4th EucheMs chemistry congress

Poster Session 1
s1068
chem. Listy 106, s587–s1425 (2012)
Poster session 1 - organic chemistry
P - 0 4 1 3
SyntheSiS And inveStiGAtionS of MuLtiPLe
hydroGen Bonded SuPrAMoLeCuLAr hoSt –
GueSt CoMPLexeS
P. otte 1 , u. LüninG 1
1 Otto-Diels-Institut, Organische Chemie, Kiel, Germany
In supramolecular chemistry, molecular recognition via noncovalent
binding sites such as hydrogen bonds is common. It is
necessary to have complementary hydrogen bond acceptor (A)
and hydrogen donor (d) patterns. A single hydrogen bond is
relatively weak, but the combination of multiple hydrogen bonds
can lead to stable host - guest complexes. [1]
Due to the existence of attractive and repulsive secondary
hydrogen bonds, binding patterns with as many attractive
secondary hydrogen bonds as possible are the target. An example
with a DDDD-AAAA pattern shows an association constant of
105-106M-1 . [2]
It is reasonable to synthesize molecules whose preferred
conformation is the one which can form the highest number of
hydrogen bonds. If an intramolecular bond has to be broken to get
the needed binding pattern, a loss of energy at the expense of the
complex stability would be the consequence. [3] Therefore, the aim
should be to stabilize the preferred conformation by using, for
example, intramolecular hydrogen bonds. [4]
Due to the orthogonality of the binding sites, highly specific
dendrimeric systems could be generated. [5]
references:
1. J. Taubitz, U. Lüning, Eur. J. Org. Chem. 2008,
5922–5927.
2. B. A. Blight, C. A. Hunter, D.A.Leigh, H. McNab,
P. I. T. Thomson, Nature Chemistry, 2011, 3, 244–248.
3. S. Brammer, U. Lüning, C. Kühl, Eur. J. Org. Chem. 2002,
4054–4062.
4. E.W. Meijer et al. Science 1997, 278, 1601–1604.
5. J. Eckelmann, C. Dethlefs, S. Brammer, A. Dogan,
A. Uphoff, U. Lüning, Chem. Eur. J. 2012, DOI:
10.1002/chem.201200181
Keywords: Hydrogen bonds; Host-guest systems; Molecular
recognition; Supramolecular chemistry;
4 th EucheMs chemistry congress
P - 0 4 1 4
in Situ CLiCK CheMiStry for huMAn
ACetyLChoLineSterASe inhiBitorS
diSCovery
e. oueiS 1 , C. ronCo 1 , G. rASteLLi 2 , A. roMieu 1 ,
v. toGnetti 3 , L. JouBert 3 , f. nAChon 2 , L. JeAn 1 ,
C. SABot 1 , P. y. renArd 1
1 Université de Rouen UMR 6014 CNRS COBRA, Equipe de
Chimie Bioorgnanique, Mont-Saint-Aignan, France
2 Institut de Recherche Biomédicale des Armées, Cellule
Enzymologie Département de Toxicologie, La tronche, France
3 Université de Rouen UMR 6014 CNRS COBRA, Equipe
analyse et modélisation, Mont-Saint-Aignan, France
In situ click chemistry is a new approach (K.B. sharpless
and coll. Angew. Chem. Int. Ed. 2002, 41, 1053-1057) to lead
discovery applied to target guided synthesis (TGS) that allows a
biological target to assemble its own inhibitors. Indeed, in the
presence of the targeted multisite enzyme and a series of building
blocks bearing complementary reactive functions, ligands with
the best affinities would react to form an irreversible bond. The
enzyme serves as a template for the reaction.
Being implicated in the pathogenesis of the Alzheimer’s
disease, recombinant human (rh) strain of Acetylcholinesterase
(AChE) is our enzyme of choice for the application of this
concept. New Huprine (Hup) derivatives were found to be very
potent AChE inhibitors, presenting IC values in the
50
subnanomolar range (P.Y. Renard and coll. ChemMedChem, 2011,
8, 876-888). These acylation site inhibitors were tested for in situ
click chemistry with known peripheral site ligands
(tetrahydroisoquinoline, PIQ) in the presence of rh and mouse
AChE. The in situ Huisgen reaction was successful, allowing the
formation of two new potent heterodimeric inhibitors using for
the first time human AChE. In addition, the click reaction
occurred unprecedentedly in the gorge of the enzyme far from the
acylation active site inducing different regioselectivities than
those already described in the literature.
Furthermore, new click reactions are being explored such
as the hetero Diels Alder reaction. Polysubstituted
3-hydroxypyridines scaffolds are obtained from the corresponding
5-alkoxyoxazoles and dienophiles. The reaction needs activation
(thermal or catalytic) to form an irreversible bond, what makes it
a very interesting target for in situ click chemistry since it should
not proceed without the enzyme. Huprine derivatives bearing
a terminal electron-poor olefin and PIQ derivatives a
5-alkoxyoxazole ring are being investigated for the in situ click
chemistry approach with AChE as the target.
Keywords: click chemistry; host-guest systems; inhibitors;
enzymes; regioselectivity;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc