Novel steroid inhibitors of glucose 6-phosphate dehydrogenase

Niall M Hamilton, Martin Dawson, Emma E Fairweather, Nicola S Hamilton, James R Hitchin, Dominic I James, Stuart D Jones, Allan M Jordan, Amanda J Lyons, Helen F Small, Graeme J Thomson, Ian D Waddell, Donald J Ogilvie

Research output: Contribution to journalArticlepeer-review

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. © 2012 American Chemical Society.
Original languageEnglish
Pages (from-to)4431-45
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number9
DOIs
Publication statusPublished - 10 May 2012

Keywords

  • Antineoplastic Agents
  • Cell Survival
  • Enzyme Inhibitors
  • Glucosephosphate Dehydrogenase
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Pregnanes
  • Structure-Activity Relationship

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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