title: Spiro[fluoreneisothiazolidin]one dioxides: new aldose reductase and L-hexonate dehydrogenase inhibitors.
abstract: The first examples of spiro[fluorene-9,4'- and -9,5'-isothiazolidin]one dioxides (1 and 2) were synthesized and screened for activity as aldose reductase and L-hexonate dehydrogenase inhibitors. Compared to compounds 1, and 9,5'-compounds 2, synthesized from fluorene-9-sulfonamides by alkylation at C(9) with ethyl bromoacetate followed by cyclization, were more active, but relatively nonselective, inhibitors of aldose reductase and L-hexonate dehydrogenase, with IC50 values for in vitro inhibition of both enzymes on the order of 10(-7)-10(-8) M. However, the isomeric 9,4'-compounds 1, prepared by alkylation of fluorene-9-carboxylic acid esters with bromo- or iodomethanesulfonamide followed by cyclization, were more selective inhibitors of L-hexonate dehydrogenase with IC50 values of about 10(-6) M.
authors.affiliation: Alcon Laboratories, Inc., Fort Worth, Texas 76115-0600.
authors.forename: M T
authors.initials: MT
authors.lastname: DuPriest
authors.forename: B W
authors.initials: BW
authors.lastname: Griffin
authors.forename: D
authors.initials: D
authors.lastname: Kuzmich
authors.forename: L G
authors.initials: LG
authors.lastname: McNatt
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D013844:Thiazoles; D002237:Carbohydrate Dehydrogenases; C020590:L-glucuronate reductase; D000449:Aldehyde Reductase