title: Synthesis and evaluation of dithiolethiones as novel cyclooxygenase inhibitors.
abstract: 3H-1,2-Dithiole-3-thiones substituted with a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) or a 3,5-di-tert-butyl-4-methoxyphenyl group at the C5 position were prepared and their ability to inhibit the cyclooxygenase isoenzymes, COX-1 and COX-2 was evaluated. Both compounds were potent inhibitors of COX-2 (relative to rofecoxib), and while the phenol was a weak inhibitor of COX-1, the methyl ether gave no measurable inhibition. Docking studies of the two compounds into the COX-1 and -2 active sites showed that the methyl ether could only fit in the COX-2 active site whereas the phenol could be docked into both COX-1 and -2. This study reports a new mode for inhibitor binding to COX-1 and -2 and a novel structural scaffold for the development of COX-2 selective inhibitors.
authors.affiliation: Howard Florey Institute, Parkville, Vic. 3010, Australia.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Zanatta
authors.forename: David T
authors.initials: DT
authors.lastname: Manallack
authors.forename: Bevyn
authors.initials: B
authors.lastname: Jarrott
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D013871:Thiones; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2