title: Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase.
abstract: The first successful preparation of mono- and disubstituted 3,7-dihydroxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the resultant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobromo- and dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophosphatase with IC50 values in the low-micromolar range. The results are discussed in the context of the recently described novel mode of inhibition of the enzyme by 3,7-dihydroxytropolones.
authors.affiliation: Marion Merrell Research Institute, Strasbourg, France. Serge.Piettre@osiris.univ-rouen.fr
authors.forename: S R
authors.initials: SR
authors.lastname: Piettre
authors.forename: C
authors.initials: C
authors.lastname: André
authors.forename: M C
authors.initials: MC
authors.lastname: Chanal
authors.forename: J B
authors.initials: JB
authors.lastname: Ducep
authors.forename: B
authors.initials: B
authors.lastname: Lesur
authors.forename: F
authors.initials: F
authors.lastname: Piriou
authors.forename: P
authors.initials: P
authors.lastname: Raboisson
authors.forename: J M
authors.initials: JM
authors.lastname: Rondeau
authors.forename: C
authors.initials: C
authors.lastname: Schelcher
authors.forename: P
authors.initials: P
authors.lastname: Zimmermann
authors.forename: A J
authors.initials: AJ
authors.lastname: Ganzhorn
mesh_terms: D001665:Binding Sites; D004164:Diphosphonates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014334:Tropolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D011994:Recombinant Proteins; C079103:L 690330; C002647:inositol 1-phosphate; D014334:Tropolone; C057099:3,7-dihydroxytropolone; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase