Improved small-molecule macroarray platform for the rapid synthesis and discovery of Antibacterial chalcones

Article abstract of DOI:10.1021/co100053p

Bacterial resistance to current antibiotics is a major global health threat. Consequently, there is an urgent need for the identification of new antibacterial agents. We are applying the small-molecule macroarray platform to rapidly synthesize and screen

Full text of DOI:10.1021/co100053p

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Improved Small-Molecule Macroarray Platform for the Rapid
Synthesis and Discovery of Antibacterial Chalcones
Joseph R. Stringer,† Matthew D. Bowman,† Bernard Weisblum,‡ and Helen E. Blackwell*,†
†Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706-1322, United States
‡Department of Pharmacology, University of Wisconsin, 1300 University Avenue, Madison, Wisconsin 53706-1510, United States
S Supporting Information
b
ABSTRACT: Bacterial resistance to current antibiotics is a major
global health threat. Consequently, there is an urgent need for the
identification of new antibacterial agents. We are applying the
small-molecule macroarray platform to rapidly synthesize and
screen compounds for activity against methicillin-resistant Staphylo-
coccus aureus (MRSA). Herein, we report the synthesis of a 1,3-
diphenyl-2-propen-1-one (chalcone) macroarray using a Rink-
amide linker-derivatized cellulose support. The Rink linker al-
lowed for the incorporation of a broader array of library building
blocks relative to our previous syntheses because milder reaction
conditions could be utilized; significantly higher compound loadings
were also achieved (∼80% vs ∼15%). Analysis of the 174-member
chalcone macroarray in off-support antibacterial screening assays
revealed three chalcones with minimum inhibitory concentration
(MIC) values against MRSA comparable to currently used antibac-
terial drugs and low hemolytic activities. These results serve to
further showcase and extend the utility of the small molecule
macroarray for antibacterial discovery.
KEYWORDS: cellulose, chalcone, MRSA, rink linker, small molecular macroarray, SPOT-synthesis
’ INTRODUCTION
and 2-methyl-3-cyanopyridine libraries using our small-molecule
macroarray platform.17 The antibacterial screening assays re-
vealed four compounds, most notably two chalcones, with minimum
inhibitory concentration (MIC) against MRSA in the low
micromolar range (e10 μM). While this study demonstrated
the compatibility of the macroarray platform for new antibacte-
rial discovery, we sought to improve certain aspects of the library
synthesis route, expand the size of the possible chalcone libraries,
and thereby, uncover additional compounds with antibacterial
activity. For example, attachment of the initial hydroxyacetophe-
none building blocks to the Wang linker-derivatized cellulose
support via nucleophilic substitution proceeded with low con-
version rates in this previous work (∼15%).17 Additionally, certain
commercially available hydroxyacetophenones were insoluble in
the KOtBu/DMF reagent solution required to couple the hydroxy-
acetophenones to the Wang-support, which limited the size and
resulting structural diversity of the libraries.
The growing resistance of bacteria to antibiotics constitutes a
global health emergency.1,2 Methicillin-resistant Staphylococcus
aureus (MRSA) has received considerable recent attention be-
cause of its dramatically increasing prevalence in both hospital
and community settings.3-8 There is an immense and growing
need for the identification of new antibacterial agents active
against MRSA.9 One approach toward the discovery such com-
pounds entails the synthesis and screening of structurally diverse
combinatorial libraries of small molecules.10,11
Our laboratory has developed methods for the efficient parallel
synthesis of chemical libraries using small-molecule macro-
arrays.12-20 The small-molecule macroarray approach offers
certain advantages over traditional solid-phase supports.21 The
macroarray support (cellulose filter paper) is inexpensive, me-
chanically robust, easy to manipulate, and compatible with a
variety of on- and off-support biological screening assays.17,19
These attributes make the small-molecule macroarray a versatile
tool for the synthesis and screening of compound libraries for the
discovery of agents that can modulate biological processes.
