Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix metalloproteinase inhibitors: Developing a structure-activity relationship

Article abstract of DOI:10.1016/j.bmcl.2009.02.044

The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyron

Full text of DOI:10.1016/j.bmcl.2009.02.044

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1970–1976
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix
metalloproteinase inhibitors: Developing a structure–activity relationship
*
Yi-Long Yan, Melissa T. Miller, Yuchen Cao, Seth M. Cohen
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases.
Development of inhibitors to modulate MMP activity has been an active area of investigation for thera-
peutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups
(ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors
(MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl back-
bones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes
for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors)
are also explored. The MMP inhibition profiles and structure–activity relationship of synthesized hydrox-
ypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position
of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for
MMPi activities.
Received 25 January 2009
Accepted 10 February 2009
Available online 14 February 2009
Keywords:
Drug design
Inhibitors
Metalloproteinases
Pyrones
Zinc
Ó 2009 Elsevier Ltd. All rights reserved.
Matrix metalloproteinases (MMPs) are a class of hydrolytic
metalloenzymes involved in the degradation of the extracellular
matrix (ECM).1–3 At the catalytic center of MMPs is a conserved
tris(histidine)-bound zinc(II) ion. The protein matrix surrounding
the zinc center is comprised of a series of subsite pockets desig-
nated as S10, S20, S30, S1, S2, and S3 (Fig. 1). The different structures
of the MMP subsites, and the amino acids comprising those sub-
sites, lead to substrate selectivity for different MMP isoforms.
MMPs are involved in tissue remodeling, wound healing, and
growth. The misregulated activities of these enzymes are also
implicated in a variety of diseases such as cancer, arthritis, athero-
sclerosis, and heart disease.1–3 Thus, a number of investigations in
both academia and industry have been carried out to develop
MMP inhibitors (MMPi) as therapeutics to treat MMP-related
diseases.1–4 A typical MMPi has two parts (Fig. 1): a zinc-binding
group (ZBG) able to chelate a zinc(II) ion thus blocking the access
of the substrate to the catalytic center, and a peptidomimetic back-
bone that provides non-covalent interactions with the subsite
pockets thus tuning inhibitor potency and selectivity. Often in an
MMPi a linking group (L) can also be defined that connects the
backbone substituent to the ZBG. Most reported MMPi employ a
hydroxamic acid as the ZBG with at least part of the backbone di-
rected toward the S10 pocket.1–4 This strategy has been successful
in providing potent MMPi, but hydroxamate inhibitors have limita-
tions including in vivo hydrolysis and dose-limiting side effects. To
overcome the drawbacks of hydroxamic acids, new MMPi with
alternative ZBGs have been explored.
Hydroxypyrones and hydroxythiopyrones have versatile metal
coordination chemistry.5–10 Among the most commonly studied
hydroxypyrones are natural products maltol and kojic acid
(Fig. 2), which are widely used as food and cosmetics additives,
suggesting that they possess good biocompatibility.11 Hydroxypy-
rones have been explored for the development of new MMPi.
Tris(pyrazolyl)borate zinc(II) complexes, used to mimic the MMP
catalytic zinc(II) center, show that hydroxypyrones and hydroxy-
thiopyrones can bind to the zinc(II) ion in a bidentate fashion.12
Maltol (hydroxypyrone) and thiomaltol (hydroxythiopyrone) are
more effective ZBGs against MMP-3 (stromelysin) when compared
to a simple hydroxamate ligand.13,14 Using hydroxypyrone as the
ZBG, a series of potent and selective pyrone-based inhibitors of
MMP-3 have been developed by attaching an aryl backbone to
the 2-position of the pyrone ring.15,16 Simple hydroxythiopyrones
have shown much higher inhibition activity (30ꢀ60 fold) than
corresponding hydroxypyrones.14 This observation promoted us
to explore the potential of a hydroxythiopyrone ZBG for develop-
ment of full length MMP inhibitors. Unlike hydroxamate terminal
chelators, in which the inhibitor backbone can only be extended
in one direction, the hydroxypyrone ring has several positions
(2-, 5-, an 6-) to attach backbones (Fig. 2). Hence, it is possible to
develop novel hydroxypyrone-based inhibitors with multiple
backbones to interact with MMP pockets (Fig. 1). In this report,
we describe the syntheses of hydroxythiopyrone-based MMP
inhibitors and their inhibition activities are compared with that
* Corresponding author. Tel.: +1 858 822 5596; fax: +1 858 822 5598.
E-mail address: scohen@ucsd.edu (S.M. Cohen).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.044

Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
1971
Figure 1. Schematic interactions between MMPs and MMP inhibitors.
Figure 2. Structures of hydroxamate, hydroxypyrone, and hydroxythiopyrone chelators.
of corresponding hydroxypyrones. The synthetic schemes for
developing double-handed hydroxypyrone-based inhibitors have
been explored. Hydroxypyrones and their hydroxythiopyrone ana-
logues have also been widely reported in other biomedical applica-
tions such as iron balance in anemia and iron overload disorder,7,8
aluminium removal in Alzheimer’s disease,9,18,19 treatment of dia-
betes,20–23 and contrast agents for medical imaging.24 As such, the
synthetic studies and activity analysis provided here should be a
valuable reference for development of new hydroxypyrones and
hydroxythiopyrones for a wide range of medicinal applications.
Previously, our laboratory has reported several potent and
selective hydroxypyrone MMPi with aryl backbones at the 2-posi-
tion.15,16 Thus, we first synthesized corresponding 2-backbone
hydroxythiopyrones and evaluated their inhibition activities
(Scheme 1).15,16 Intermediate 1 was prepared according to a liter-
ature method.8 A coupling reaction of compound 1 with 4-
methoxybenzylamine in the presence of EDCI and HOBt provided
amide 2 in 71% yield. It was found that coupling reagent 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide (EDCI) was preferable
over dicyclohexylcarbodiimide (DCC), due to the difficulty in
removing dicyclohexylurea (DCU) from reaction mixtures employ-
ing DCC. The benzyl protecting group on compound 2 was easily
removed by stirring in CH3CO2H/HCl (v/v 1:1) at room temperature
overnight to give the previously reported hydroxypyrone AM-4
(referred to here as compound 3) in 81% yield. The corresponding
hydroxythiopyrone AM-4S (3-S) was synthesized in 61% yield by
thionation of compound 3 with P4S10 in the presence of hexame-
thyldisiloxane (HMDO).25 The methyl group on the aryl backbone
of compound 3 was removed by reaction with BBr3 resulting in
the new hydroxypyrone 4 in 63% yield.
The inhibitory activities of synthesized hydroxypyrones and
hydroxythiopyrones against MMPs were evaluated against human
MMP catalytic domain using a fluorescent substrate assay.17 MMP-
1 (collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin)
are examples of MMPs with shallow, intermediate, and deep S10
pockets, respectively. For comparison of structural impact on the
inhibitor activity, all inhibitors were evaluated at a concentration
of 50 lM against the aforementioned MMPs (Table 1). IC50 values
were determined in cases where an inhibitor showed relatively
strong inhibition against a given MMP.
Inhibition data comparison of 2-substituted thiopyrone 3-S and
pyrone 3 and 4 shows that hydroxythiopyrone 3-S led to higher
inhibition than hydroxypyrones 3 and 4 for all MMPs tested at
50
l
M concentration. This outcome agrees with the earlier finding
O
O
O
HCl:CH3CO2H
(v/v 1:1), rt
O
O
O
O
O
O
N
H
NH2R
OH
Bn
N
H
EDCI, HOBt, CH2Cl2
71%
81%
OH
OCH3
O
O
Bn
OCH3
3 (AM-4)
2
1
O
O
P4S10, HMDO
N
H
3
Benzene, reflux
61%
OH
OCH3
S
3-S (AM-4S)
O
O
O
N
H
BBr3, CH2Cl2, rt
63%
3
OH
OH
4
Scheme 1. Synthetic scheme for 2-C backbone MMPi.

1972
Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
Table 1
Percent inhibition at inhibitor concentrations of 50
l
M and select IC50 values (in parentheses)
MMP-1
Compound ID
Structure
MMP-2
MMP-3
3-S (AM-4S)
70 1 (30)
94 1 (19)
97 1 (16.4 2.3)
3 (AM-4)
29
6
4
26
2
4
93 2 (2.4)a
4
66
—
25
—
94 1 (3.7 1.2)
AM-2S
(5.6)b
AM-2a
9a-S
9a
(>50)
(9.3)
(0.24)
62 2 (44)
98 1 (14.4)
91 1 (13.3)
12
31
16
52
15
49
2
1
4
14
85
11
3
2
4
44
2
9b-S
91 1 (13.9 0.9)
9b
22
45
28
36
4
14a-Sc
94 (23)
14a
4
5
21
1
1
1
14b-S
69 1 (30)

Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
1973
Table 1 (continued)
Compound ID
Structure
MMP-1
MMP-2
MMP-3
14b
15
15
17
1
5
33
24
2
5
18
32
1
1
21
13
1
18
1
<1
22
26
18
21
3
4
24
15
4
4
32
26
1
2
30
6
1
63 1 (37.7 1.2)
4
1
a
Data cited from Ref. 15.
Data cited from Ref. 29.
Data cited from Ref. 26.
b
c
that O,S donor ligands are more potent ZBGs than O,O ligands.13,14
But it is interesting to note that thiopyrone 3-S and AM-2S have
poorer IC50 values than corresponding pyrone 3 and AM-2 (Table
1) against MMP-3.15,16 X-ray structures of thiomaltol and maltol
tris(pyrazolyl)borate zinc(II) complexes reveal that the hydroxy-
thiopyrone and hydroxypyrone ligands coordinate to tris(pyrazol-
yl)borate zinc(II) in different geometries (Fig. 3),12 suggesting that
substituents at the same positions of thiopyrone and pyrone rings
may interact with MMP active sites in different fashions. These
findings promote us to investigate 5- and 6-substituted hydrox-
ypyrones and hydroxythiopyrones.
The synthesis of inhibitors with backbones in the 6-C position
was performed according to Scheme 2, resulting in compounds
9a, 9b, 9a-S, and 9b-S. The ring hydroxyl of kojic acid (5) was selec-
tively protected with a benzyl group by treatment with BnBr in the
presence of NaOH to give compound 6. The hydroxymethyl group
of 6 was oxidized to carboxylic acid 7 in 65% yield using Jones re-
agent. The aryl backbones were introduced by coupling reactions
using EDCI/HOBt which afforded compounds 8a and 8b in
73ꢀ74% yield. The removal of the benzyl protecting groups from
compound 8a and 8b was conducted in mixed-solvents HCl/
CH3CO2H/CF3CO2H (v/v 10:10:1) at 60 °C, providing compounds
9a and 9b in 76ꢀ80% yield. In contrast to the benzyl group depro-
tection of compound 2 (Scheme 1), the benzyl group in 8a and 8b
survived in CH3CO2H/HCl (v/v 1:1) at room temperature, but addi-
tion of CF3CO2H with increased temperature promoted its removal.
This observation indicates that the substitution pattern on the pyr-
one can significantly change the electronic properties of the 3-ben-
zyloxy group on the ring. Thionation of 9a and 9b by P4S10 in the
presence of HMDO provided 9a-S and 9b-S in 61ꢀ68% yield.25
Syntheses of 5-C backbone inhibitors 14a, 14b, 14a-S, and 14b-
S followed a scheme recently developed in our laboratory (Scheme
3),26 with some modifications. In the intramolecular condensation
of activated bromo ester 10 to produce 3,3-diethyoxypyran-4-one
11, previously we used 2 equiv each of ethyl b-keto ester and NaH
in order to make a homogeneous anion solution. Ethyl b-keto ester
has an Rf value similar to that of product 11 and is difficult to sep-
arate in large-scale preparations. In the improved procedure,
O
O
O
OH
O
Y
ZBG
X
OH
O
S
N
O
O
Zn
N
TpPh,Me
O
Zn
S
Zn
N
TpPh,Me
=
(Tpph,Me)Zn(Thiomaltol)
(Tpph,Me)Zn(Maltol)
hydrotris(3,5-phenylmethylpyrazolyl)borate
Figure 3. Geometries of maltol- and thiomaltol-tris(pyrazolyl)borate zinc(II) complexes.

