title: Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin.
abstract: Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure-activity relationships around the core bicyclic thioxofuropyridinone and pendant furan ring. This resulted in the identification of a submicromolar inhibitor of the perforin-induced lysis of Jurkat T-lymphoma cells.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Gersande
authors.initials: G
authors.lastname: Lena
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Vivien R
authors.initials: VR
authors.lastname: Sutton
authors.forename: Annette
authors.initials: A
authors.lastname: Ciccone
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Browne
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D054353:Perforin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005663:Furans; D011728:Pyridones; D013871:Thiones; D054353:Perforin