A versatile approach to affinitychromic polythiophenes

Article abstract of DOI:10.1021/ja027387l

The preparation of both postfunctionalizable and chromic poly[3-(N-succinimido-p-phenylcarboxylate(tetraethoxy)oxy)-4-methylthiophene] is reported. The N-hydroxysuccinimide ester side group can easily react with different amine-bearing molecules in the so

Full text of DOI:10.1021/ja027387l

Published on Web 09/28/2002
A Versatile Approach to Affinitychromic Polythiophenes
Ste´phanie Bernier, Se´bastien Garreau, Ma¨ıte´ Be´ra-Abe´rem, Catherine Gravel, and
Mario Leclerc*
Contribution from the Canada Research Chair in ElectroactiVe and PhotoactiVe Polymers,
Centre de recherche en sciences et inge´nierie des macromole´cules, De´partement de Chimie,
UniVersite´ LaVal, Quebec City, Qc, Canada, G1K 7P4
Received June 20, 2002
Abstract: The preparation of both postfunctionalizable and chromic poly[3-(N-succinimido-p-phenylcar-
boxylate(tetraethoxy)oxy)-4-methylthiophene] is reported. The N-hydroxysuccinimide ester side group can
easily react with different amine-bearing molecules in the solid state to yield a library of new polythiophene
derivatives. The resulting polymers can be dissolved in various solvents, and interactions between the
side chains (ligands) and different analytes (targets) can be detected from modifications of both the side-
chain and the backbone conformations resulting in important color changes (i.e., affinitychromism). This
colorimetric polymeric transducer could therefore lead to highly valuable, versatile, and inexpensive tools
for highthroughput screening and drug discovery.
Introduction
could be solved by a second generation of active arrays where
the substrate is itself colored, luminescent, or electroactive. In
Combinatorial chemistry has recently revolutionized the
pharmaceutical industry because it allows the efficient and
parallel synthesis of hundreds of organic compounds.1-3 How-
ever, the large number of chemical compounds synthesized in
parallel brings another important problem, which is related to
the localization, identification, and determination of the biologi-
cal activity of one specific compound. For instance, some
biological activities can be detected within a library of organic
compounds, but the determination of the exact nature of the
chemical compound(s) responsible for such an activity is a
difficult task. Some solutions have already been proposed.
Among them, the (micro)fabrication of positionally addressable
two-dimensional arrays of synthetic precursors is a powerful
tool for the parallel synthesis of different organic compounds.4,5
Moreover, it is possible to use these different substrates to verify
the interaction or activity of these compounds by tagging, for
instance, a fluorescent probe to the target. By utilizing a
fluorescence microscope, we found it is then possible to localize
onto the surface where interactions are taking place and,
consequently, to identify the chemical structure of the organic
compound bound to the surface that is responsible for such
interactions.
other words, we could avoid any tagging process by using a
responsive polymer which could serve as a solid-state precursor
for the preparation or the covalent attachment of a large number
of different chemical compounds but could also have the optical
or electrical properties of the resulting polymers modified upon
complexation or interaction with a given target. If successful,
this approach could easily generate (or bind) a library of
potential ligands and have their affinity to different targets
directly tested in a few minutes without the use of any sophis-
ticated technique. This ambitious program seems now possible
by the utilization of functionalized polythiophenes.6-8 Indeed,
some polythiophenes can detect, transduce, and, sometimes,
amplify chemical or physical information into an optical (or
electrical) signal. These optical changes are related to a
conformational transition of the polymer backbone, between a
planar and a nonplanar form, triggered by adequately function-
alized and responsive side chains. More precisely, it has been
suggested that these optical effects are driven by a delicate
balance between repulsive steric interactions and attractive
interchain (or intrachain, due to chain folding) interactions, the
latter being necessary to get a planar conformation in the case
of chromic poly(3-alkoxy-4-methylthiophene)s.6-8 Recently, the
term assisted-planarization mechanism9 or aggregation-induced
However, this method has the disadvantage of necessitating
the addition of a photoactive, electroactive, or radioactive
tagging agent onto the target (i.e., the analyte). This problem
(6) (a) Fa¨ıd, K.; Leclerc, M. J. Am. Chem. Soc. 1998, 120, 5274. (b)
Kumpumbu-Kalemba, L.; Leclerc, M. Chem. Commun. 2000, 1847.