1974
Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
O
O
O
O
O
O
O
NH2R
Jone's Reagent
HO
HO
HO
BnBr, NaOH
EDCI, HOBt, CH2Cl2
Acetone, rt
65%
Bn
Bn
H2O, CH3OH
69%
O
O
OH
73−74%
7
5
6
O
O
O
R
O
O
a =
HCl:CH3CO2H:CF3CO2H
(v/v 10:10:1)
R
O
O
R
O
N
N
N
H
P4S10, HMDO
H
H
60 oC
Bn
OCH3
b =
OH
Benzene, reflux
O
OH
76−80%
61−68%
O
9a-S, 9b-S
9a, 9b
8a, 8b
Scheme 2. Synthetic scheme for 6-C backbone MMPi.
1.0 equiv of ethyl b-keto ester and 2.0 equiv of NaH were em-
ployed. The reaction was first stirred at room temperature for 1 h
to form intermediate I then refluxed to generate product 11. In
the preparation of amide 13a and 13b, EDCI/HOBt was employed
as the coupling system instead of DCC/DMAP or DCC/NHS to avoid
DCU contamination during product purification. After coupling of
the backbone, the remaining synthetic procedures were performed
as previously reported.26 In contrast to the high yields (60ꢀ70%) in
formation of the hydroxythiopyrones 3-S, 9a-S, and 9b-S from the
corresponding hydroxypyrones, thionation of 14a and 14b pro-
vided 14a-S and 14b-S in relatively low yields (16ꢀ18%).25 The
low yields in this transformation were tentatively explained by a
steric effect at the keto position of 14a and 14b which arose from
the neighboring 3-hydroxy and 5-amido groups. Demethylation of
14b by BBr3 affords 15 in 63% yield.
In vitro evaluation of 5- and 6-substituted inhibitors shows that
hydroxythiopyrones such as 9a-S, 9b-S, 14a-S, and 14b-S were
consistently more potent than their hydroxypyrone counterparts
9a, 9b, 14a, and 14b for all MMPs tested. For hydroxypyrone inhib-
itors, only inhibitors with backbones at the 2-position (e.g., 3, 4,
and AM-2) were selective against MMP-3 over MMP-1 and MMP-
2; and all 5- and 6-backbone hydroxypyrones 9a–b, 14a–b, and
15 were overall less potent for all MMPs and generally lacked iso-
form selectivity. The high potency and selectivity of these 2-C
backbone hydroxypyrone inhibitors for MMP-3 is consistent with
the favorable orientation of the 2-substituent of the hydroxypy-
rone toward the MMP-3 S10 pocket.15 The low inhibition of
MMP-1 by the 2-C backbone inhibitors confirms the incompatibil-
ity between the bulky aryl backbones and the smaller S10 pocket in
this MMP. 9a showed higher inhibition against MMP-3 over other
MMPs, while 9a-S showed comparable inhibition for MMP-2 and
MMP-3; compound 14a was not potent and lacked selectivity for
all MMPs, but 14a-S showed some preference against MMP-2.
These findings further highlight the interplay between the ZBG
structure and the position of the backbone on the ZBG can be opti-
mized to improve both potency and selectivity.
