CuII Coordination Chemistry of Patellamide Derivatives: Possible Biological Functions of Cyclic Pseudopeptides

Two synthetic derivatives of the naturally occurring cyclic pseudooctapeptides patellamide AF and ascidiacyclamide, that is, H4pat2, H4pat3, as well as their CuII complexes are described. These cyclic peptide derivatives differ from the naturally occurring macrocycles by the variation of the incorporated heterocyclic donor groups and the configuration of the amino acids connecting the heterocycles. The exchange of the oxazoline and thiazole groups by dimethylimidazoles or methyloxazoles leads to more rigid macrocycles, and the changes in the configuration of the side chains leads to significant differences in the folding of the cyclic peptides. These variations allow a detailed study of the various possible structural changes on the chemistry of the CuII complexes formed. The coordination of CuII with these macrocyclic species was monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric (UV/Vis) and circular dichroic (CD) titrations, and electron paramagnetic resonance (EPR) spectroscopy. Density functional theory (DFT) calculations and molecular mechanics (MM) simulations have been used to model the structures of the CuII complexes and provide a detailed understanding of their geometric preferences and conformational flexibility. This is related to the CuII coordination chemistry and the reactivity of the dinuclear CuII complexes towards CO2 fixation. The variation observed between the natural and various synthetic peptide systems enables conclusions about structurereactivity correlations, and our results also provide information on why nature might have chosen oxazolines and thiazoles as incorporated heterocycles.