Sulfonate-containing thiiranes as selective gelatinase inhibitors

Article abstract of DOI:10.1021/ml100254e

Matrix metalloproteinases (MMPs) are important zinc-dependent endopeptidases. Two members of this family of enzymes called gelatinases (MMP-2 and MMP-9) have been implicated in a number of human diseases, including cancer, neurological and cardiovascular

Full text of DOI:10.1021/ml100254e

pubs.acs.org/acsmedchemlett
Sulfonate-Containing Thiiranes as Selective
Gelatinase Inhibitors
Sebastian A. Testero,† Mijoon Lee,† Rachel T. Staran, Mana Espahbodi, Leticia I. Llarrull,
Marta Toth, Shahriar Mobashery,* and Mayland Chang*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
ABSTRACT Matrix metalloproteinases (MMPs) are important zinc-dependent
endopeptidases. Two members of this family of enzymes called gelatinases
(MMP-2 and MMP-9) have been implicated in a number of human diseases,
including cancer, neurological and cardiovascular diseases, and inflammation, to
name a few. We describe in this report the preparation and evaluation of two
structural types of thiirane inhibitors that show selectivity toward gelatinases. The
biphenyl series targets both gelatinases, whereas the monophenyl analogues
exhibit potent inhibition of only MMP-2. The latter structural type also exhibits
improved water solubility and metabolic stability, both traits desirable for progress
of these molecules forward in gelatinase-dependent animal models of disease.
KEYWORDS Slow-binding gelatinase inhibitors, thiiranes, matrix metalloprotein-
ases
atrix metalloproteinases (MMPs), members of a
family of 26 closely related zinc-dependent endo-
peptidases, are involved in important pathological
thiirane and formation of a stable zinc-thiolate complex. We
have demonstrated that the mechanism of inhibition is the
second one and that compound 1 is a slow-binding
inhibitor.12 The thiirane moiety in these inhibitors serves
as a caged thiolate, which is unleashed in the active site of
gelatinases (closely related MMP-2 and MMP-9) to result in
potent inhibition of these enzymes.12 The deprotonation
reaction that leads to opening of the thiirane moiety is the
rate-limiting step, which leads to slow-binding and, at times,
tight-binding inhibition of gelatinases.13-15
A major route of metabolism of these compounds is
hydroxylation at the para position in the terminal phenyl
group.16 A computational exercise in which the terminal
phenyl ring was modified led to a focused library of 452
compounds, which were docked and scored for the good-
ness of their fit in the active site of MMP-2 (also known as
gelatinase A).17 An unexpected finding from this in silico
docking and scoring exercise was that several of the com-
pounds that scored among the top 50 were sulfonate-con-
taining molecules of the general structure 2. In the present
report, we have synthesized and evaluated a series of
sulfonate-containing compounds of the two structural
classes 2 and 3 (Figure 1). As will be discussed, both these
sets of compounds are exquisite slow-binding inhibitors that
exhibit selectivity in targeting gelatinases.
M
and physiological functions.1-4 Upregulation of these en-
zymes has been implicated in cancer progression, neurolog-
ical disorders, arthritis, and cardiovascular diseases, just to
name a few. Because of the important therapeutic potential,
MMP inhibitors are highly sought as a means of disease
intervention.5,6 Virtually all known MMP inhibitors were
developed to chelate the active-site zinc ions of these
enzymes, and as such, they are broad-spectrum inhibitors.7
This lack of selectivity has been problematic in clinical trials
of MMP inhibitors as anticancer agents, as the long-term use
of the molecules showed serious side effects.2,6,8,9
A general structure for an MMP inhibitor includes a zinc-
binding group, typically a zinc chelator. The most explored of
such a zinc chelator in inhibitors has been the hydroxamate
group.7 Unfortunately, hydroxamates suffer from many
shortcomings, which we will not discuss here in the interest
of brevity. Newer generations of inhibitors utilize carboxyl-
ates, phosphates and phosphinates, pyrimidines, and thio-
lates as the entities that interact with the active-site zinc
ion.5,7,10 A few years prior, we disclosed the family of
thiirane-based selective gelatinase (MMP-2 and MMP-9)
inhibitors, of which compound 1 is the prototypic member
(Figure 1).11 Compound 1 was shown previously to be a
potent inhibitor of gelatinases with time-dependent kinetics
for the inhibition, a hallmark of either covalent inhibition
or slow-binding inhibition. Two mechanisms are possible.
