Ketomethylenebestatin: synthesis and aminopeptidase inhibition.
The synthesis of (6R,5S,2RS)-6-amino-5-hydroxy-2-isobutyl-4-oxo-7- phenylheptanoic acid (9), a carbaanalogue of the aminopeptidase (AP) inhibitor bestatin (1) is described. This synthesis was carried out by a malonic ester alkylation with the suitably protected halomethyl ketone of (2S,3R)-AHPBA*), followed by a second alkylation with isobutyl bromide of the resulting 4-ketodiester, and subsequent decarboxylation and deprotection. The inhibitory potencies of the 1:1 diastereomeric mixture 9 against AP-B, AP-M and Leu-AP were approximately 10-fold lower than those of bestatin.
Herranz
R
R
Instituto de Química Médica, Juan de la Cierva, Madrid, Spain.
Castro-Pichel
J
J
García-López
M T
MT
Gómez-Monterrey
I
I
Pérez
C
C
Vinuesa
S
S
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D013552:Swine
D006538:Heptanoic Acids; C082772:ketomethylenebestatin; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex