Structure-activity relationship for thiirane-based gelatinase inhibitors

Article abstract of DOI:10.1021/ml300050b

An extensive structure-activity relationship study with the template of 2-(4-phenoxyphenylsulfonylmethyl)thiirane (1), a potent and highly selective inhibitor for human gelatinases, is reported herein. Syntheses of 65 new analogues, each in multistep processes, allowed for exploration of key structural components of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced inhibitory activity and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and the α position of the sulfonyl group in the aliphatic side chain.

Full text of DOI:10.1021/ml300050b

Letter
pubs.acs.org/acsmedchemlett
Structure−Activity Relationship for Thiirane-Based Gelatinase
Inhibitors
Mijoon Lee, Masahiro Ikejiri, Dennis Klimpel, Marta Toth, Mana Espahbodi, Dusan Hesek,
Christopher Forbes, Malika Kumarasiri, Bruce C. Noll, Mayland Chang, and Shahriar Mobashery*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: An extensive structure−activity relationship
s t u d y w i t h t h e t e m p l a t e o f 2 - ( 4 -
phenoxyphenylsulfonylmethyl)thiirane (1), a potent and
highly selective inhibitor for human gelatinases, is reported
herein. Syntheses of 65 new analogues, each in multistep
processes, allowed for exploration of key structural compo-
nents of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group
were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced
inhibitory activity and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1
that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and the α position of the
sulfonyl group in the aliphatic side chain.
KEYWORDS: Gelatinase, SAR, matrix metalloproteinases
SB-3CT (compound 1) is a potent and highly selective
inhibitor of human gelatinases and a prototype for the thiirane
class of matrix metalloproteinase (MMP) inhibitors.1 Com-
pound 1 has been evaluated in animal models of stroke and
cancer metastasis, among others, and found to have protective
effects on brain and antimetastatic properties in cancer.2−6 The
selectivity that this inhibitor exhibits is highly desirable, and
when combined with the unique mechanism of action (Figure
1A),7 it makes the thiirane class of gelatinase inhibitors of
interest. To explore the properties of these molecules further,
we undertook to prepare a large number of thiirane molecules
based on the molecular template of the structure of SB-3CT for
the purpose of establishing the structure−activity relationship
(SAR; Figure 1B). First, we have looked at sulfone surrogates,
such as sulfonamide, aminosulfone, and methylsulfone. We also
have looked at sp2-hybridized moieties such as ketone, oxime,
and sulfoxide as replacements for the sulfone. The second
direction of SAR was to evaluate the importance of the
diphenyl ether moiety. We have explored methylene, carbonyl,
methyl ether, and ester as connections between the two phenyl
rings, but we have also explored direct connection between the
two rings without any intervening moieties. Finally, substitution
in the terminal rings was explored. Since this aspect proved to
be fruitful for the generation of a series of active molecules, it
was explored in greater depth. A point of interest for the
modification of the terminal ring is the fact that it is also the site
of both in vitro and in vivo metabolism of SB-3CT.8,9 Avoiding
major metabolism at this site, while retaining activity, would be
beneficial to discovery of second-generation molecules.
introduced and the commercial availability of the starting
material. When a given aromatic bromide was commercially
available, the compound was subjected to route A, which
consists of lithiation of arylbromide, which was then treated
with sulfur to generate the corresponding thiolate.10,11 The
resulting thiolate was allowed to react with epichlorohydrin to
give the corresponding complex more chlorohydrin, which was
transformed to epoxide by treatment with base. Oxidation of
the sulfide to sulfone with m-chloroperoxybenzoic acid,
followed by oxygen-to-sulfur exchange using thiourea gave
the desired thiirane molecules, such as 1, 16, 17, and 30. When
suitable aniline derivatives were available, route B was used to
incorporate the sulfonylmethylthiirane moiety. First, the amine
was diazotized using isoamyl nitrite in the presence of acetic
acid.12 The resulting diazonium salt was converted to
thioacetate,13 which was subsequently subjected to a series of
standard chemical transformations (basic hydrolysis, alkylation,
epoxide ring formation, oxidation, and thiirane formation) to
yield compounds of the types 9, 10, and 18. When a desired
phenol was commercially available, route C was generally
pursued, which involves O-thiocarbamate formation, followed
by thermal rearrangement to S-thiocarbamate.1 S-Thiocarba-
mate was then hydrolyzed to the corresponding thiolate under
basic conditions (route C/D).
