Multifunctional Cyclam Derivatives with Carbohydrates and Peptides

Multifunctional chelating systems with linked biomolecules provide the possibility to develop novel diagnostic and therapeutic agents with enhanced stability and improved bio-availability. In this perspective, cyclam derivatives 1 are attractive candidates for developing new metalloradiopharmaceuticals. Biomolecules like sugars and peptides direct the solubility behavior and the targeting efficiency.

Michael addition on cyclam with methyl acrylate and subsequent aminolysis with ethylene diamine delivered the tetraamino product 2.¹ Ligands with four sugar units 3 were obtained by thiourea-bridging of sugar isothiocyanates with 2.² Peptide coupling led to conjugates 4 with the hexapeptide neurotensin(8-13) which is interesting for the targeting of ductal pancreatic carcinomas.

Isothermal titration calorimetry (ITC) was used in order to characterize the interaction between glycoclusters 3 and the lectin Concanavalin A. In vitro binding studies between ligand 4 and the neurotensin receptor 1 (NTR1) were performed using the human colon adenocarcinoma cell line HT-29.

The glycoclusters 3 showed a distinct glycoside clustering effect which can be explained by an entropy advantage for the tetramer compared to the sugar monomer. Thiourea-containing compounds 3 form very stable Cu(II) complexes with slow kinetics.³ On the other hand, a rapid attainment of Cu(II) complexation equilibria was observed in the case of the peptide conjugate 4.

Multifunctional sugar and peptide conjugates of branched cyclam derivatives possess interesting complexation and targeting properties. Peripheral modifications provide the opportunity of tailoring the bio-distribution.

1. Stephan, H.; Geipel, G.; Appelhans, D.; Bernhard, G.; Tabuani, D.; Komber, H.; Voit, B. Tetrahedron Lett. 2005, 46, 3209.
2. Stephan, H.; Röhrich, A.; Noll, S.; Steinbach, J.; Kirchner, R.; Seidel, J. Tetrahedron Lett. 2007, 48, 8834.
3. Röhrich, A.; Noll, S.; Stephan, H.; Steinbach, J.; Bergamini, G.; Balzani, V. in „Technetium, Rhenium and other Metals in Chemistry and Nuclear Medicine“ U. Mazzi (Ed.), SGE Editoriali, Padova, Italy, 2006, 7, 233.