ISMSC 2007 - Università degli Studi di Pavia

Supramolecular control of a metal center embedded in a biomimetic
hydrophobic cavity: the Funnel Complexes.
Olivia Reinaud
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601,
Université René Descartes, 45 rue des Saints-Pères, F-75270 Paris Cedex 06, France
E-mail: Olivia.Reinaud@univ-paris5.fr
Modeling the active site of an enzyme is an important tool for a better understanding of its
catalytic cycle. Classically however, biomimetic inorganic chemistry is mainly focused on
reproducing the first coordination sphere of the metal ion and little information is available
concerning the influence, or even the control, that the microenvironment provided by a protein
can have on the reactivity of the metal.
The aim of our work is to design supramolecular systems that will mimic both the coordination
core and the hydrophobic pocket of a metallo-enzyme active site. Our strategy is to synthesize
calix[6]arene-based ligands that allow the control of the coordination sphere of the metal ion
together with the approach and the binding of an external molecule.
Three generations have been yet developed: the first 1 offers three nitrogenous arms, the
second 2 has a fourth hemi-labile binding site X, the third 3 presents a capped calixarene
exemplified by the calix-tren ligand that allows a better control of the geometry of the
supramolecular edifices. Characterization and comparative behavior of the corresponding zinc
and copper complexes will be presented.
His His His
M
L
S
N
N
M
L
N
n+
X n+
N N
N M
L
I II III
Enzyme active site Calix-models
X n+
N
N M
N
[1]. S. Blanchard, L. Le Clainche, M.-N. Rager, B. Chansou, J. P. Tuchagues, A. Duprat, Y. Le Mest, O.
Reinaud, Angew. Chem., Int. Ed., 1998, 37, 2732; O. Sénèque, M.-N. Rager, M. Giorgi, O. Reinaud, J.
Am. Chem. Soc., 2000, 122, 6183; O. Sénèque, M. Giorgi, O. Reinaud Supramol. Chem. 2003, 15, 573;
U. Darbost, O. Sénèque, Y. Li, G. Bertho, J. Marrot, M.-N. Rager, O. Reinaud, Ivan Jabin, Chem. Eur. J.
2007, 13, 2078. D. Coquière, J. Marrot and O. Reinaud, Chem. Commun. 2006, 3924.
[2]. O. Sénèque, M. Campion, B. Douziech, M. Giorgi, Y. Le Mest, O. Reinaud, Dalton Trans. 2003,
4216; O. Sénèque, M.-N. Rager, M. Giorgi, T. Prangé, A. Tomas, O. Reinaud. J. Am. Chem. Soc. 2005,
127, 14833.
[3]. U. Darbost, M.-N. Rager, S. Petit, I. Jabin, O. Reinaud, J. Am. Chem. Soc. 2005, 127, 8517; G.
Izzet, B. Douziech, T. Prangé, A. Tomas, I. Jabin, Y. Le Mest, O. Reinaud, Proc. Natl. Acad. Sci. USA,
2005, 102, 6831; X. Zeng, D. Coquière, A. Alenda, E. Garrier, T. Prangé, Y. Li, O. Reinaud, I. Jabin,
Chem. Eur. J. 2006, 12, 6393. G. Izzet, X. Zeng, H. Akdas, J. Marrot and O. Reinaud, Chem Commun.
2007, 810. G. Izzet, X. Zeng, D. Over, B. Douziech, J. Zeitouny, M. Giorgi, I. Jabin, Y. Le Mest, O.
Reinaud, Inorg. Chem. 2007, 46, 375. G. Izzet, M.-N. Rager, O. Reinaud, Dalton Trans. 2007, 771.
L
IL 11
Why are Certain Cyclopeptides so Efficient Anion Hosts?
Stefan Kubik
Fachbereich Chemie - Organische Chemie, Technische Universität Kaiserslautern,
Erwin-Schrödinger-Strasse, D-67663 Kaiserslautern, Germany
We recently demonstrated that cyclic hexapeptide 1 containing L-proline and 6-aminopicolinic
acid subunits strongly binds to sulfate or halides even in competitive protic solvents such as
80% water/methanol.[1] The main reason for this, for a neutral host, unusual property turned out
to be the sandwich-type structure of the complexes formed in which the anion is included into a
cavity between two interdigitating cyclopeptide moieties.
O
HN
N
N
O
O
N
N
NH
NH
O
O
N
N
O
O
N
O
N
HN
HN
O
N
N
O
N
O
N
O
NH
H
N
X
O O
1 2
H
N
O
HN
N
N
O
O
N
N
NH
NH
O
O
N
IL 12
The 2:1 anion complexes of 1 were subsequently converted into 1:1 complexes by covalently
linking two cyclopeptide rings together. Biscyclopeptides of the general structure 2 have thus
been obtained that are highly efficient neutral hosts for inorganic anions in aqueous media.[2]
Anion affinity as well as selectivity of these biscyclopeptides depend on the structure of the
linker X which was optimized using molecular modeling in collaboration with Benjamin P. Hay
(Pacific Northwest National Laboratory, Richland, USA) and dynamic combinatorial chemistry in
collaboration with Sijbren Otto (University of Cambridge, UK).[3]
Although the anion affinity of such biscyclopeptides is partly a result of the almost perfect
preorganisation of the two cyclopeptide rings for anion binding as well as the fact that the anion
is shielded in the complex from the surrounding solvent molecules, it seemed unlikely that
stability constants of the sulfate complexes of some of these biscyclopeptide of 10 6 - 10 7 M -1 in
33% water/acetonitrile or 50% water/methanol can be rationalized on the basis of these effects
alone. Indeed, a detailed structural analysis of the biscyclopeptide/anion complexes as well as
of the solvent dependence of complex stability revealed that intra-receptor interactions between
biscyclopeptide regions that are not directly involved in anion binding is an important factor
contributing to complex stability.[4] Engineering such intra-receptor interactions into synthetic
hosts therefore seems to be an attractive and powerful strategy to boost host-guest affinities.
[1] S. Kubik, R. Goddard, R. Kirchner, D. Nolting and J. Seidel, Angew. Chem. Int. Ed. 2001, 40,
2648-2651.
[2] S. Kubik, R. Kirchner, D. Nolting and J. Seidel, J. Am. Chem. Soc. 2002, 124, 12752-12760.
[3] S. Otto and S. Kubik, J. Am. Chem. Soc. 2003, 125, 7804-7805.
[4] Z. Rodriguez-Docampo, S. I. Pascu, S. Kubik and S. Otto, J. Am. Chem. Soc. 2006, 128,
11206-11210.
N
O