(7) Ho, H. A.; Boissinot, M.; Bergeron, M. G.; Corbeil, G.; Dore´, K.; Boudreau,
D.; Leclerc, M. Angew. Chem., Int. Ed. 2002, 41, 1548.
(8) (a) Leclerc, M.; Fa¨ıd, K. AdV. Mater. 1997, 9, 1087. (b) Leclerc, M. AdV.
Mater. 1999, 11, 1491. (c) McCullough, R. D. AdV. Mater. 1998, 10, 93.
(d) McQuade, D. T.; Pullen, A. E.; Swager, T. M. Chem. ReV. 2000, 100,
2537.
(9) (a) Politis, J. K.; Somoza, F. B., Jr.; Kampf, J. W.; Curtis, M. D.; Gonzalez
Ronda, L.; Martin, D. C. Chem. Mater. 1999, 11, 2274. (b) Apperloo, J.
J.; Janssen, R. A. J.; Malenfant, P. R. L.; Fre´chet, J. M. J. Macromolecules
2000, 33, 7038.
* To whom correspondence should be addressed. E-mail: mario.leclerc@
chm.ulaval.ca.
(1) Wilson, S. R., Czarnik, A. W., Eds. Combinatorial Chemistry: Synthesis
and Application; Wiley & Sons: Toronto, 1997.
(2) Szostak, J., Ed. Chem. ReV. 1997, 97, 347.
(3) Borman, S. Chem. Eng. News 1999, 77 (10), 33; 2000, 78 (20), 53.
(4) Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.; Solas,
D. Science 1991, 251, 767.
(5) Sundberg, S. A.; Barrett, R. W.; Pirrung, M.; Lu, A. L.; Kiangsoontra, B.;
Holmes, C. P. J. Am. Chem. Soc. 1995, 117, 12050.
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J. AM. CHEM. SOC. 2002, 124, 12463-12468
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A R T I C L E S
Bernier et al.
planarization10 was coined to explain these results in solution.
In the reverse process, such planar assemblies can be disrupted
owing to a disordering of the flexible side chains, a cooperative
twisting of the main chain being assumed with this dismantling.
In addition to optical transitions induced by heating (thermo-
chromism) or solvent quality changes (solvatochromism), novel
phenomena have been generated in solution, including the
detection of ions (ionochromism) and molecular recognition of
chemical or biological moieties (affinitychromism). Along these
lines, we would like to report the development of both
postfunctionalizable and chromic polythiophenes and the dem-
onstration of their potential for applications in highthroughput
screening and drug discovery.
dissolved in toluene and evaporated two times to remove any trace of
water. The acid was stored under nitrogen until use. To a solution of
compound 3 in 50 mL of anhydrous CH2Cl2 were added 0.46 g (4.00
mmol, Aldrich Co.) of N-hydroxysuccinimide, 0.91 g (4.41 mmol,
Aldrich Co.) of N,N′-dicyclohexylcarbodiimide, and 10.00 mg (0.08
mmol, Aldrich Co.) of 4-(N,N′-dimethyl)aminopyridine. The mixture
was stirred for 35 h. The flask of solution was dipped into cold water,
and the precipitate was removed by filtration through a Bu¨chner funnel.
This operation was repeated three times. The product was purified by
column chromatography (silica gel, diethyl ether followed by acetonitrile
as eluents) to give a pale yellow oil (yield: 85%).
1H NMR (300 MHz, CDCl3, ppm). 2.09 (s, 3H); 2.90 (s, 4H); 3.68-
3.75 (m, 8H); 3.87 (m, 4H); 4.10 (t, 2H, J ) 4.8 Hz); 4.20 (t, 2H, J )
4.4 Hz); 6.16 (d, 1H, J ) 3.3 Hz); 6.81 (m, 1H); 6.98 (d, 2H, J ) 9.2
Hz); 8.09 (d, 2H, J ) 8.8 Hz).
13C NMR (75 MHz, CDCl3, ppm). 12.73; 25.54 (2C); 67.83; 69.46;
69.67; 69.74; 70.71; 70.73; 70.92; 70.95; 96.61; 114.80 (2C); 117.25;
119.97; 129.17; 132.85 (2C); 155.91; 161.47; 164.19; 169.45 (2C).
HRMS. Calculated for C24H29O9S1: 507.1563. Found: 507.1567.
Poly[3-(N-succinimido-p-phenylcarboxylate(tetraethoxy)oxy)-4-
methylthiophene] (P1). A three-electrode one-compartment cell was
employed. The working electrode and the counter electrode were
platinum plates, and the Ag/AgNO3 (0.010 M in 0.1 M Bu4NBF4/CH3-
CN) electrode was chosen as reference. The corresponding monomer
was electropolymerized at a concentration of 0.1 M in 0.1 M Bu4NBF4/
CH3CN by successive cyclings at 200 mV/s between 0.0 and 1.7 V.
After the polymerization, the polymer was rinsed with fresh acetonitrile,
acetone, and methanol.
Instrumentation. FTIR spectra were recorded using a Nicolet Magna
560 spectrometer, with a resolution of 4 cm-1, from KBr pellets or
films cast from CHCl3 solution on NaCl disks. 1H and 13C NMR spectra
were obtained on a Bruker AMX300 apparatus in deuterated chloroform
solution at 298 K. Number-average (Mn) and weight-average (Mw)
molecular weights were determined by size exclusion chromatography
(SEC) with an HPLC pump using a Waters 515 differential refracto-
meter. The calibration curve was made with a series of monodispersed
polystyrene standards in THF (HPLC grade, Aldrich). UV-vis absorp-
tion spectra were recorded on a Hewlett-Packard diode-array spectro-
photometer (model 8452A) equipped with a temperature control unit,
using 1 mm path length quartz cells. The temperature was measured
with a thermocouple, with ∆T ≈ 2 °C. Electrochemical measurements
have been performed with a Solartron potentiostat-galvanostat, model
SI 1287, driven by a Corrview software.
Experimental Section
Materials. 3-(((2-Iodoethyl)triethoxy)oxy)-4-methylthiophene (1)
was prepared according to already published procedures,11 and all other
starting materials were purchased from Aldrich Co. and used without
further purification.
3-[(Ethyl-4-phenylcarboxylate)-1-(tetraethoxy)oxy]-4-methylth-
iophene (2). Under argon, 1.20 g (3.0 mmol) of 3-(((2-iodoethyl)-
triethoxy)oxy)-4-methylthiophene (1) and 0.71 g (4.28 mmol, Aldrich
Co.) of p-hydroxyethylbenzoate were dissolved in 25 mL of anhydrous
acetone. Subsequently, 1.28 g (9.27 mmol) of K2CO3 and 0.08 g (0.48
mmol) of KI were added to the solution. The mixture was refluxed for
60 h. After cooling, the precipitate was filtered through a Bu¨chner
funnel, and the solid was washed with acetone. The filtrate was
evaporated and extracted with water and chloroform. The organic layer
was dried over magnesium sulfate, and the residue was purified by
column chromatography (silica gel, 20% hexane in diethyl ether as
eluent) to give a yellow oil (yield: 90%).
1H NMR (300 MHz, CDCl3, ppm). 1.37 (t, 3H, J ) 7.0 Hz); 2.08
(s, 3H); 3.67-3.74 (m, 8H); 3.85 (m, 4H); 4.09 (t, 2H, J ) 4.5 Hz);
4.16 (t, 2H, J ) 4.8 Hz); 4.34 (q, 2H, J ) 7.0 Hz); 6.15 (d, 1H, J )
3.3 Hz); 6.80 (m, 1H); 6.91 (d, 2H, J ) 8.8 Hz); 7.98 (d, 2H, J ) 8.8
Hz).
13C NMR (75 MHz, CDCl3, ppm). 12.68; 14.38; 60.53; 67.56;
69.48; 69.62 (2C); 70.64; 70.65; 70.83 (2C); 96.59; 114.12 (2C); 119.96;
123.00; 129.00; 131.45 (2C); 155.89; 166.16.
HRMS. Calculated for C22H30O7S1: 438.1712. Found: 438.1718.
3-((4-(p-Carboxyphenyl)tetraethoxy)oxy)-4-methylthiophene (3).
To a solution of 24 mL of 5 M NaOH (aq)/EtOH (1:1) was added 1.50
g (3.45 mmol) of compound 2. The resulting mixture was refluxed for
16 h. Afterward, the solvent was evaporated, and the resulting product
was dissolved with diethyl ether. The organic layer was extracted with
water, and HCl was added to the aqueous layer until the pH reached a
value of 3. Finally, the acid layer was extracted with ethyl acetate.