When a suitable diphenyl ether was not commercially
availablewhich was actually most of the timesit needed to
be synthesized. Although there are many ways to construct the
diphenyl ether,14 three main methods were used in our work:
Most of the compounds of Figure 1 were synthesized by the
routes depicted in Scheme 1. The suitable synthetic route was
chosen according to the property of the functional group to be
Received: March 13, 2012
Accepted: May 2, 2012
Published: May 2, 2012
© 2012 American Chemical Society
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Figure 1. SAR of gelatinase inhibitors based on the structural template of SB-3CT (1).
a
Scheme 1
a
Reagents and conditions: (route A) nBuLi or Mg; S, THF; (route B) isoamyl nitrite, AcOH, 1,2-benzene disulfonylamide; KSAc, DMSO; (route C)
thiocarbamoyl chloride, DABCO or iPr2EtN; 150−200 °C; (route D) KOH, reflux, MeOH; epichlorohydrin; (route E) m-CPBA; Ullmann (i) CuI,
Cs2CO3, dimethylglycine·HCl, 90 °C, dioxane; direct aromatic substitution (ii) Cs2CO3, DMF or NaOH, DMF; Cu mediated Suzuki type coupling (iii)
Cu(OAc)2, Et3N, 4 Å molecular sieves, CH2Cl2. All compounds were prepared as racemates.
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Ullmann condensation (using CuI as a catalyst),15 Suzuki
coupling conditions (using copper(II) acetate),16,17 and direct
aromatic substitution in the case of activated aromatic halide,
such as hexafluorobenzene or 1-fluoro-4-nitrobenzene or 2-
chloro-4-substituted pyridine derivatives under basic condi-
tions. Four pairs of reagents for these couplings are given in the
dotted square boxes in Scheme 1. Many aryl halides, phenols,
and aryl boronic acids (colored in green) are commercially
available, and they can constitute the terminal phenyl-ring
component. We used four components for the middle ring
(44−47, colored in red), with the exception of 1,4-
dibromobenzene; the others were based on 4-hydroxythiophe-
nol. Pathways A,10,11,18 D,19 and E19−21 have been used
previously by us in preparation of a handful of thiiranes that
have been reported. These included syntheses of compounds
6,7 14,22 30,9,18 35a,18 36,19 37a,19 38,20 and 42.21 These
compounds are included in the set of SAR-3 for side-by-side
comparison with all the rest of the analogues. All compounds in
this study were prepared as racemates, based on the fact that
both enantiomers of SB-3CT showed the same inhibitory
activity against gelatinases in a previous study.10
Certain derivatives obviously could be prepared by multiple
routes, yet some target molecules were only accessible by a
single set of reactions. For instance, SB-3CT (1) could be
prepared by most of the routes described in Scheme 1.
Aromatic halides would react readily with magnesium or n-BuLi
to give the corresponding organometallic reagents, so route A is
not appropriate for their synthesis. Instead, halogen-containing
compounds (19−22) were prepared by a copper-catalyzed
Suzuki-type coupling reaction16,17 using the corresponding
halogenated boronic acids. In the case of the pentafluorinated
compound (23), it was obtained only when pentafluorinated
compound (48) was subjected to route E. Several attempts
using pentafluorophenyl boronic acid or 1-iodopentafluoro-
benzene under Ullmann condensation, or via route D using 49,
gave no product, or undesired compounds 50 or 51. Details for
the failed and successful attempts toward synthesis of
pentafluorinated derivatives are given in the Supporting
Information.
e were synthesized using pentafluorophenyl ester in the
presence of the corresponding amine.
We prepared a total of 65 new compounds by the multistep
reactions disclosed above for this SAR study of the thiirane
inhibitors. These compounds were evaluated in a high-
throughput manner with the purified catalytic domain of
MMP-2 (also known as gelatinase A). Thiiranes serve as slow-
binding inhibitors of gelatinases, which exhibit a time-
dependence for enzyme inhibition. The mechanism of
inhibition of gelatinases entails an enzyme-mediated reaction
on the inhibitor, which results in potent inhibition by the
product of this enzymic transformation.7 As such, two
measurements were taken in each case, one without
preincubation and one with a 2-h preincubation of the enzyme
with the inhibitor. If the slow-binding mechanism were to be
operative, the enzyme activity remaining after preincubation
should be less than that without it. First, the enzyme activity in
the presence of 30 μM inhibitor was measured. At this
concentration, SB-3CT (1), as a reference inhibitor, completely
inhibits MMP-2 (0% activity remaining). Any compound that
showed good inhibition at this concentration was further
evaluated at 3 μM and at 300 nM by the same method. The
blue bar graphs in Figure 2 showed MMP-2 inhibition of a
limited set of compounds at [I] = 30 μM. The turquoise bar
graphs in Figure 2 showed MMP-2 inhibition of the better
inhibitors at inhibitor concentrations of 300 nM. The full set of
analyses is given in the Supporting Information. This analysis
established the SAR. The key SAR findings are as follows: (i)
The sulfonylmethylthiirane is required for inhibition (cf. SAR-
1). Any insertion of N or C atoms before or after the sulfone
moiety leads to a loss of potency (2−5). Sulfone replacement
by ketone, oxime, or sulfoxide (used as a diastereomeric
mixture) resulted in poorer inhibitors of MMP-2 (6−8). All of
the findings support our recently proposed mechanism that
inhibition is due to the deprotonation of proton at the carbon α
to the sulfone (Figure 1A).7 All of the SAR-1 compounds have
either less acidic α-methylenes, or the structure of the inhibitor
bound in the active site of gelatinase would not poise it for the
abstraction of proton by the enzyme. (ii) The diaryl ether
would appear to be important for good inhibition (cf. SAR-2).
Deletion of the terminal phenyl ring resulted in decreased
gelatinase inhibition (13 and 14). Any additional atom (11 and
12) or deletion of the oxygen between the two aryl groups (e.g.,
biphenyl 16 and 17) resulted in decreased gelatinase inhibition.
The para substitution for the middle ring is important, as m-
phenoxyphenyl (18) and m-biphenyl compounds (17) were
generally poorer inhibitors than their p-substituted counterparts
(1 and 16, respectively). Replacement of the terminal ring with
the cyclohexyl group (15) followed the same trend with the
rest of SAR-2 compounds. (iii) Substitution in the terminal
phenyl ring is tolerated at the para and meta positions. All
halogen substitutions show reasonable inhibitory potency, while
potency decreased as the size of halogen increases. The same
size-dependent trend was observed for other nonhalogen
substituents. The alkoxy substituent is better than the
corresponding alkyl substituent (−OCF3 29a vs −CF3 28a),
while this trend reversed between derivatives with −OCH3 29b
vs −CH3 28b. (iv) Replacement of the terminal phenyl ring
with an electron-poor aromatic group leads to a loss of potency
(tetra and penta fluorinated compounds, 23−25). (v) The
pyridine-containing compounds were generally poorer inhib-
itors than their phenyl counterparts (40 vs 38 and 41 vs 28a).
SAR-3 gave a series of compounds with various functional
groups at the terminal ring. Among them were certain
functionalities that gave a handle for further derivatization,
such as −OH (30),18 −NH2 (36),19 and −CO2H (42).21 We
have successfully demonstrated that incorporation of the
methylsulfonyl moiety to the p-hydroxy- (30a) and NH2-
compounds (36) resulted in excellent gelatinase inhibitors.18,20
In this study, we generated a series of esters and amides of
compound 42.21 This series is based on the X-ray structures of
gelatinases, which indicate that there is room for additional
functionalities that can be incorporated into the carboxylic acid
moiety in compound 42. The synthesis of the ester-type
inhibitors 42a−f was achieved by an EDC-coupling reaction
with the corresponding alcohol. The amid-type inhibitors 43a−
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ACS Medicinal Chemistry Letters
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Figure 2. High-throughput screening of synthetic compounds at 30 μM (in blue) and at 300 nM (in turquoise) with MMP-2. The analyses for the
full set of compounds are given in the Supporting Information.
Poor inhibition by tetra-/pentafluorinated compound or by
pyridine containing compounds was initially difficult to explain.
Computational docking and scoring of these molecules into the
active site of MMP-2 illustrated that the terminal phenyl ring of
the poor inhibitors 23 and 25 tends to extend into the solvent,
whereas that for the good inhibitors gets embedded in the S1
loop (Figure S2 in the Supporting Information). This could be
partially due to the larger footprint of the fluorinated terminal
phenyl rings; however, as shown in other systems,23,24 the
distinct electrostatics of the fluorinated ring could also be a
contributor, as it would influence interactions with the protein
surface. We determined the X-ray crystal structures of selected
compounds in the hope of shedding light on the activities of
these inhibitors (Figure 3). There are no obvious structural
points that stand out. The only discernible difference was that
the sulfur atom in the thiirane ring of all three inactive
compounds (A, B, and C in Figure 3) is pointing toward the
middle phenyl ring, while that of active compounds (D, E, and
F in Figure 3) is pointing away from the phenyl ring. If this
difference has a mechanistic explanation for the inhibition
outcome, it is not at the present obvious, as there exists
freedom of rotation for the bonds in the sulfonylmethylthiirane
moiety. The most likely explanation is that the structural
modifications afford differential interactions in the MMP-2
active site that the existing X-ray structures cannot explain.
