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Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action
Author(s) -
Royo Santiago,
Rodríguez Santiago,
Schirmeister Tanja,
Kesselring Jochen,
Kaiser Marcel,
González Florenci V.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500204
Subject(s) - chemistry , moiety , mode of action , dipeptidyl peptidase , stereochemistry , docking (animal) , ic50 , combinatorial chemistry , dual mode , kinetics , enzyme , biochemistry , in vitro , medicine , nursing , engineering , aerospace engineering , physics , quantum mechanics
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 IC 50 value of 16.4 n M and k inact / K i =1.6×10 6 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.