The resulting organic layer was dried over magnesium sulfate. The
crude product was decolorized on activated carbon with hot acetone
and filtered through Celite 521 to obtain a white solid. mp: 74-76 °C
(yield: 93%).
Results and Discussion
As shown in Scheme 1, the desired thiophene monomer has
been easily prepared in three straightforward steps, starting from
3-(((2-iodoethyl)triethoxy)oxy)-4-methylthiophene.11 The present
substitution pattern of the thiophene unit has been designed on
the basis of our previous investigations,6-8 which have shown
that the presence of an alkoxy substituent at the 3-position
combined with a methyl group at the 4-position leads, upon
oxidative polymerization, to regioregular (>95% head-to-tail
coupled) and chromic polythiophenes. The relatively long and
hydrophilic spacer is there to allow easy postfunctionalization
reactions and possible electroactivity in aqueous and polar
organic solutions. Finally, a N-hydroxysuccinimide (NHS) ester
group has been incorporated because it can support oxidative
electropolymerization of pyrrole or thiophene units.12-14 This
1H NMR (300 MHz, CDCl3, ppm). 2.10 (s, 3H); 3.67-3.76 (m,
8H); 3.87 (m, 4H); 4.10 (t, 2H, J ) 4.5 Hz); 4.19 (t, 2H, J ) 4.4 Hz);
6.16 (d, 1H, J ) 3.2 Hz); 6.81 (m, 1H); 6.94 (d, 2H, J ) 9.2 Hz); 8.04
(d, 2H, J ) 9.2 Hz).
13C NMR (75 MHz, CDCl3, ppm). 12.73; 67.66; 69.66; 69.73;
70.71; 70.72; 70.82; 70.93; 96.61; 114.33 (2C); 119.96; 121.92; 129.17;
132.29 (2C); 155.89; 163.25; 171.53.
HRMS. Calculated for C20H26O7S1: 410.1399. Found: 410.1403.
3-(N-Succinimido-p-phenylcarboxylate(tetraethoxy)oxy)-4-meth-
ylthiophene (4). First of all, 1.64 g (4.00 mmol) of compound 3 was
(12) Ba¨uerle, P.; Hiller, M.; Scheib, S.; Sokolowski, M.; Umbach, E. AdV. Mater.
1996, 8, 214.
(13) Korri-Youssoufi, H.; Garnier, F.; Srivastava, P.; Godillot, P.; Yassar, A. J.
Am. Chem. Soc. 1997, 119, 7388.
(10) Levitus, M.; Schmieder, K.; Ricks, H.; Shimizu, K. D.; Bunz, U. H. F.;
Garcia-Garibay, M. A. J. Am. Chem. Soc. 2001, 123, 4259.
(11) Le´vesque, I.; Leclerc, M. Macromolecules 1997, 30, 4347.
(14) Li, G.; Kossmehl, G.; Hunnius, W.; Zhu, H.; Kautek, W.; Plieth, W.;
Melsheimer, J.; Doblhofer, K. Polymer 2000, 41, 423.
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An Approach to Affinitychromic Polythiophenes
A R T I C L E S
Figure 1. 1H NMR spectrum of poly(3-[N-succinimido-p-phenylcarboxylate(tetraethoxy)oxy]-4-methylthiophene) (P1) in CDCl3.
Scheme 1
chemical moiety is also known to react with amines under very
mild conditions to form the corresponding amides in high yields.
Therefore, as anticipated, the electropolymerization of monomer
4 has led to the formation of a thin film of the corresponding
electroactive polymer (P1) on diverse electrodes (ITO, Pt, etc.).
Moreover, this polymer is soluble in CHCl3, THF, and DMSO
and can be (re)cast to yield thin polymer films with good
mechanical properties. The number-average molecular weight
of this polymer is 14 kDa with a polydispersity index of 1.2.
NMR and IR data are in good agreement with its expected
1
structure. In particular, as shown in Figure 1, the H NMR
spectrum of polymer 1 exhibits a well-defined and sharp signal
at 2.3 ppm which is related to the methyl group at the 4-position
and is in agreement with the presence of a regioregular head-
to-tail backbone.15 Moreover, the absence of peaks near 6.2 and
6.8 ppm (characteristic of protons at the 2- and 5-positions,
respectively) indicates a relatively high molecular weight with
a degree of polymerization higher than 20.
