title: Cytotoxicity and cytoprotective activity in naphthalenediols depends on their tendency to form naphthoquinones.
abstract: We consider the cytotoxicity and the protection against oxidative stress for members of the naphthalenediol family and the known antioxidant epigallocatechin gallate (EGCG). Compounds include the 1,2-naphthalenediol (1,2-ND), 1,4-ND, 2,3-ND, 1,8-ND, and 1,4-dipropyl-2,3-naphthalenediol (DPND). The cell line is an adherent clone of rat pheochromocytoma (PC12-AC). Oxidative stress was induced by the peroxyl radical generator AAPH. The relative order of cytotoxicity was 1,4-ND > 1,2-ND > DPND > 2,3-ND > 1,8-ND > EGCG, with EC(50)'s of 15, 40, 160, >250, >250, >>250 muM, respectively. Despite their high toxicity, both 1,4-ND and 1,2-ND showed narrow zones of protective behavior whereas DPND, 2,3-ND and 1,8-ND and especially EGCG showed an extended protective range. The total protection obtained for the combination of cells/oxidative stressor/protective compounds (PC12-AC/AAPH/naphthalenediols) was defined by an integrated measure, the cytoprotective area (CPA). We relate the observed cytotoxicity and CPA to the different electronic structures of the naphthalenediols, characterized by the first and second bond dissociation enthalpies and the pK(a)'s for parent (diol) and semiquinone. Since the 2,3- and 1,8-naphthalenediols do not form quinones, their cytotoxicity is much lower than for the compounds which do. Thus selected members of the naphthalenediol family show promise as antioxidants.
authors.affiliation: Department of Chemistry, Carleton University, 1125 Colonel By Dr., Ottawa, Canada K1S 5B6.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Flueraru
authors.forename: Alexandru
authors.initials: A
authors.lastname: Chichirau
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Chepelev
authors.forename: William G
authors.initials: WG
authors.lastname: Willmore
authors.forename: Tony
authors.initials: T
authors.lastname: Durst
authors.forename: Martin
authors.initials: M
authors.lastname: Charron
authors.forename: L R C
authors.initials: LR
authors.lastname: Barclay
authors.forename: James S
authors.initials: JS
authors.lastname: Wright
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009284:Naphthols / Q000737:chemistry*; D009285:Naphthoquinones / Q000737:chemistry*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011809:Quinones / Q000737:chemistry; D051381:Rats; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: C509559:1,4-dipropyl-2,3-naphthalenediol; D000975:Antioxidants; D005609:Free Radicals; D009284:Naphthols; D009285:Naphthoquinones; D011809:Quinones; D013778:Tetrazolium Salts; D013844:Thiazoles; C042334:1,2-dihydroxy-1,2-dihydronaphthalene; D002392:Catechin; C045651:epigallocatechin gallate; C022616:thiazolyl blue