The first mechanism is covalent O-alkylation of Glu404, and
the second is Glu404 catalyzed deprotonation at the methy-
lene adjacent to the sulfone, initiating ring-opening of the
In our continuing efforts to explore the potential for
thiirane-based gelatinase inhibitors;both as medicinal
compounds and as selective mechanistic tools in elucidation
Received Date: October 19, 2010
Accepted Date: December 7, 2010
Published on Web Date: December 13, 2010
r
2010 American Chemical Society
177
DOI: 10.1021/ml100254e ACS Med. Chem. Lett. 2011, 2, 177–181
|

pubs.acs.org/acsmedchemlett
Figure 1
Scheme 1. Syntheses of Sulfonate Derivates of 4
Scheme 2. Synthetic Route to 4-(Thiiran-2-ylmethylsulfonyl)phenol (10) and Syntheses of Sulfonyl Derivatives 3a-d
of the functions of these important enzymes in biological
systems;we report herein the syntheses and evaluation of
two series of sulfonate-containing thiirane compounds that
exert potent and selective inhibition of gelatinases. The
compounds in the first series have the structure 2 and were
synthesized from the phenolic derivative 4 in one step.
The 7-step synthesis of compound 4 was reported earlier
in the context of its identification as a major metabolite of com-
pound 1.17 The various sulfonates of this type were prepared
in 82%-87% yields (Scheme 1). This class of compounds is
quite stable, with considerable shelf time. The compounds
are easily purified by silica gel chromatography.
In an effort to simplify the syntheses, increase water
solubility, and minimize metabolic lability and the structural
complexity of these molecules, the next series of com-
pounds eliminated the left-terminal aromatic ring, which
gave rise to the structural class 3. The general synthetic route
to these compounds is depicted in Scheme 2. Selective
S-alkylation of the commercially available 4-hydroxythio-
phenol 5 with allyl bromide and subsequent acetylation of
the phenol provided compound 7 in high yields. Oxidation of
the sulfur and the olefin moieties in 7 was achieved by the
use of an excess of m-CPBA to afford the oxirane 8 in 69%
yield. Conversion of the epoxide to the corresponding
thiirane was accomplished by treatment with thiourea to
obtain the desired product. Partial deacetylation took place
at times in this reaction. Regardless, treatment of the resultant
mixture of the thiiranes with imidazole in methanol at room
temperature gently removed the acetyl group of 9 to afford the
phenol 10 in 78% yield for the 2 steps. The final step, conversion
of the phenol of 10 to the corresponding sulfonates, proceeds
smoothly within 10 min to give derivatives 3a-d in high yields.
The synthetic thiiranes were evaluated by in vitro kinetics
for their ability to inhibit purified MMP-1, MMP-2, MMP-3,
MMP-7, MMP-9, and MMP-14 by the methodology that our
laboratories has reported earlier (Table 1).18 We also inves-
tigated the type of inhibition that was observed. As reported
earlier in our mechanistic studies of the thiirane-type gela-
tinase inhibitors, slow-binding behavior is a hallmark of the
mechanism of action of this type of inhibitors.12,19,20 We
showed that inhibitor 1 exhibited slow-binding inhibition of
gelatinases, which we proposed to be at the root of
selectivity.12 As proposed earlier, gelatinases deprotonate R
to the aromatic sulfone moiety, which leads to the opening of
the thiirane ring and the release of the thiolate. Hence, the
thiirane behaves as a caged thiolate, which becomes avail-
able within the active site of gelatinases. Inhibitor 1 either did
not inhibit other MMPs or did so very poorly, as merely a
r
2010 American Chemical Society
178
DOI: 10.1021/ml100254e ACS Med. Chem. Lett. 2011, 2, 177–181
|

pubs.acs.org/acsmedchemlett
Table 1. Kinetic Parameters for Inhibition of MMPs by Selected Compounds
inhibitor
enzyme
kon  10-3 (M-1 s-1
)
koff  103 (s-1
)
Ki (μM)
1a
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
MMP-7
MMP-9
MMP-14
MMP-1
MMP-2
MMP-3
206 ( 60
1.1 ( 0.1
1.8 ( 0.1
5.5 ( 0.4
0.0139 ( 0.0004
15 ( 6
0.0018 ( 0.0004
96 ( 41
0.14 ( 0.03
45 ( 4
7.1 ( 0.5
1.0 ( 0.2
0.11 ( 0.10
1.3 ( 0.2
0.6 ( 0.2
0.11 ( 0.01
140 ( 7
2ab
2b
2c
0.023 ( 0.005
0.60 ( 0.03
18 ( 3
21 ( 2
0.005 ( 0.001
0.15 ( 0.1
NI (40 μM)
0.070 ( 0.013
38% (20 μM)
8% (40 μM)
0.33 ( 0.05
0.36 ( 0.81
NI (20 μM)
0.034 ( 0.008
22% (20 μM)
5% (20 μM)
0.52 ( 0.06
0.24 ( 0.02
NI (30 μM)
0.061 ( 0.013
5% (20 μM)
NI (30 μM)
0.38 ( 0.04
0.79 ( 0.03
41 ( 6
19 ( 2
4.6 ( 0.4
2.5 ( 0.1
1.5 ( 0.2
9.0 ( 2.0
38 ( 4
1.3 ( 0.3
3.2 ( 0.3
7.6 ( 0.6
1.6 ( 0.1
1.8 ( 0.1
2d
3a
3b
3c
18 ( 2
1.1 ( 0.2
5.3 ( 0.5
2.5 ( 1.0
4.2 ( 0.5
3.3 ( 0.3
2.0 ( 0.1
2.0 ( 0.8
1.7 ( 0.2
1.3 ( 0.2
0.39 ( 0.07
29% (200 μM)
11 ( 2
0.0045 ( 0.0006
0.26 ( 0.06
0.50 ( 0.03
0.25 ( 0.6
0.20 ( 0.03
3.9 ( 1.7
0.42 ( 0.05
0.48 ( 0.09
7% (200 μM)
0.09 ( 0.01
62% (200 μM)
26 ( 5
4.3 ( 0.5
0.40 ( 0.01
0.0023 ( 0.0002
0.15 ( 0.01
0.6 ( 0.1
1.8 ( 0.2
1.6 ( 0.4
12 ( 2
0.15 ( 0.03
11 ( 3
30% (200 μM)
0.28 ( 0.11
58% (200 μM)
35 ( 10
2.9 ( 0.3
0.8 ( 0.3
0.0023 ( 0.0003
0.15 ( 0.01
0.8 ( 0.2
0.9 ( 0.2
1.5 ( 0.1
6.2 ( 1.5
0.047 ( 0.005
32 ( 4
3d
NI (200 μM)
0.24 ( 0.05
25% (200 μM)
4.5 ( 0.5
1.1 ( 0.2
r
2010 American Chemical Society
179
DOI: 10.1021/ml100254e ACS Med. Chem. Lett. 2011, 2, 177–181
|

pubs.acs.org/acsmedchemlett
Table 1. Continued
inhibitor
enzyme
kon  10-3 (M-1 s-1
)
koff  103 (s-1
)
Ki (μM)
MMP-7
MMP-9
MMP-14
0.011 ( 0.001
0.54 ( 0.08
1.4 ( 0.6
1.9 ( 0.1
1.7 ( 0.4
120 ( 11
3.5 ( 0.6
20 ( 4
0.086 ( 0.001
a Reported in refs 11 and 22. b Reported in ref 16.
Table 2. Metabolic Stability, Intrinsic Clearance, and Aqueous
linear-competitive inhibitor. This behavioral pattern is re-
peated for the inhibitors reported herein, but the profile of
the inhibition for these new compounds appears to be
somewhat different, as will be described below.
