Dipeptidyl alpha-fluorovinyl Michael acceptors: synthesis and activity against cysteine proteases.
The synthesis of novel dipeptidyl alpha-fluorovinyl sulfones using a Horner-Wadsworth-Emmons approach on N-Boc-l-phenylalaninal is described. Inhibitory assays against a Leishmania mexicana cysteine protease (CPB2.8DeltaCTE) revealed low biological activity. Relative rates of Michael additions of 2'-(phenethyl)thiol with vinyl sulfone and alpha-fluorovinyl sulfone were determined, and ab initio calculations on several Michael acceptor model structures were performed; both were in agreement with the biological testing results.
Steert
Koen
K
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium.
El-Sayed
Ibrahim
I
Van der Veken
Pieter
P
Krishtal
Alisa
A
Van Alsenoy
Christian
C
Westrop
Gareth D
GD
Mottram
Jeremy C
JC
Coombs
Graham H
GH
Augustyns
Koen
K
Haemers
Achiel
A
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000201:enzymology / Q000469:parasitology; D008958:Models, Molecular
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D003546:Cysteine Endopeptidases