Mono- and dinuclear copper(II) complexes of pendant-arm macrocyclic polyamines: Synthesis, characterization and investigation as hydrolytic cleavage agents for DNA

Based on the 10-methyl-1,4,8,12-tetraazacyclopentadecane-10-amine (1) parent, macrocycles 10-benzylamine-10-methyl-1,4,8,12-tetraazacyclopentadecane (2), 10-(2'-pyridinylmethanamino) -10-methyl-1,4,8,1 2-tetraazacyclopentadecane (3) and 5-(hydroxymethyl)-5'-(10 ''-methyl-1 '',4 '',8 '',12 ''-tetraazacyclopentadecane-10 ''-amino)-(2,2'-dipyridine) (4), as well as the p-xylene-linked dinucleating macrocycle 1,4-bis( 10'-methyl-1',4',8',12'-tetraazacyclopentacecane-10'-aminomethyl)benzene (5) and its o-xylene analogue (6), have been synthesized as free ligands and or copper(II) complexes and characterized spectroscopically. Cyclic voltammetry of the Cu(II) complexes of 2 - 6 are also reported, with involvement of the pendant groups in complexation influencing voltammetric behaviour. Potentionnetric titrations of 1, 2, 5 and 6 and their Cu(II) complexes yielded pK(a) values. Both dimers 5 and 6, as well as their mononuclear close analogues 1 and 2, have proven to be inefficient as hydrolytic cleavage agents for DNA, as was also the case for mononuclear Cu(II) complexes of N-4-macrocycles with a range of N-pendant groups based on the 3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene framework (7). Mononuclear triazamacrocyclic Cu(II) complexes show greater activity. Of other dinuclear systems examined, dicopper(II) complexes of the relatively rigid compartment ligands 3,13-dimethyl-3,13-dinitro-1,5,11,15-tetraazacycloeicosane-8,18-diol and -dithiol are also inactive. Whereas the 1:1 Cu(II):L complexes of cyclam and its N,N',N '',N '''-tetrakis(methylbenzyl) substituted analogue are inactive, the tetrakis(2-methylpyridine)-substituted analogue as a 2:1 Cu(II):L species mu-hydroxy {tetrakis(2'-methylpyridine)-1,4,8,11-tetraazacyclotetradecane} dicopper(II) is very efficient as a cleavage agent for plasmid DNA, with both single and double strand cleavage steps observed with rate constants (at pH 7.6, 37 degrees C, 0.8 mM complex, 0.12 mg/mL plasmid) of 1.2x10(-4) and 3.5x10(-6) s(-1) respectively. This is attributed to the capacity for concerted binding to the phosphodiester unit and nucleophilic attack by the coordinated hydroxide molecule that is activated by bridging between the two metal centres.