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.