title: Synthesis, absolute configuration, and bacterial mutagenicity of the 8 stereoisomeric vicinal diol epoxides at the terminal benzo ring of carcinogenic dibenz[a,h]anthracene.
abstract: The synthesis of the 8 possible stereoisomeric diol epoxides (DEs) at the terminal benzo ring of carcinogenic dibenz[a,h]anthracene (DBA) is reported. trans-3,4-Dihydroxy-3,4-dihydro-DBA (1) afforded the 4 bay region DEs: the enantiomeric pairs of the anti diastereomers (+)-3/(-)-3 and of the syn diastereomers (-)-4/(+)-4, respectively. trans-1,2-Dihydroxy-1,2-dihydro-DBA (2) served as precursor of the 4 reverse DEs: the enantiomeric pairs of the anti diastereomers (+)-5/(-)-5 and of the syn diastereomers (-)-6/(+)-6, respectively. The transformation of the olefinic double bond in the enantiomeric trans-dihydrodiols to epoxides was achieved by either (i) oxidation with m-chloroperoxybenzoic acid or (ii) formation of a bromohydrin with N-bromoacetamide/H(2)O followed by dehydrobromination with an anion exchange resin. Because of the pseudodiequatorial conformation of the hydroxyl groups in 1, both reactions proceeded highly stereoselectively, while the stereoselectivity was impaired by the pseudodiaxial conformation of the hydroxyl groups in 2. Diastereomers and racemic compounds were efficiently separated without derivatization by HPLC on achiral or chiral stationary phases, respectively. The absolute configurations of the DEs were deduced from the absolute configuration of 1 and 2 considering the regio- and stereoselectivity of the subsequent reactions and resulted in (+)-(1R,2S,3S,4R)-3/(-)-(1S,2R,3R,4S)-3, (-)-(1S,2R,3S,4R)-4/(+)-(1R,2S,3R,4S)-4, (+)-(1R,2S,3S,4R)-5/(-)-(1S,2R,3R,4S)-5, and (-)-(1R,2S,3R,4S)-6/(+)-(1S,2R,3S,4R)-6. The bacterial mutagenicity of the 8 stereoisomeric DEs was determined in histidine-dependent strains TA98 and TA100 of Salmonella typhimurium in the absence of a metabolizing system. In general, the bay region DEs of DBA were stronger mutagens than the reverse DEs. In strain TA98, the syn diastereomers of bay region DEs were stronger mutagens than their anti isomers, while in the case of reverse DEs the anti diastereomers were more potent than their syn isomers. In strain TA100, all syn diastereomers surpassed the bacterial mutagenicity of their anti isomers. Concerning the bay region DEs of DBA, this corresponds to the situation described for benzo[a]pyrene: of the 4 enantiomeric bay region DEs of DBA and benzo[a]pyrene, the syn diastereomer with [(R,S)-diol (R,S)-epoxide] absolute configuration is the most potent mutagen in both bacterial strains, while the anti isomer with [(S,R)-diol (R,S)-epoxide] configuration is the weakest mutagen.
authors.affiliation: Institute of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Frank
authors.forename: Mario
authors.initials: M
authors.lastname: Funk
authors.forename: Franz
authors.initials: F
authors.lastname: Oesch
authors.forename: Karl L
authors.initials: KL
authors.lastname: Platt
mesh_terms: D001551:Benz(a)Anthracenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002273:Carcinogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004852:Epoxy Compounds / Q000737:chemistry* / Q000633:toxicity*; D008968:Molecular Conformation; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D012486:Salmonella typhimurium / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D001551:Benz(a)Anthracenes; D002273:Carcinogens; D004852:Epoxy Compounds; C026486:1,2,5,6-dibenzanthracene