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-e₆ 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 13¹ (formic), 15² (acetic), and 17³ (propionic) of chlorin e₆ (14). Cellular investigations of several amino acid conjugates of chlorin-e₆ revealed that the 13¹-aspartylchlorin-e₆ derivative is more phototoxic than its 15²- and 17³-regioisomers, in part due to its nearly linear molecular conformation.