3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxy-propan-2-one derivatives: new classes of aminopeptidase inhibitors.
3-Amino-2-hydroxy-propionaldehydes [H2NCH(R)CHOHCHO with R = H, i-Bu, CH2Ph] were designed as metallo-aminopeptidase inhibitors based on the metal active site chelation concept. These compounds were found to be micromolar inhibitors of aminopeptidase-M (AP-M, EC 3.4.11.2) with potencies similar to bestatin (Ki = 3.5 microM). Notably, compound 5a (R = H) is a selective inhibitor of AP-M (Ki = 7 microM) with respect to cytosolic leucine aminopeptidase (LAPc, EC 3.4.11.1) (Ki = 385 microM). However, due to their easy oligomerization, these compounds are low practical value. In contrast, the corresponding isomeric 3-amino-1-hydroxy-propan-2-one derivatives [H2NCH(R)COCH2OH with R = H, i-Bu, CH2Ph, i-Pr, CH2Biph] are well defined structures. These hydroxymethylketones also exhibit micromolar affinities on AP-M. Compound 6c (R = CH2Ph) was the most potent (Ki = 1 microM). Selectivity studies of 6a (R = H) and 6b (R=i-Bu) show a preference for AP-M. Compound 6a is moderately active on AP-M (Ki = 25 microM) and inactive on LAPc. This new class of inhibitors is proposed to bind as bidentates, analogous to hydroxamates.
Tarnus
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Marion Merrell Research Institute, Strasbourg Center, France.
Rémy
J M
JM
d'Orchymont
H
H
D000447:Aldehydes / Q000737:chemistry*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D005985:Glyceraldehyde / Q000031:analogs & derivatives* / Q000737:chemistry; D007668:Kidney / Q000201:enzymology; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D063208:Methionyl Aminopeptidases; D051381:Rats; D013552:Swine
C103402:3-amino-2-hydroxypropionaldehyde; D000447:Aldehydes; D005985:Glyceraldehyde; D000626:Aminopeptidases; D007931:Leucyl Aminopeptidase; D063208:Methionyl Aminopeptidases; C019721:aminopeptidase B