We recently reported the synthesis and antibacterial screening
of several 1, 3-diphenyl-2-propen-1-one (chalcone), pyrimidine,
Received: November 2, 2010
Revised:
December 28, 2010
Published: January 06, 2011
r
2011 American Chemical Society
175
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RESEARCH ARTICLE
Scheme 1. Synthesis of Rink-Amide Linker Derivatized Cellulose Support IV
In an effort to improve the coupling efficiencies of the aceto-
phenone building blocks and increase the number of compatible
acetophenones available for chalcone and heterocycle macro-
array construction, we explored the use of an alternative chemical
linker for macroarray synthesis. We reasoned that the well-
characterized Rink-amide linker22,23 would allow efficient attach-
ment of carboxylic acid-derivatized acetophenones to the cellu-
lose support via an amide bond using mild coupling reagents,
such as N,N0-diisopropylcarbodiimide (DIC). We therefore
sought to develop a Rink-amide linker variant of our cellulose
support platform and test this platform through the synthesis of a
new chalcone macroarray. Herein, we report the results of these
studies. We were able to generate a 174-member chalcone library
in high purities using mild reaction conditions on the Rink-linker
support system. Moreover, off-support antibacterial assays of the
macroarray revealed three previously unreported chalcones with
potent antibacterial activities against MRSA and low hemolytic
activities.
Chalcone Macroarray Construction. Synthesis of the chal-
cone macroarray first required covalent attachment of an aceto-
phenone building block to the amino support IV. We reasoned
that this coupling could be achieved by amide bond formation
between the amino support IV and an acetophenone derivatized
with a carboxylic acid “handle” using a standard carbodiimide (DIC)
coupling reaction. This envisaged reaction is shown in Scheme 2.
We chose to test six different acetyl phenoxyacetic acid building
blocks (A-F) containing various substitution patterns for in-
corporation into the chalcone macroarray (Figure 1). These
acetyl phenoxyacetic acids were readily synthesized in solution in
good yields and purities by reaction of an appropriate hydroxy-
acetophenone with methyl bromoacetate, followed by basic ester
hydrolysis (see Supporting Information).
The acetyl phenoxyacetic acids A-F were efficiently coupled
to amino support IV in a spatially addressed manner using
standard DIC coupling reactions at 43 °C (Scheme 2). Through
a series of optimization experiments, we found that performing
this reaction at 43 °C (on a sand bath) afforded the highest product
purities relative to higher and lower temperatures. Loading
efficiencies for acids A-F were calculated by cleaving a subset
of the acids, analysis by HPLC, and comparison to calibration
curves generated from authentic samples of the resulting primary
amide acetophenone derivatives (see Supporting Information).
Using this DIC coupling method, we routinely achieved acetyl
phenoxyacetic acid loadings of ∼400 nmol/cm2 (∼80% coupling
efficiency to amino support IV). Notably, this is a significant
improvement over our previous synthetic method of attaching
acetophenone building blocks to a Wang linker-support using
nucleophilic substitution chemistry, which gave coupling efficiencies
of ∼15%.17
’ RESULTS AND DISCUSSION
Amino Cellulose Functionalization. Derivatization of cellu-
lose supports with the acid-cleavable Rink-amide linker has
previously been described, primarily for the SPOT-synthesis of
peptide libraries.20,21,24 We used a modified version of these
reported protocols in the current study that incorporated features
from our past cellulose support syntheses (Scheme 1).12-15,17 First,
planar cellulose support I (Whatman 1CHR filter paper) was
tosylated to generate support II, and then reacted with a flexible
diamine spacer to yield amine-derivatized support III. The
Fmoc-protected Rink-amide linker was spotted onto support
III in a spatially addressed fashion using a micropipet (to
minimize use of this relatively expensive reagent), followed by
a blanket acetylation step to cap any unreacted spacer amines on
the support. Fmoc deprotection of the linker-functionalized
support using piperidine afforded the amino support IV. Using
this method, we reproducibly obtained Rink linker loadings of
∼500 nmol/cm2, as determined by standard UV Fmoc quanti-
fication at 296 nm (see Supporting Information).25
With the support-bound acetophenone macroarray V in hand,
completion of the chalcone macroarray VI was accomplished by
Claisen-Schmidt condensations with various benzaldehydes
(1-29) (Scheme 2). We chose to incorporate an expanded set
of structurally diverse benzaldehydes relative to our previous
chalcone library in order to explore a broader range of functional
group substitution patterns in the chalcone scaffold. We utilized
our previously reported conditions for the Claisen-Schmidt reaction
on planar supports.17 These reactions yielded a 174-member
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RESEARCH ARTICLE
Scheme 2. Chalcone Macroarray Synthesisa
a DIC = N,N0-diisopropylcarbodiimide, DMF = N,N0-dimethylformamide, TFA = trifluoroacetic acid.
chalcone macroarray (VI) by combining the six acetyl-phenoxy-
acetic acids and 29 variably substituted benzaldehydes (Figure 1).
Compound Cleavage and Analysis. We subjected the chal-
cone macroarray (VI) to acid-mediated cleavage to investigate
product purities. Individual compound spots of chalcone array VI
were punched out of the array, placed in glass vials, and cleaved
with TFA vapor in a sealed desiccators (according to our pre-
viously reported method).17 The cleaved chalcone products
(VII) were then eluted from the support spots with acetonitrile,
the solvent was removed in vacuo, and DMSO was added to
each sample to generate individual compound stock solutions
(∼2 mM based on initial acetophenone loading). We randomly
selected 35 chalcone products (VII) (20% of the library) and
analyzed their purities by HPLC with UV detection at 254 nm.
This subset of chalcones displayed moderate to excellent purities
(72-99%), with an average purity of 87% (see Supporting
Information Table S-1). The amount of chalcone product obtained
(∼113 nmol/spot) was sufficient for postsynthesis antibacterial
assays and analytical characterization.
Antibacterial Screening of Chalcone Macroarrays. We
sought to determine if any of the new chalcones (VII) had
antibacterial activity against MRSA. We tested the antibacterial
activities of the entire 174-member chalcone library against a
MRSA strain (ATCC 33591) using a standard solution-phase
absorbance assay that measures bacterial growth.26 We tested
aliquots of the chalcone stock solutions to obtain estimates of
MIC values over a range of concentrations (3.1-50 μM) according
to our previously reported method for off-support macroarray
antibacterial assays of products.17 Notably, we discovered three
chalcones (B19, F17, and F19) that displayed estimated MIC
values against MRSA below 6.3 μM (Figure 2 and Table 1). We
selected these lead compounds for further study and quantitative
MIC measurements.
chalcones B19, F17, and F19 (see Supporting Information). We
were pleased to observe that the actual and estimated MIC values
for B19, F17, and F19 were in close agreement (<3-6 μM vs
3-4 μM, respectively; Table 1), indicating that our estimates of
the quantities of cleaved products from the macroarray were
accurate. For comparison, we obtained the MIC values for the
two antibacterial drugs linezolid and ciprofloxacin against MRSA.
Notably, the three chalcones (B19, F17, and F19) displayed
MIC values that were only ∼3-4ꢀ higher than ciprofloxacin
(1 μM) and comparable to linezolid in this assay (4 μM;
Table 1).
To extend our characterization of the most active chalcones,
we measured the hemolytic activities of B19, F17, and F19 using
human red blood cells. Hemolysis assays are a standard tech-
nique to assess the toxicity of antibacterial agents against human
cells. F19 showed <10% hemolytic activity at 10 μM, which
is ∼3ꢀ its effective MIC value (Table 1). Both B19 and F17
exhibited <10% hemolysis at a concentration of 20 μM, which is
4ꢀ their effective MIC values (see Supporting Information for
data). Such low hemolytic activities are advantageous properties
for antibacterial agents, and ongoing studies in our laboratory are
focused on determining the mechanisms of antibacterial action of
these and related chalcones.
’ SUMMARY
In summary, we have demonstrated the compatibility of the
Rink-amide linker with chalcone macroarray synthesis and have
applied this linker system in the synthesis of a 174-member chalcone
library (VI). The use of the Rink linker allowed us to efficiently
construct the chalcone macroarray using milder reaction condi-
tions relative to our previous syntheses. Off-support antibacterial
assays of the resulting chalcone products (VII) uncovered three
previously unreported chalcones that display potent MIC values
against MRSA. These studies serve to expand the utility of the
small molecule macroarray approach for the synthesis and discovery
of biologically active compounds. In addition, our results provide
We determined the actual MIC values for chalcones B19, F17,
and F19 against MRSA using stock solutions of authentic
chalcone samples (Table 1). A straightforward two-step, solution-
phasesynthesisprocedurewasemployedtogeneratepuresamples of
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Figure 1. Two sets of building blocks used in the synthesis of the chalcone macroarray. (Top) Acetyl phenoxyacetic acids A-F. (Bottom)
Benzaldehydes 1-29.
support for further study of chalcone scaffolds27-29 in antibac-
terial development.
designate spot locations. In this format, 120 compound spots
(area/spot = 0.3 cm2) could be accommodated on a single sheet
without any detectable cross contamination. A calibrated micro-
pipet was used to deliver all spotted reagents.
