Institute for Organic Chemistry, University of Duisburg-Essen, Universitätsstraße 5, D-45117 Essen

Here, we present the conceptual design of artificial receptors 13 bycombining the tweezer 10 with the guanidiniocarbonyl pyrrole 6 viasuitable linkers to bind RGD sequences selectively. Synthesis of firstprototypes and the evaluation of their binding properties are inprogress.By varying the spacer we expect selective recognition of RGDcontaining proteins. Drugs against integrin depended diseases can beconsidered as a potential application.

[1] Kessler H. et al., Angew. Chem., 1997, 109, 1440–1456.[2] Zanardi F. et al., J. Med. Chem., 2008, 51 (6), 1771-1782.[3] Klärner F. et al., J. Am. Chem. Soc., 2005, 127, 14415–14421.[4] Schmuck C. et al., Synthesis, 2006, 1, 89–96.

HO O

NH2

m

n

O

O

HN

O

CO2Me

HN

O

NH2

H2N

O

13

NH

O3P

2

m

n

Different receptors 13 will beobtained by varying thelinker.In future research bindingstudies with different RGD-containing substrates will becarried out with the obtainedreceptors.

Receptor for the negativelycharged aspartate residue (D) ofthe RGD-sequence.4

A versatile receptor for arginine(R).3

Scheme 1. Guanidiniocarbonylpyrrole cation. Scheme 2. Molecular tweezer.

The scope of our research is theconnection of the binding motifs(Scheme 1-2) by a suitable linker.

Molecular modelling (Fig. 4)* hasshown that sterically unhinderedbut rigid spacers should be used.

Aromatic linkers are potentialcandidates. As can be seen fromFigures 3 and 4 the ditopic binding

motif provides a binding pocket forglycoproteins with a solventexposed RDG-sequence.

A variety of receptors can besynthesized via coupling reactionsbetween the linker molecules.

* Monte Carlo conformational search,Macro-Model Ver. 8.0, force field Amber*,GB/SA water solvation.

New Approach to Artificial Receptors as Mimics for Integrin-Receptors

n = 1-2, m = 0-1

Integrins play a pivotal role in cell processes such as cell-adhesion,cell-differentiation, and cell-signaling and play a crucial effect indiseases like acute renal failure, osteoporosis, apoplectic stroke,and human tumor metastasis.1

Fig. 3. Binding pocket with the substrate

Fig. 4Fig. 2

RGD-containing substrate

Fig. 1. RGD-sequence.

Artificial receptor

LinkerThe interior cleft of theintegrin vitronectin (Fig. 2)shows binding constants tothe Arginine-Glycine-Aspar-tate (RGD) sequence in ananomolar range (Fig. 1).2

Inhibition of signal transduction

by

Johannes Hofmann and Carsten Schmuck

capturing the RGD-containing trans-mitter with an arti-ficial receptor.

R = alkyl