Abstract:
:Fully deprotected phosphonamidate dipeptides, predicted as effective inhibitors of cytosolic leucine aminopeptidase, showed unexpected instability in water solution at pH below 12. Their hydrolysis rate was strictly correlated with basicity of the N-terminal amino group. To improve this feature a phosphonamidate analogue containing less basic, aromatic 2-aminophenylphosphonate residue in P1 position of the inhibitor was designed. The target compound was synthesised starting from diethyl 2-nitrophosphonate in several step procedure. The decrease in basicity of the terminal amino moiety of the modified analogue in fact resulted in satisfactory improvement of hydrolytic stability of the P-N bond. The developed phosphonamidate was proved to be fully resistant to hydrolysis above pH 7. Surprisingly, tested in enzymatic assays towards leucine aminopeptidase (optimum pH 8.5), it did not exhibit inhibition activity up to milimolar concentration. The explanation could be that diminishing the basic character of the terminal amino group may result in a change of its affinity towards the zinc ions.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Mucha A,Kunert A,Grembecka J,Pawełczak M,Kafarski Pdoi
10.1016/j.ejmech.2006.03.023subject
Has Abstractpub_date
2006-06-01 00:00:00pages
768-72issue
6eissn
0223-5234issn
1768-3254pii
S0223-5234(06)00144-9journal_volume
41pub_type
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