Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors.
To evaluate N-hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N-hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H-D-Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4-5 orders of magnitude) than the isosteric (R)-succinylhydroxamate analogue, which displays IC(50) in the range of nM vs MMP-1, -3, -7 and sub-nM vs MMP-2, -8, and -9. The peptidyl 1-hydroxyurea 1a attained an IC(50) of 20 microM vs MMP-9, and substantially approaches inhibition of known N-hydroxyureas based on aminoacids or peptides against other zinc metalloenzymes and non-peptidic N-hydroxyureas against MMPs. Strong preference of the O-N1-C=O unit for the antiperiplanar amide bond conformation seems to be the major limit for more effective zinc chelation. Methylation of a peptidyl 1-hydroxyurea at N3, to promote the synperiplanar O-N1-C=O conformation required for zinc chelation and improve affinity, resulted in release of a methylimidazolidine-2,4-dione through an undesired intramolecular reaction reminiscent of the Edman peptide degradation.
Campestre
Cristina
C
Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Via dei Vestini 31, 66013 Chieti, Italy.
Tortorella
Paolo
P
Agamennone
Mariangela
M
Preziuso
Serena
S
Biasone
Alessandro
A
Nuti
Elisa
E
Rossello
Armando
A
Gallina
Carlo
C
D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry*
D004151:Dipeptides; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013386:Succinates; D020782:Matrix Metalloproteinases; D006918:Hydroxyurea