Urea derivatives of 1,4,7,10-tetraazacyclododecane - Synthesis and bindingproperties

The reaction between 1,4,7,10-tetraazacyclododecane (cyclen) and partially protected derivatives and isocyanates gives macrocyclic ureas in good yield s. Bridged biscyclens with aliphatic or aromatic spacers were obtained from the reaction between diisocyanates and partially protected cyclen. The sub stituted cyclen derivatives with one or two urea moieties coordinate zinc(I I) and copper(II) ions to form stable rnononuclear and dinuclear complexes. Potentiometric titration revealed that the urea substitution significantly changes the basicity of the remaining secondary amino groups of the macroc ycle. In comparison with that of cyclen (1), which has two basic amino grou ps, the basicity of one amino group in 1,4,7,10-tetraazacyclododecane-1-car boxylic acid butylamide (6b) is reduced by 5 orders of magnitude. The bindi ng affinity of cyclen (1), urea derivatives of cyclen, and metal complexes to double stranded DNA was measured under physiological conditions, using a n ethidium bromide displacement assay. The binding affinities correlate wit h the positive charge of the protonated cyclic amines. Their metal complexe s show even higher affinities, which presumably result from different bindi ng motifs.