Rhenium inhibitors of cathepsin B (ReO(SYS)X (where Y = S, py; X = Cl, Br, SPhOMe-p)): Synthesis and mechanism of inhibition.
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.
Mosi
Renee
R
AnorMED Inc., Suite 200, 20353 64th Avenue, Langley BC V2Y1N5, Canada.
Baird
Ian R
IR
Cox
Jennifer
J
Anastassov
Virginia
V
Cameron
Beth
B
Skerlj
Renato T
RT
Fricker
Simon P
SP
D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012211:Rhenium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D009942:Organometallic Compounds; C015428:perrhenate; D012211:Rhenium; D002403:Cathepsins; D002401:Cathepsin B; C534130:CTSK protein, human; D056657:Cathepsin K