title: 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.
authors.affiliation: Louisiana State University , Department of Chemistry, Baton Rouge, LA, USA.
authors.forename: R G Waruna
authors.initials: RG
authors.lastname: Jinadasa
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.forename: M Graça H
authors.initials: MG
authors.lastname: Vicente
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Smith
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002735:Chlorophyllides; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010165:Palladium; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D002735:Chlorophyllides; D056831:Coordination Complexes; D017319:Photosensitizing Agents; D011166:Porphyrins; C062985:phytochlorin; D010165:Palladium