title: Structure-activity relationship of new octaethylporphyrin-based benzochlorins as photosensitizers for photodynamic therapy.
abstract: An in vitro and in vivo structure-activity relationship study was carried out on a series of benzochlorins with variable lipophilicity. The structural features evaluated in this study include the length of the alkyl or fluoroalkyl groups attached to the six-member exocyclic ring either by an ether or by a carbon-carbon bond. In preliminary in vitro (radiation-induced fibrosarcoma [RIF] cells) and in vivo screening (C3H mice, bearing RIF tumors), all Zn (II) benzochlorins were found to be effective. However, benzochlorins bearing alkyl groups with carbon-carbon bonds showed enhanced efficacy compared with the related alkyl ether analogs. A comparative intracellular localization study of the newly synthesized benzochlorins with Rhodamine-123 indicated that the effective photosensitizers localize in mitochondria, and a displacement study with PK11195 showed their partial affinity for the peripheral benzodiazepine receptor (PBR). Interestingly, compared with the Zn(II) benzochlorin that was found to be quite effective in vivo, the corresponding free-base analog produced less photosensitizing activity and was found to localize in lysosomes. A comparative study with dansyl-proline confirmed the binding of the effective benzochlorins to Site II of human serum albumin (HSA). However, no direct correlation was observed between the binding constant values (to HSA or to PBR) of benzochlorins and their photosensitizing ability.
authors.affiliation: Department of Dermatology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Graham
authors.forename: Guolin
authors.initials: G
authors.lastname: Li
authors.forename: Yihui
authors.initials: Y
authors.lastname: Chen
authors.forename: Janet
authors.initials: J
authors.lastname: Morgan
authors.forename: Allan
authors.initials: A
authors.lastname: Oseroff
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dougherty
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Pandey
mesh_terms: D000818:Animals; D005354:Fibrosarcoma / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000628:therapy; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000627:therapeutic use; D011166:Porphyrins / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins