Abstract
Lysosomal cysteine peptidase cathepsin B (catB) is an important tumor-promoting factor involved in tumor progression and metastasis representing a relevant target for the development of new antitumor agents. In the present study, we synthesized 11 ruthenium compounds bearing either the clinical agent nitroxoline that was previously identified as potent selective reversible inhibitor of catB activity or its derivatives. We demonstrated that organoruthenation is a viable strategy for obtaining highly effective and specific inhibitors of catB endo- and exopeptidase activity, as shown using enzyme kinetics and microscale thermophoresis. Furthermore, we showed that the novel metallodrugs by catB inhibition significantly impair processes of tumor progression in in vitro cell based functional assays at low noncytotoxic concentrations. Generally, by using metallodrugs we observed an improvement in catB inhibition, a reduction of extracellular matrix degradation and tumor cell invasion in comparison to free ligands, and a correlation with the reactivity of the monodentate halide leaving ligand.
Highlights
Cathepsin B (EC 3.4.22.1; cathepsin B (catB)) is a lysosomal cysteine peptidase that belongs to clan CA of the papain family (C1).The proteolytic activity of this enzyme is crucial in the mechanisms of cancer progression
The bromido, iodido, and azido analouegs 1b−d were, synthesized using acetone as a solvent to allow the removal of NaCl directly from the reaction mixture and facilitate precipitation by addition of n-hexane as, when precipitating from a DCM solution, we often observed the formation of oily products
(catB) inhibiting derivatives, we have demonstrated that organoruthenation of the lead nxH scaffold is a viable strategy for obtaining highly effective catB inhibitors, the agents that efficiently reduce tumor cell invasion
Summary
Cathepsin B (EC 3.4.22.1; catB) is a lysosomal cysteine peptidase that belongs to clan CA of the papain family (C1). For ruthenium complexes with nitroxoline derivatives 2b, 3a, and 4a the average Kd values were lower in comparison to the Ki values for endopeptidase activity inhibition obtained using fluorescent substrates in a enzyme kinetics assay: i.e. 14.4-fold (6.2 ± 0.9 μM) for 4a, 7.5-fold (13.9 ± 1.2 μM) for 3a, and 3.6-fold (39.0 ± 5.8 μM) for 2b (Figure 3B). Ruthenium complexes with nitroxoline derivatives 2b, 3a, and 4a significantly impaired invasion of MCF-10A neoT cells (Figure 6C,D) In this group, compound 2b was the best inhibitor with 86 ± 8% inhibition of cell invasion, whereas 3a and 4a decreased this process by 54 ± 8% and 38 ± 8%, respectively (Figure 6D). In addition to catB, the compounds may affect other specific targets involved in cell invasion
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