Syntheses and Cellular Investigations of 173-, 152-, and 131-Amino Acid Derivatives of Chlorin e6

Abstract

A series of amino acid conjugates of chlorin e₆, containing lysine or aspartic acid residues in positions 17³, 15², or 13¹ of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in five steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 15²-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 13¹ regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 17³-substituted chlorin e₆ conjugates are L-shaped, the 15² and 13¹ regioisomers assume extended conformations, and the 13¹ derivatives are nearly linear. It is hypothesized that the 13¹-aspartylchlorin e₆ conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 15² derivative.