The resulting polythiophene derivative is electroactive in a
0.1 M KCl aqueous solution, with an oxidation potential around
+0.7 V versus SCE. As observed with other regioregular poly-
(3-alkoxy-4-methylthiophene)s,6-8,15 polymer 1 is thermochro-
mic (a violet-to-yellow color transition) in the solid state,
exhibiting an absorption maximum at 550 nm (with the presence
of two vibronic bands at 543 and 584 nm) at room temperature,
which shifts to 423 nm at 150 °C. A near-isosbestic point is
observed in these temperature-dependent optical measurements,
which has been explained by the coexistence of only two
conformational structures: one being related to a highly con-
jugated and coplanar conformation of the backbone and the other
one to a twisted, nonplanar conformation of the main chain.
This polymer is also solvatochromic, giving a yellow solution
(15) (a) Daoust, G.; Leclerc, M. Macromolecules 1991, 24, 455. (b) Le´vesque,
I.; Leclerc, M. Chem. Mater. 1996, 8, 2843. (c) Le´vesque, I.; Bazinet, P.;
Roovers, J. Macromolecules 2000, 33, 2952. (d) Brustolin, F.; Goldoni,
F.; Meijer, E. W.; Sommerdijk, N. A. J. M. Macromolecules 2002, 35,
1054.
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A R T I C L E S
Bernier et al.
Figure 2. FTIR spectra of pristine polymer 1 (top) and polymer 3 (after treatment with butylamine for 15 min) (bottom).
Scheme 2
in a good solvent (i.e., chloroform) and leading to a violet
solution upon the addition of a poor solvent (i.e., methanol).
The possibility of postfunctionalization through a reaction
between the NHS group and different amine-bearing molecules
has been verified by electrochemistry and infrared spectroscopy.
As mentioned above, preformed polymer 1 exhibits an oxidation
wave at +0.7 V versus SCE in a 0.1 M KCl aqueous solution.
Upon treatment with a 0.1 M 2-aminoethylferrocenylmethyl
ether12 acetonitrile solution, the cyclic voltammogram of the
resulting polymer (polymer 2, see Scheme 2) exhibits a second
reversible redox wave at +0.35 V versus SCE, characteristic
of the ferrocene unit. Interestingly, polymer 2 and other similar
polymers could be used in different catalytic reactions. IR
analyses have been also carried out to verify the postfunction-
alization of the polymeric precursor. Pristine polymer 1 shows
two strong absorption bands at 1760 and 1734 cm-1 which are
characteristic of the NHS group. Upon treatment with a 0.1 M
solution of butylamine in acetonitrile for 15 min, these infrared
bands disappeared, whereas two new bands appeared at 1632
and 3314 cm-1, characteristic of the newly formed amide bond
in polymer 3 (see Scheme 2 and Figure 2).
Moreover, it is possible to dissolve polymer 1 in chloroform
and to cast (from 100 µL of a 0.01 M polymer solution in
chloroform) a thin film in the bottom of a glass or polymeric
well. Solid-state postfunctionalization of different wells has then
been carried out by using 100 µL of a 0.1 M acetonitrile solution
of butylamine or 2-(aminomethyl)-15-crown-5 (see Scheme 2).
After 15 min, careful washing of the treated surfaces was carried
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An Approach to Affinitychromic Polythiophenes
A R T I C L E S
Figure 3. Visual detection of ionochromic effects with polymer 1, polymer 3, and polymer 4 in the presence of different salts in THF.
Figure 4. UV-visible absorption spectra of polymer 4 (2.5 × 10-3 M) in
different THF solutions.
out with dry acetonitrile. The modified polymeric film is then
dissolved in a given solvent (THF, DMSO, chloroform), and
the affinity of the modified side chains is then evaluated against
different targets. For instance, polymer 4 has been evaluated in
Figure 5. Visual detection of affinitychromic effects with polymer 1,
polymer 3, and polymer 5 in the absence or presence of the protein avidin,
in a DMSO/H2O (3:1) solution.
THF solutions containing different alkali metal salts. Polymer
1 and butylamine-treated, polymer 3 have also been tested for
comparison purposes. As shown in Figures 3 and 4, the yellow
solution of 15-crown-5 modified polymer (polymer 4) exhibits
a maximum of absorption at 435 nm in THF. However, upon
addition of different alkali metal salts (10-6 mol in a 400 µL of
THF solution), the absorption spectra exhibit new absorption
bands at 548 and 589 nm which are the optical signature of a
coplanar and presumably aggregated structure for the polymer.