Most reported MMPi interact with MMPs at the primed side of
the active site (i.e., right-handed inhibitors). Inhibitors with back-
bones designed to interact with both the primed and unprimed
pockets, so-called ‘double-handed’ inhibitors, may have higher
selectivity and potency (Fig. 1).3,27,28 Hydroxypyrones and
hydroxythiopyrones have several positions (2-, 5-, and 6-) for
derivatization (Fig. 2), and thus are ideal for development of MMPi
with multiple backbones. In Scheme 4, a structural extension at
both sides of the hydroxypyrone chelator was achieved. Intermedi-
ate 16 was obtained in 60% yield by refluxing compound 11 in for-
mic acid in the presence of water. A hydroxymethyl group was
introduced at the 2-position of compound 16 by reaction with
O
O
O
O
O
O
O
O
O
OEt
NaH
NO2
OEt
Br
O
(1.0 eq)
OEt
O
O
O O
NaH (2.0 eq)/THF
83%
Br
Br
O
I
O
II
10
O
O
O
O
O
NH2R
O
O
NaOH/H2O, rt
60%
HO
OEt
EtO
O
EDCI, HOBt, CH2Cl2
>95%
O
O
.
O
12
O
R
Br
O
11
O
.
O
III
O
O
O
HCO2H/H2O
reflux
H
H
N
H
N
P4S10, HMDO
O
a=
N
R
R
OH
OH
Benzene, reflux
16−18%
O
79−82%
O
O
OCH3
O
O
O
S
b=
13a, 13b
14a, 14b
14a-S, 14b-S
HO
O
H
BBr3, CH2Cl2, rt
N
14b
OH
63%
O
O
15
Scheme 3. Synthetic scheme for 5-C backbone MMPi.

Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
1975
O1
O
O
O
6
OH
OH
2
HCO2H/H2O
HCHO
5
O
EtO
EtO
EtO
3
OH
NaOH/H2O, THF
4
reflux
60%
O
rt
60%
O
O
O
O
O
17
16
11
O
O
S
MsCl
CH2Cl2, NEt3
67%
O
O
OH
H2N
O
Br
EtO
EtO
OBn
K2CO3/DMF
61%
CH3CN, Et3N, reflux
73%
OBn
O
O
O
O
18
19
O
O
HCO2H/CF3CO2H
reflux
N
H
N
H
EtO
EtO
OBn
51%
OH
21
O
O
O
O
20
MeO
O
MeO
O
OH
OH
HCHO
H
H
N
N
NaOH/H2O, THF
OH
rt
65%
O
O
O
O
22
14b
Scheme 4. Synthetic scheme for double-handed (2-C, 5-C) MMPi intermediates.
formaldehyde in the presence of NaOH aqueous solution. This
hydroxymethylation reaction takes advantage of the ring hydroxyl
of 16 resulting in compound 17 in 60% yield. Compared with the
natural products kojic acid and maltol (Fig. 2), synthon 17 is highly
versatile and provides synthetic handles for further functional
extension at both sides of the hydroxypyrone chelator. The struc-
ture of 17 was unambiguously assigned by determining a single
X-ray crystal structure of the compound complexed with iron
(see Supplementary data). The ring hydroxyl was selectively ben-
zylated using benzyl bromide in the presence of K2CO3 providing
intermediate 18 in 61% yield. Mesylation of 18 provided sulfonic
acid ester 19 in 67% yield. The 4-biphenylmethyl backbone was
introduced by refluxing mesylate 19 with 4-biphenylmethylamine
in CH3CN resulting in compound 20 in 73% yield. The benzyl group
was removed by refluxing compound 20 in HCO2H/CF3CO2H mixed
solvents, which afforded compound 21 in 51% yield. As the 5-ester
and 6-methyl groups provide attachment points for further func-
tionalization of compound 21, it is possible to synthesize novel
hydroxypyrone inhibitors with multiple backbones to interact with
MMP active sites. Similarly, compound 14b, with an amido back-
bone at the 5-position, could also be hydroxymethylated at the
2-position generating compound 22 and thus providing a second
route for introducing a new backbone at this position.
tach the backbone, we reason that the backbone linkage might be
another important factor governing the interaction between an
inhibitor and MMPs. Thus two analogous compounds of AM-2,
compounds 26 and 30 with ether and amino linkages, respectively,
were synthesized to investigate the impact of the linker on inhib-
itor potency.
The synthesis of compound 26 is shown in Scheme 5. Interme-
diate 23 was prepared from kojic acid (5) following a reported
method.8 The hydroxyl group on the pyrone ring was selectively
protected with a PMB (p-methoxybenzyl) group using PMBCl to
give compound 24. The introduction of a 4-biphenylmethyl back-
bone was attained by treatment of compound 24 with 4-bromo-
methyl-biphenyl in the presence of NaH that led to the formation
of compound 25. The selective removal of the PMB group was
achieved by treatment of compound 25 with CF3CO2H at room
temperature in CH2Cl2 providing inhibitor 26 in 84% yield. The
use of a benzyl (BnBr) group instead of a PMB group to protect
the pyrone hydroxyl group was also examined. It was found that
the benzyl protecting group was not cleaved with CF3CO2H at room
temperature. The benzyl group could be removed by refluxing in
CH3CO2H/CF3CO2H (v/v 1:1) or hydrogenation in the presence of
Pd/C, but under such conditions the 4-biphenylmethyl backbone
was also partially removed, resulting in a low yield and difficulty
in purifying product 26.
The simple double-handed intermediates 21 and 22 were not
potent against the MMPs screened. Comparing the structure of
21 with potent inhibitor AM-2, which uses an amido linkage to at-
The preparation of compound 30 is shown in Scheme 6. Treat-
ment of intermediate 24 with methanesulfonyl chloride at 0 °C
O
O
O
O
Br
OH
HO
OH
PMBBr
NaH/DMF
26%
K2CO3/DMF
55%
OH
O PMB
OH
O
O
24
23
5 (Kojic acid)
O
O
O
O
CF3CO2H
O
25
PMB
OH
O
CH2Cl2,rt
84%
O
26
Scheme 5. Synthetic scheme for compound 26.

1976
Y.-L. Yan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1970–1976
O
S
O
O
O
O
O
O
MsCl
CH2Cl2, NEt3, 0 ºC
H2N
O
Cl
OH
O
PMB
PMB
PMB
CH CN, Et N, reflux
O
O
O
3
3
21%
77%
27
28
24
O
O
N
CF3CO2H
N
H
H
CH2Cl2, rt
88%
OH
O
PMB
O
O
29
30
Scheme 6. Synthetic scheme for compound 30.
provided the mesylate ester 27 in 50% yield. The major side prod-
uct in this transformation was the corresponding chloride 28 (21%
yield). The 4-biphenylmethyl backbone was introduced by reflux-
ing of 27 with 4-biphenylmethylamine in CH3CN in the presence
of triethylamine, resulting in compound 29. Again, the PMB pro-
tecting group was easily removed by treatment with CF3CO2H at
room temperature to give compound 30. In the preparation of
30, a benzyl protecting group was tested instead of the PMB pro-
tecting group, but again the 4-biphenylmethyl backbone was par-
tially removed, as was found in the preparation of compound 26.
The inhibition data for compounds AM-2, 26, and 30 reveals the
importance of the backbone linkage. The three inhibitors have the
same ZBG and 4-biphenylmethyl backbone, but each has a differ-
ent linker, namely amido (AM-2), ether (26), and amino (30). Com-
pounds 26 and 30 are much less potent than AM-2 against MMP-3,
which may be partially explained by favorable hydrogen bonding
between the amido carbonyl group of AM-2 and the amino acid
L164 in the MMP.15 In addition, the ether linkage of 26 and the
amino linkage of 30 are electron-donating, while the amido linkage
of AM-2 is electron-withdrawing. The differing electronic effects of
linkers at the 2-position leads to significant differences in the pKa
values of the hydroxypyrone chelator,30 with the amide compound
being more acidic than either the ether- or amino-linked com-
pound (unpublished results). These findings suggest that the link-
ing group between the backbone and the ZBG can significantly
influence the efficacy of an inhibitor through both direct (e.g., H-
bonding) and inductive (e.g., ligand acidity) effects that must be
carefully considered for successful MMPi design.
A.L. Rheingold for assistance with the X-ray structure determina-
tion. This material is based upon work supported in part by the
NIH (R01 HL00049-01) and the American Heart Association
(0430009N).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.02.044.
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The authors thank Dr. Yongxuan Su for mass spectral analyses
of all compounds, Dr. J.R. Stork, Dr. A.G. DiPasquale, and Professor