title: Salen-manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents: structure-activity relationship studies.
abstract: Synthetic catalytic scavengers of reactive oxygen species (ROS) may have broad clinical applicability. In previous papers, two salen-manganese complexes, EUK-8 and EUK-134, had superoxide dismutase (SOD) and catalase activities and prevented ROS-associated tissue injury. This study describes two series of salen-manganese complexes, comparing catalytic ROS scavenging properties and cytoprotective activities. The compounds vary widely in ability to scavenge hydrogen peroxide, with this activity most influenced by salen ring alkoxy substitution and aromatic bridge modifications. In contrast, all compounds show comparable SOD activities. The most active alkoxy-substituted catalase mimetics protected cultured cells from hydrogen peroxide, and a subset of these were also neuroprotective in a rodent stroke model. Thus, structural modification of the prototype EUK-8 yields compounds with enhanced catalase activity and, in turn, biological effectiveness. This supports the concept that salen-manganese complexes represent a class of SOD and, in particular, catalase mimetics potentially useful against ROS-associated diseases.
authors.affiliation: Eukarion, Inc., 6F Alfred Circle, Bedford, Massachusetts 01730, USA. s.doctrow@eukarion.com
authors.forename: Susan R
authors.initials: SR
authors.lastname: Doctrow
authors.forename: Karl
authors.initials: K
authors.lastname: Huffman
authors.forename: Catherine Bucay
authors.initials: CB
authors.lastname: Marcus
authors.forename: Georges
authors.initials: G
authors.lastname: Tocco
authors.forename: Evelyne
authors.initials: E
authors.lastname: Malfroy
authors.forename: Christy A
authors.initials: CA
authors.lastname: Adinolfi
authors.forename: Henry
authors.initials: H
authors.lastname: Kruk
authors.forename: Keith
authors.initials: K
authors.lastname: Baker
authors.forename: Natalie
authors.initials: N
authors.lastname: Lazarowych
authors.forename: Julius
authors.initials: J
authors.lastname: Mascarenhas
authors.forename: Bernard
authors.initials: B
authors.lastname: Malfroy
mesh_terms: D000818:Animals; D002374:Catalase / Q000737:chemistry; D002460:Cell Line; D019610:Cytoprotection; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D017895:Manganese Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry
chemical_list: D005029:Ethylenediamines; D016166:Free Radical Scavengers; D017895:Manganese Compounds; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase