Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action. Issue 9 (14th July 2015) - Royo, Santiago
Abstract Dipeptidyl enoates were prepared through a high‐yielding two‐step synthetic route. They have a dipeptidic structure with a 4‐oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S, E)‐ethyl 5‐((S)‐2‐{[(benzyloxy)carbonyl]amino}‐3‐phenylpropanamido)‐7‐methyl‐4‐oxooct‐2‐enoate (6) was the most potent, with an IC50 value of 16.4 nM and kinact/Ki=1.6×106 M−1 s−1 against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.