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Rhenium inhibitors of cathepsin B (ReO(SYS)X (where Y = S, py; X = Cl, Br, SPhOMe-p)): Synthesis and mechanism of inhibition.

Abstract
The synthesis of four new oxorhenium(V) complexes containing the "3 + 1" mixed-ligand donor set, ReO(SYS)X (where Y = S, py; X = Cl, Br), is described. All of the complexes tested exhibited selectivity for cathepsin B over K. Most notably, compound 6, ReO(SSS-2,2')Br (IC50(cathepsin B) = 1.0 nM), was 260 times more potent against cathepsin B. It was also discovered that complexes containing the same tridentate (SSS) ligand were more potent when the leaving group was bromide versus chloride (e.g., IC50(cathepsin B): ReO(SSS-2,2')Cl (4), 8.8 nM; ReO(SSS-2,2')Br (6), 1.0 nM). Mechanistic studies with cathepsin B showed that both compounds 2 (ReO(SpyS)(SPhOMe-p)) and 4 were active-site-directed. Compound 2 was determined to be a tight-binding, reversible inhibitor, while compound 4 was a time-dependent, slowly reversible inhibitor. The results described in this paper show that the oxorhenium(V) "3 + 1" complexes are potent, selective inhibitors of cathepsin B and have potential for the treatment of cancer.
AuthorsRenee Mosi, Ian R Baird, Jennifer Cox, Virginia Anastassov, Beth Cameron, Renato T Skerlj, Simon P Fricker
JournalJournal of medicinal chemistry (J Med Chem) Vol. 49 Issue 17 Pg. 5262-72 (Aug 24 2006) ISSN: 0022-2623 [Print] United States
PMID16913715 (Publication Type: Journal Article)
Chemical References
  • Cysteine Proteinase Inhibitors
  • Ligands
  • Organometallic Compounds
  • perrhenate
  • Rhenium
  • Cathepsins
  • Cathepsin B
  • CTSK protein, human
  • Cathepsin K
Topics
  • Binding Sites
  • Cathepsin B (antagonists & inhibitors, chemistry)
  • Cathepsin K
  • Cathepsins (antagonists & inhibitors, chemistry)
  • Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Humans
  • Ligands
  • Molecular Structure
  • Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
  • Rhenium (chemistry)
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors

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