title: Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels-Alder cycloadducts.
abstract: Acylnitroso cycloadducts have proven to be valuable intermediates in the syntheses of a plethora of biologically active molecules. Recently, organometallic reagents were shown to open bicyclic acylnitroso cycloadducts and, more interestingly, the prospect of highly regioselective openings was raised. This transformation was employed in the synthesis of a compound with excellent inhibitory activity against 5-lipoxygenase ((±)-4a, IC(50) 51 nM), an important mediator of inflammation intimately involved in a number of disease states including asthma and cancer. Optimization of the copper-mediated organometallic ring opening reaction was accomplished allowing the further exploration of the biological activity. Synthesis of a number of derivatives with varying affinity for metal binding as well as pendant groups in a range of sizes was accomplished. Analogues were tested in a whole cell assay which revealed a subset of the compounds to be inhibitors of enzyme translocation, a mode of action not previously known and, potentially, extremely important for better understanding of the enzyme and inhibitor development. Additionally, the lead compound was tested in vivo in an established colon cancer model and showed very encouraging anti-tumorogenic properties.
authors.affiliation: Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Bolger
authors.forename: Wen
authors.initials: W
authors.lastname: Tian
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D003500:Cyclization; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport
chemical_list: D016859:Lipoxygenase Inhibitors; D009574:Nitro Compounds; D001094:Arachidonate 5-Lipoxygenase