Amino Acid Derivatives of Chlorin-e₆-A Review

Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 (15) are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e(6) aspartic acid conjugate as (13), NMR and other synthetic procedures described herein arrived at the correct structure (15), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e6 chemistry (including the intramolecular formation of an anhydride (24)) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 13 (formic), 15(2) (acetic), and 17(3) (propionic) of chlorin e(6) (14). Cellular investigations of several amino acid conjugates of chlorin-e(6) revealed that the 13(1)-aspartylchlorin-e(6) derivative is more phototoxic than its 15(2)- and 17(3)-regioisomers, in part due to its nearly linear molecular conformation.