ISMSC 2007 - Università degli Studi di Pavia

Catalyst discovery using dynamic combinatorial chemistry
Leonard J. Prins, Giulio Gasparini, Paolo Scrimin
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy
Dynamic combinatorial chemistry (DCC) relies on the generation of dynamic libraries of
molecular structures held together either by non-covalent interactions or reversible covalent
bonds.[1] Consequently, the libraries are at thermodynamic equilibrium and the addition of a
target to the library results in a spontaneous shift in the library composition favouring the library
member with the highest affinity for the target. In the last years, dynamic combinatorial
chemistry has been successfully applied for the identification of receptors for metal ions, small
organic molecules and biomolecules. Catalyst discovery using DCC remains a largely
unexplored area; the few catalysts which have been isolated, generally gave very modest rate
accelerations.[2] Here, we show that an approach called ‘tethering’ is a powerful strategy for
catalyst discovery using DCC.
The tethering strategy is based on the covalent coupling of the target to a molecular scaffold.
Library components that interact with the target are captured via the ‘pseudo’-intramolecular
formation of a reversible covalent bond. This approach has been very successfully applied for
the discovery of substrates for a series of proteins.[3] We have applied this approach for the
selection of molecules able to bind to a phosphonate (as a model of the transition state of a
carboxylate ester hydrolysis). An initial analysis of a simple model system has revealed that the
success of applying the tethering strategy strongly depends on the experimental conditions.[4]
The boundary conditions and the ‘best’ method to perform the library screening will be
discussed. Next, the correlation between the observed amplification in the dynamic library and
the catalytic activity will be presented.
N
N
H
O O
P
O
TBA
1A
N
N
H
O O
P
O
TBA
1B
O
O
N
Cl
+
+
H 2N
N
H
O
H 2N
N
H
B
O
A
N
Cl
amplification
80
70
60
amplification
50
0 10 20 30 40 50
concentration
NO amplification
OP 7
[1] P.T. Corbett, J. Leclaire, L. Vial, K.R. West, J.-L. Wietor, J.K.M. Sanders, S. Otto, Chem.
Rev., 2006, 106, 3652-3711.
[2] B. Brisig, J.K.M. Sanders, S. Otto, Angew.Chem.Int.Ed. 2003, 42, 1270-1273.
[3] D.A. Erlanson, A.C. Braisted, D.R. Raphael, M. Randal, R.M. Stroud, E.M. Gordon, J.A.
Wells, Proc. Natl. Acad. Sc. (USA) 2000, 97, 9367-9372.
[4] G. Gasparini, M. Martin, L.J. Prins, P. Scrimin, Chem. Comm. 2007, DOI: 10.1039/
b617450g.
Structure-Activity Studies on Oligoester Ion Channels
Thomas M. Fyles, Horace Luong
Department of Chemistry, University of Victoria, Victoria, BC V8W 3V6, Canada
One of the many motivations for synthesizing ion channels is that it is difficult to study
structure-function relationships in the large and complex proteins that make up natural ion
channels. In a synthetic channel that can mimic the functions of a natural ion channel such
structure-function studies can (in principle) be simplified. Structure-function optimization of ionic
conductance also holds the potential use for applications in nanodevices such as sensors,
separations and signal propagation. 1
We have recently reported that active oligoester ion channels can be synthesized by a
relatively concise and efficient solid-phase method. 2 This method provides simple access to an
array of oligoester compounds from a set of -hydroxyacids (general structure below).
Recently we have incorporated -aminoacids to produce oligoester-amide channels. As with
other reported channel-forming systems, we can produce series of compounds that vary in total
length and/or lipophilicity. Our method also allows us to prepare constitutional isomers in which
length and lipophilicity are held constant, but the distribution of sites for interaction with lipids,
ions, and water can be varied systematically. Some examples are shown below:
An =
HO2C A1 X1 A2 X2 A3 X3 A4 Y
O
OR
R
The transport activities of the synthesized compounds incorporated into vesicles were
monitored using a pH-triggered fluorescent dye assay. Our results clarify the roles of the
various lipophilic groups, the overall length of the main strand, and the number and locations of
the central ester carbonyls. Overall amphiphilic characteristics are also significant as indicated
by the substantial activity differences between the constitutional isomers 1 and 2.
[1] Fyles, T.M. Chem. Soc. Rev. 2007, 36, 335-347.
[2] Fyles, T.M.; Hu, C.W.; Luong, H. J. Org. Chem. 2006, 71, 8545-8551.
CH 2
n
R
X n =
O
N
H
C 12H 25O
O
O Y =
HO2C CH2 7 O
O
CH2 11 O
O
O
O
CH2 O
7
OH
OC12H25 O
HO2C O
CH2 7 O
O
CH2 11 O
1
O
CH2 7
OH
2
O
OH
O
H
OP 8