These results are essentially the same as those observed on
parent polymers directly obtained from the corresponding
monomers:16 the lithium salt showing the weakest effect and
the potassium salt leading to the strongest ionochromic effect.
These different behaviors can be explained by the formation of
a more stable complex between two 15-crown-5 ligands and
one potassium ion,16,17 which forces the aggregation of the
conjugated backbone. Interestingly, polymers 1 and 3 did not
show any ionochromic effect, their respective absorption
maximum being constant at 435 nm in the different THF
solutions.
Furthermore, and following the same procedures of those
previously described, polymer 1 has been treated with 0.01 M
biotin hydrazide (Pierce) dissolved in 0.1 M NaHCO3 aqueous
solution. The resulting and dried polymer 5 has then been
dissolved in 400 µL of a 3:1 (v/v) mixture of DMSO/H2O. This
combination of solvents is a right compromise for the solubi-
lization of both the protein avidin and the polythiophene
derivatives. As reported in Figure 5, polymer 5 solution is pale
pink, whereas polymers 1 and 3 are violet in the same solution.
This indicates a stronger hydrophilic character for polymer 5
which is better solubilized in this highly polar mixture.
Interestingly, in the presence of avidin (Pierce), which is known
to specifically and strongly interact with the biotin moiety,18
the solution of polymer 5 undergoes, within a period of 1 h, a
(16) Boldea, A.; Le´vesque, I.; Leclerc, M. J. Mater. Chem. 1999, 9, 2133.
(17) (a) Flink, S.; Boukamp, B. A.; van den Berg, A.; van Veggel, F. C. J. M.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1998, 120, 4652. (b) Kim, J.; McQuade,
D. T.; McHugh, S. K.; Swager, T. M. Angew. Chem., Int. Ed. 2000, 39,
3868.
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A R T I C L E S
Bernier et al.
Conclusions
significant optical change to a yellow-orange color (presumably
due to a better solubilization in the presence of avidin),19
whereas solutions of polymers 1 and 3 remain violet. It is worth
noting here that an amount of only 2.0 × 10-9 mol of avidin
can strongly modify a solution containing 1.0 × 10-6 mol of
polymer 5 (on a repeat unit basis). These possibilities are directly
related to an amplification factor (ca. 250)6,7,19 which is believed
to be related to the difference in size between the protein avidin
and one repeat thiophene (binding) unit. Following this model,
the interaction of the ligand with a very large target perturbs a
significant number of neighboring thiophene units which
explains this amplification phenomenon.
This novel development of both postfunctionalizable and
affinitychromic poly(3-alkoxy-4-methylthiophene)s has led to
useful colorimetric tools for the rapid and versatile detection
of interactions between various combinations of ligands (co-
valently attached to the polymeric transducer) and targets. The
optical detection is based on a conformational transition of the
conjugated backbone occurring upon the modification of the
side-chain organization. The present results clearly indicate that
this postfunctionalization approach gives essentially the same
results as those reported for the parent polymers obtained from
the direct polymerization of the corresponding monomers.
Moreover, this new methodology may allow the covalent
binding of chemical or biochemical moieties that could not
tolerate the polymerization reactions. Clearly, this new platform,
which combines variable triggers, a transducer, and, sometimes,
an amplifier, should find applications in the areas of diagnostics,
therapeutics, and drug screening.
All of these results point out the high versatility and ease of
this postfunctionalization approach of chromic poly(3-alkoxy-
4-methylthiophene)s. This methodology cannot give an absolute
evaluation of the binding of a given target, and it cannot be
predicted from a new set of host and guest if binding will lead
to aggregation (violet form) or to the formation of well-
dissolved, isolated species (yellow form), but comparisons
within a library of compounds in different solutions can give
very valuable information about interactions among chemical
and biochemical moieties.
Acknowledgment. This work was supported by the Canada
Research Chair program and a grant from FCAR in Combina-
torial Chemistry involving Merck Frosst, Boehringer Ingelheim,
Biochem Pharma, and Astra Zeneca. The authors thank Dr. H.
A. Ho and M. Be´dard for their help in the synthesis of some
organic compounds.
(18) Wilchek, M.; Bayer, E. A. Anal. Biochem. 1988, 171, 1.
(19) Fa¨ıd, K.; Leclerc, M. Chem. Commun. 1996, 2761.
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