Solubility of MMP Inhibitors
intrinsic clearance
inhibitor
half-life (min)
[L/(h kg)]
solubility (μg/mL)
We looked for the presence or absence of time depen-
dence for inhibition of MMPs. The former is an evidence of
slow-binding behavior, and the latter its absence. Slow-
binding behavior is defined by a rapid onset of inhibition,
described by a second-order rate constant kon, which is large
and favorable for the cases listed in Table 1. The rapid onset
of inhibition is complemented by a small first-order rate
constant for dissociation of the enzyme-inhibitor complex,
koff. The ratio of koff/kon describes the dissociation constant Ki
for the inhibitor for the given enzyme. We note that all of
these compounds were slow-binding inhibitors of gelati-
nases (MMP-2 and MMP-9), with most exhibiting dissocia-
tion constants (Ki) within the nanomolar range. This general
statement is true for the biphenyl ether variants of the
general structure 2, as it is for the truncated compounds of
structure 3. Some of these compounds exhibited more
expanded profiles for slow-binding inhibition of MMPs. For
example, for the first time for the thiirane class of inhibitors,
compounds 3a-d served as slow-binding inhibitors of MMP-
14 and MMP-7 as well. Yet, this comment has to be placed in
context. Notwithstanding the observation of slow-binding
behavior, dissociation constants resulting for this pattern of
inhibition for 3a with MMP-7 and MMP-9 and for 3b, c, and d
with MMP-7, MMP-9, and MMP-14 are high in the micro-
molar range. Hence, the series of compounds 3 are indeed
exhibiting selectivity with interesting profiles. Compound
3a is a nanomolar inhibitor only for MMP-2 and MMP-14;
compounds 3b, c, and d are nanomolar inhibitors exclu-
sively for MMP-2. Compounds of series 3 are indeed selec-
tive in different ways than those of series 2. Compounds 3b,
c, and d can be construed as selective inhibitors of gelatinase
A (MMP-2), which with an appropriate level of dosing in animals
could limit the inhibition exclusively to MMP-2 in vivo.
The thiirane inhibitors were also evaluated for in vitro
metabolic stability using rat liver microsomes (Table 2). In
the biphenyl series, methyl (2a) and ethyl (2b) had improved
metabolic stability over the propyl (2c) and isopropyl (2d)
variants. In general, the monophenyl compounds 3 were
more metabolically stable than the corresponding biphenyls
2. From the in vitro half-life, intrinsic clearance (the ability of
the liver to metabolize a compound) was calculated.21 In
general, the biphenyl series had higher intrinsic clearance
than the monophenyl counterparts. All of the biphenyl
inhibitors had intrinsic clearances >70% hepatic blood flow
(the rate of blood flow through the liver; drugs with high hepatic
clearance depend on hepatic blood flow for elimination) of
1
12.0
24.8
35.9
12.6
16.2
45.3
31.8
29.8
36.1
7.02
3.39
2.34
6.67
5.19
1.86
2.65
2.83
2.33
2.3 ( 0.1
3.5 ( 0.2
4.1 ( 0.3
4.0 ( 0.1
1.1 ( 0.05
167 ( 6
2a
2b
2c
2d
3a
3b
3c
3d
114 ( 9
96 ( 14
230 ( 14
3.96 L/(h kg), indicating that these were high clearance
compounds. Inhibitor 3a had the lowest intrinsic clearance
of 1.86 L/(h kg), which was <50% of hepatic blood flow.
Aqueous solubility was also measured for the series of
thiirane inhibitors (Table 2). Aqueous solubility is a signifi-
cant contributor to the absorption, distribution, metabolism,
and elimination of a drug in the body and, thus, is an
important parameter for the selection of compounds with
druglike properties. In general, elimination of the terminal
aromatic ring increased solubility >70-fold, except for a
26-fold increase for compound 3b (ethyl) versus the corre-
sponding biphenyl (2b). The increased metabolic stability,
moderate intrinsic clearance, and improved water solubility
for the monophenyl thiirane series makes these compounds
superior drug candidates.
The class of thiirane inhibitors as selective gelatinase
inhibitors holds considerable promise as potential therapeu-
tics in treatment of the aforementioned gelatinase-depen-
dent diseases. The prototype compound 1 and the structural
variants 2 inhibit both gelatinases effectively. Notwithstand-
ing the broadening of the slow-binding profile of compound
3 to include MMP-7 and MMP-14, the kinetic parameters for
these enzyme inhibitions are such that actually only MMP-2
is inhibited potently. This consideration in conjunction with
the desirable traits of improved aqueous solubility, better
metabolic stability, moderate clearance, and a more simplified
chemical structure would make inhibitors of type 3 worthy
compounds for investigations of their effects in animal models
of disease.
SUPPORTING INFORMATION AVAILABLE General infor-
mation, experimental procedures, spectroscopic data, and 1H
NMR and 13C NMR spectra of new compounds, and general
biological assay procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
r
2010 American Chemical Society
180
DOI: 10.1021/ml100254e ACS Med. Chem. Lett. 2011, 2, 177–181
|

pubs.acs.org/acsmedchemlett
AUTHOR INFORMATION
(13) Tao, P.; Fisher, J. F.; Mobashery, S.; Schlegel, H. B. DFTstudies
of the ring-opening mechanism of SB-3CT, a potent inhibitor
of matrix metalloproteinase 2. Org. Lett. 2009, 11, 2559–
2562.
Corresponding Author: *M.C.: phone, (574) 631-2965; fax,
(574) 631-6652; e-mail, mchang@nd.edu. S.M.: phone, (574) 631-
2933; fax, (574)631-6652; e-mail, mobashery@nd.edu.
(14) Tao, P.; Fisher, J.; Shi, Q.; Vreven, T.; Mobashery, S.; Schlgel,
H. B. Matrix metalloproteinase 2 (MMP2) inhibition: QM/MM
studies of the inhibition mechanism of SB-3CTand its analog.
Biochemistry 2009, 48, 9839–9847.
Author Contributions: † Authors contributed equally to this
work.
(15) Tao, P.; Fisher, J. F.; Shi, Q.; Mobashery, S.; Schlegel, H. B.
Matrix metalloproteinase 2 (MMP2) inhibition: DFTand QM/
MM studies of the deprotonation initiated ring opening
reaction of sulfoxide analog of SB-3CT. J. Phys. Chem. 2010,
114, 1030–1037.
Funding Sources: This research was supported by a grant from
the National Institutes of Health (CA122417).
(16) Lee, M.; Villegas-Estrada, A.; Celenza, G.; Boggess, B.; Toth,
M.; Kreitinger, G.; Forbes, C.; Fridman, R.; Mobashery, S.;
Chang, M. Metabolism of a highly selective gelatinase inhi-
bitor generates active metabolite. Chem. Biol. Drug Des. 2007,
70, 371–382.
(17) Lee, M.; Celenza, G.; Boggess, B.; Blase, J.; Shi, Q.; Toth, M.;
Bernardo, M. M.; Wolter, W. R.; Suckow, M. A.; Hesek, D.; Noll,
B. C.; Fridman, R.; Mobashery, S.; Chang, M. A potent
gelatinase inhibitor with anti-tumor-invasive activity and its
metabolic disposition. Chem. Biol. Drug Des. 2009, 73, 189–
202.
ACKNOWLEDGMENT R.T.S. acknowledges support from the
University of Notre Dame College of Science Summer Undergrad-
uate Research Fellowship. L.I.L. is a Pew Latin American Fellow in
the Biomedical Sciences, supported by The Pew Charitable Trusts.
The opinions expressed are those of the authors and do not
necessarily reflect the views of The Pew Charitable Trusts. We thank
the Mass Spectrometry & Proteomics Facility (Bill Boggess, Nonka
Sevova, and Michelle Joyce), the University of Notre Dame, which
is supported by Grant CHE-0741793 from the National Science
Foundation.
(18) Ikejiri, M.; Bernardo, M. M.; Bonfil, R. D.; Toth, M.; Chang, M.;
Fridman, R.; Mobashery, S. Potent mechanism-based inhibi-
tors for matrix metalloproteinases. J. Biol. Chem. 2005, 280,
33992–34002.
(19) Bernardo, M. M.; Brown, S.; Li, Z. H.; Fridman, R.; Mobashery,
S. Design, synthesis and characterization of potent, slow-
binding inhibitors that are selective for gelatinases. J. Biol.
Chem. 2002, 277, 11201–11207.
(20) Lee, M.; Bernardo, M. M.; Meroueh, S. O.; Brown, S.; Fridman,
R.; Mobashery, S. Synthesis of chiral 2-(4-Phenoxyphenyl-
sulfonylmethyl)-thiiranes as selective gelatinase inhibitors.
Org. Lett. 2005, 7, 4463–4465.
(21) Lu, C.; Li, P.; Gallegos, R.; Uttamsingh, V.; Xia, C. Q.; Miwa,
G. T.; Balani, S. K.; Gan, L.-S. Comparison of intrinsic clear-
ance in liver microsomes and hepatocytes from rats and
humans: evaluation of free fraction and uptake in hepato-
cytes. Drug Metab. Dispos. 2006, 34, 1600–1605.
(22) Toth, M.; Bernardo, M. M.; Gervasi, D. C.; Soloway, P. D.;
Wang, Z.; Bigg, H. F.; Overall, C. M.; DeClerk, Y. A.; Tschesche,
H.; Cher, M. L.; Brown, S.; Mobashery, S.; Fridman, R. Tissue
inhibitor of metalloproteinase (TIMP)-2 acts synergistically
with synthetic matrix metalloproteinase (MMP) inhibitors
but not with TIMP-4 to enhance the (membrane type 1)-
MMP-dependent activation of pro-MMP-2. J. Biol. Chem.
2000, 275, 41415–41423.
REFERENCES
(1)
Massova, I.; Kotra, L. P.; Fridman, R.; Mobashery, S. Matrix
metalloproteinases: structures, evolution, and diversifica-
tion. FASEB J. 1998, 12, 1075–1095.
(2)
(3)
Stamenkovic, I. Extracellular matrix remodelling: the role of
matrix metalloproteinases. J. Pathol. 2003, 200, 448–464.
Sternlicht, M. D.; Coussens, L. M.; Vu, T. H.; Werb, Z. Biology
and regulation of the matrix metalloproteinases. Matrix
Metalloproteinase Inhib. Cancer Ther. 2001, 1–37.
Fanjul-Fernandez, M.; Folgueras, A. R.; Cabrera, S.; Lopez-Otin,
C. Matrix metalloproteinases: evolution, gene regulation and
functional analysis in mouse models. Biochim. Biophys. Acta
2010, 1803, 3–19.
(4)
(5)
(6)
Fisher, J. F.; Mobashery, S. Recent advances in MMP inhibitor
design. Cancer Metastasis Rev. 2006, 25, 115–136.
Dorman, G.; Cseh, S.; Hajdu, I.; Barna, L.; Konya, D.; Kupai,
K.; Kovacs, L.; Ferdinandy, P. Matrix metalloproteinase in-
hibitors: a critical appraisal of design principles and proposed
therapeutic utility. Drugs 2010, 70, 949–964.
(7)
Jacobsen, J. A.; Major Jourden, J. L.; Miller, M. T.; Cohen, S. M.
To bind zinc or not to bind zinc: an examination of innovative
approaches to improved metalloproteinase inhibition. Bio-
chim. Biophys. Acta 2010, 1803, 72–94.
(8)
(9)
Egeblad, M.; Werb, Z. New functions for the matrix metallo-
proteinases in cancer progression. Nat. Rev. Cancer 2002, 2,
161–174.
Coussens, L. M.; Fingleton, B.; Matrisian, L. M. Cancer therapy:
matrix metalloproteinase inhibitors and cancer: trials and
tribulations. Science 2002, 295, 2387–2392.
(10) Tu, G. G.; Xu, W. F.; Huang, H. M.; Li, S. H. Progress in the
development of matrix metalloproteinase inhibitors. Curr.
Med. Chem. 2008, 15, 1388–1395.
(11) Brown, S.; Bernardo, M. M.; Li, Z. H.; Kotra, L. P.; Tanaka, Y.;
Fridman, R.; Mobashery, S. Potent and selective mechanism-
based inhibition of gelatinases. J. Am. Chem. Soc. 2000, 122,
6799–6800.
(12) Forbes, C.; Shi, Q.; Fisher, J. F.; Lee, M.; Hesek, D.; Llarrull,
L. I.; Toth, M.; Gossing, M.; Fridman, R.; Mobashery, S. Active
site ring-opening of a thiirane moiety and picomolar inhibi-
tion of gelatinases. Chem. Biol. Drug Des. 2009, 74, 527–534.
r
2010 American Chemical Society
181
DOI: 10.1021/ml100254e ACS Med. Chem. Lett. 2011, 2, 177–181
|