’ EXPERIMENTAL PROCEDURES
Macroarray Synthesis. Planar cellulose membranes (Whatman
1CHR filter paper) were derivatized with a Rink-amide linker using a
modified version of previously reported protocols to yield amino
support IV (loading ∼500 nmol/cm2).20,21,24 A 1.0 M solution of
acetyl phenoxyacetic acid in 1.0 M DIC in anhydrous DMF was
prepared. After standing at room temperature for 2 min, aliquots
(6.0 μL) of this solution were applied to amino support IV using a
micropipet. The support was heated at 43 °Conasandbathandthen
washed by immersion and swirling in 150 mL portions of 1 N NaOH,
EtOH (2ꢀ), and CH2Cl2 (2ꢀ). The resulting acetophenone
General Experimental Information. All chemical reagents
and solvents were purchased from commercial sources (Alfa-
Aesar, Aldrich, and Acros) and used without further purification
with the exception of dichloromethane (CH2Cl2), which was
distilled over calcium hydride immediately prior to use. Planar
cellulose membranes (Whatman 1CHR) was purchased from
Fisher Scientific and stored in a desiccator at room temperature
until ready for use. Dots were marked on 15 cm ꢀ18 cm cellulose
sheets at distances 1.4 cm apart using a No. 2 lead pencil to
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a total volume of 50 μL in each well. A 2% (v/v) hRBC
suspension (50 μL in Tris buffer) was added to each well. The
plate was incubated at 37 °C for 1 h, and the cells were then
pelleted by centrifugation at 3500 rpm for 5 min. The super-
natant (80 μL) was transferred to a fresh 96-well plate, and
hemoglobin was detected by measuring the optical density (OD)
at 405 nm. The OD of cells incubated with an excess concentra-
tion of Triton-X100 defined 100% hemolysis; the OD of cells
incubated in Tris buffer (containing 2% (v/v) DMSO) defined
0% hemolysis (see Supporting Information for assay data).
’ ASSOCIATED CONTENT
S
Supporting Information. Full details of instrumentation,
b
macroarray construction, macroarray library purity, solution-
phase synthesis of building blocks and lead compounds, com-
pound characterization, and biological assay protocols and data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 2. Lead antibacterial chalcones uncovered in this study (B19,
F17, and F19).
Table 1. Purity and Antibacterial Activity Data for Lead
Chalcones and Controls against MRSA
’ AUTHOR INFORMATION
purity
(%)a,b
estimated MIC range
actual MIC
(μM)c,e
Corresponding Author
*E-mail: blackwell@chem.wisc.edu.
compound
(μM)c,d
B19
84
87
92
<6.3
<3.1
<6.3
4.0 ( 0.5
4.0 ( 0.5
3.2 ( 0.2
4.0 ( 1.0
1.0 ( 0.2
Funding Sources
We thank the NSF (CHE-0449959), Greater Milwaukee Foun-
dation Shaw Scientist Foundation, Burroughs Welcome Fund,
and Johnson & Johnson for financial support of this work.
F17
F19
linezolid
ciprofloxacin
a From HPLC analyses of crude macroarray compounds (UV detection
at 254 nm). b Certain chalcones were mixtures of cis and trans isomers
(see Supporting Information for details). c Methicillin-resistant S. aureus
ATCC 33591 (MRSA). d From serial dilution of spot stock solutions of
crude macroarray compounds. e From authentic sample of the com-
pound. Only trans isomers of chalcones were evaluated. Error reflects
step size in the serial dilution.
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macroarray V was dried under a stream of N2 gas for 15 min.
Thereafter, a 1.0 M solution of benzaldehyde in 1 N NaOH in 50%
aq. ethanol was prepared, and aliquots (6.0 μL) of this solution were
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