0.065
0.020
0.013
1.102
0.052
3.108
0.835
0.521
4.613
0.039
0.062
0.034
20.82
0.867
0.068
0.023
0.218
0.019
0.621
0.385
0.126
1.789
0.017
0.044
0.004
7.303
0.029
0.006
0.006
0.184
0.021
1.677
0.202
0.177
1.839
0.035
0.056
0.022
4.633
0.040
0.016
0.008
0.858
0.097
7.508
0.492
0.791
7.903
1.453
2.046
0.744
N.A.
0.146
0.086
0.017
1h (R0¼Bn, R¼H, Y¼40-Me)
1i (R0¼Bn, R¼H, Y¼40-OMe)
1j (R0¼Bn, R¼H, Y¼20-Cl, 50-Cl)
1k (R0¼H, R¼OMe, Y¼H)
1m (R0¼H, R¼OMe, Y¼40-OMe)
Galardin
9
10
11
12
13
a N.A.: no activity up to 50 mM.
potency (4 nM), which implies that the 40-methoxy
group is favored for inhibition of MMP-15. This
conclusion is further supported by that the other two 40-
methoxy substituted compounds 1c and 1n also
displayed better selectivity to MMP-15 (entries 3 and
12). Existing additional hydrogen bonding or having a
suitable space at the 40-position is proposed for
explaining this phenomenon.
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5. Summary
As
a
summary, we have found some tetra-
hydroisoquinoline embodied sulfonamide hydroxamates
were potent inhibitors for MMPs. Some isozyme selec-
tivity was observed for compounds possessing suitable
substituents. A detailed explanation for these subtle
differences using computer modeling, as well as the design
of more selective compounds based upon this informa-
tion are actively pursued in our laboratory and will
report in due course.
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Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030 to D.M., 39725032 to Q.Y.) and
Ministry of Science and Technology of China for their
financial support.
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