Dipeptide-derived nitriles containing additional electrophilic sites: potentially irreversible inhibitors of cysteine proteases.
Heterocyclic and open-chain dipeptide-derived nitriles have been synthesized, containing an additional electrophilic center enabling the subsequent covalent modification of the thioimidate nitrogen formed in situ at the active site of the enzyme. The inhibitory potential of these nitriles against the cysteine proteases papain and cathepsins L, S, and K was determined. The open-chain dipeptide nitriles 8 and 10 acted as moderate reversible inhibitors, but no evidence for an irreversible inhibition of these enzymes was discernable.
Löser
Reik
R
Pharmazeutisches Institut, Pharmazeutische Chemie I, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. reikloeser@gmx.de
Gütschow
Michael
M
D020134:Catalytic Domain; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003500:Cyclization; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009570:Nitriles; D002403:Cathepsins; D056668:Cathepsin L; D010206:Papain; C028217:cathepsin S; D056657:Cathepsin K