Several of the most potent of the compounds were selected
on the basis of the screening result and were further analyzed
by detailed kinetics to document the mode of inhibition, to
evaluate the dissociation constants, and to demonstrate the
selectivity in inhibition of gelatinases (Table 1). These
compounds inhibited MMP-2 invariably in the nanomolar
range. The Ki values for MMP-9 were usually a few fold higher
than those for MMP-2, but these molecules would appear to
inhibit both gelatinases (MMP-2 and MMP-9). Several, such as
compounds 19a, 19b, 22a, 26, 32, 33a, 36, and 38a include
MMP-14 in their spectrum of inhibition. The inhibition of
MMP-2, -9, and -14 was slow-binding in nature, consistent with
Figure 3. X-ray crystal structures of compounds 23 (A), 25 (B), 40
(C), 37a (D), 22a (E), and 38 (F) in the capped-stick representation.
Table 1. Kinetic Parameters for Inhibition of MMPs by Selected Compounds, and Half-Lives for Metabolism
Ki (μM)
half-life in rat liver S9
(min)
a
b
a
a
b
b
compd
X
MMP-1
MMP-2
MMP-3
6
MMP-7
96 41
9% (20 μM)
MMP-9
MMP-14
c
1
p-H
p-F
m-F
p-I
206 60
d
0.0139 0.0004
0.061 0.007
0.45 0.1
15
0.6 0.2
0.037 0.003
0.580 0.140
0.19 0.04
4.4 0.3
3.7 0.1
2.9 0.2
7.2 0.9
13 0.5
a
19a
19b
22a
26
NI (20 μM)
7% (100 μM)
50% (20 μM)
27
0.044 0.005
NI (125 μM) 3.0 0.3
d
8
d
d
NI (60 μM)
0.60 0.11
18% (60 μM)
4.1 0.5
NI (10 μM)
0.29 0.07
p-CH2OH 205
8
6
0.078 0.013
0.006 0.003
0.30 0.09
48.5
31.0
5
4
0.390 0.085
0.160 0.080
0.47 0.10
0.215 0.012
0.090 0.050
0.28 0.10
c
30a
p-OH
128
2.2 0.2
23
11
2
1
32
p-OiPr
11% (50 μM)
17
12
4
4
30% (20 μM)
19% (75 μM)
33a
p-OMOM 6% (100 μM)
0.18 0.05
0.16 0.05
0.14 0.04
7.7 0.4
27
c
35a
p-OMs
p-NH2
p-OCF3
140
7
0.023 0.005
0.575 0.030 18.2
3
0.005 0.005
0.145 0.010
0.22 0.02
2
c
36
10% (250 μM) 0.024 0.015
3% (20 μM) 0.110 0.040
23.4 1.6
16% (250 μM) 0.87 0.11
11 2, 50
7.3 0.3
4
d
38a
14% (20 μM)
NI (20 μM)
0.930 0.090
5.08 0.510
a
b
Ki is calculated from a Dixon plot as competitive inhibition. Ki is calculated from the ratio of koff/kon. Slow-binding parameters (koff and kon values)
are given in the Supporting Information. Reported earlier, and given here for the sake of side-by-side comparison: 1,1 30a,9 35a,18 36.19 NI, no
c
d
inhibition.
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ACS Medicinal Chemistry Letters
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the mechanism that we have disclosed for the thiirane inhibitor
class involving an enzyme-mediated reaction within the active
site.7 On the other hand, the entire set of compounds given in
Table 1 were either not inhibitory or only poorly so for MMP-
1, -3, and -7, as representatives of other classes of MMPs. In the
few cases for which it was warranted that we evaluate the Ki
values, the kinetic mechanism was linear competitive and not
slow-binding inhibition. The slow-binding inhibition is the
hallmark of the thiirane class of compounds for potent
inhibition.7
Metabolic stability for compounds listed in Table 1 was
evaluated in rat liver S9. SB-3CT (1) had a half-life of 4.4 0.3
min. SB-3CT is primarily metabolized by oxidation at the para
position of the terminal phenyl ring and at the methylene
adjacent to the sulfone moiety to generate the sulfinic acid.9 In
general, addition of electron-withdrawing groups at the terminal
phenyl ring decreased the half-life relative to that of SB-3CT,
while electron-donating groups increased the half-life. Addition
of fluorine at the para position (compound 19a) decreased the
AUTHOR INFORMATION
Corresponding Author
*Tel: +1-574-631-2933. Fax: +1-574-631-6652.
Funding
This work was supported by the National Institutes of Health
(Grant CA122417).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.L. is an Innovation Fellow, supported by the Edison
Foundation. The Mass Spectrometry & Proteomics Facility of
the University of Notre Dame is supported by Grant CHE-
0741793 from the National Science Foundation. Dr. Viktor
Krchnak is acknowledged for helpful discussions. Celeste
Warrel determined the kinetics parameters for compound
22a, and Ansa Huang did the same for compound 38a.
half-life to 3.7
0.1 min. Blocking the para position of the
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material is available free of charge via the Internet at http://
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