Syntheses and cellular investigations of 17 3-, 15 2-, and 13 1-amino acid derivatives of chlorin e 6
Abstract
A series of amino acid conjugates of chlorin e 6, containing lysine or aspartic acid residues in positions 17 3, 15 2, or 13 1 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 15 2-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 13 1 regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 17 3-substituted chlorin e 6 conjugates are L-shaped, the 15 2 and 13 1 regioisomers assume extended conformations, and the 13 1 derivatives are nearly linear. It is hypothesized that the 13 1-aspartylchlorin e 6 conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 15 2 derivative. © 2011 American Chemical Society.