title: Novel steroid inhibitors of glucose 6-phosphate dehydrogenase.
abstract: Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3β-alcohol can be replaced with 3β-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.
authors.affiliation: Cancer Research UK Drug Discovery Unit, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4 BX, UK. nhamilton@picr.man.ac.uk
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.forename: Martin
authors.initials: M
authors.lastname: Dawson
authors.forename: Emma E
authors.initials: EE
authors.lastname: Fairweather
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Hamilton
authors.forename: James R
authors.initials: JR
authors.lastname: Hitchin
authors.forename: Dominic I
authors.initials: DI
authors.lastname: James
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Jones
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lyons
authors.forename: Helen F
authors.initials: HF
authors.lastname: Small
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Thomson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Waddell
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011278:Pregnanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011278:Pregnanes; D005954:Glucosephosphate Dehydrogenase