Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action. Issue 9 (14th July 2015)

• Record Type: Journal Article
• Authors: Royo, Santiago; Rodríguez, Santiago; Schirmeister, Tanja; Kesselring, Jochen; Kaiser, Marcel; González, Florenci V.
• Is Part Of: ChemMedChem. Volume 10:Issue 9(2015:Sep.)
• Page Start: 1484
• Page End: 1487
• Publication Date: 2015-07-14
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500204
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>S</italic>, <italic>E</italic>)‐ethyl 5‐((<italic>S</italic>)‐2‐{[(benzyloxy)carbonyl]amino}‐3‐phenylpropanamido)‐7‐methyl‐4‐oxooct‐2‐enoate (<bold>6</bold>) was the most potent, with an IC₅₀ value of 16.4 n<sc>M</sc> and <italic>k</italic>_inact/<italic>K</italic>_i=1.6×10⁶ <sc>M</sc>⁻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.</p> </abstract>