Accessing New Phenanthroline-Oxazine Scaffolds as Copper-Dependent DNA Damaging Probes.

1,10-Phenanthroline (phen) is a versatile ligand commonly used in coordination chemistry, with particular interest in its ability to promote DNA binding and damage when coordinated with transition metals. Structural modifications of phen modulate the recognition and reactivity of the associated complexes at the nucleic acid interface. A promising new modification of phen stems from the incorporation of amino acid derivatives at the 5- and 6-positions leading to phenanthroline-oxazine scaffolds, which improve the pharmacokinetic and pharmacodynamic properties of resultant complexes. However, a limited number of phenanthroline-oxazine (PO) scaffolds have been reported and accessing new natural amino acid derivatives has, thus far, been synthetically intractable. Herein, we advance the synthetic conditions required for accessing new POs. We identified the type of amino acid substrate coupled with solvent selection and reaction temperature were the main influencing parameters for accessing new PO scaffolds. In total, eleven new PO ligands were successfully synthesized, purified, and characterized. The new scaffolds were then examined for their Cu-dependent DNA binding and damaging profiles and we correlate structure-activity relationships to specific PO modifications.