Synthesis and evaluation of new omega-borono-alpha-amino acids as rat liver arginase inhibitors.
Recent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new omega-borono-alpha-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)-l-cysteine (BEC) and 2-amino-6-boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH)(2) and the alpha-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA.
Busnel
Olivier
O
Laboratoire de Synthèse et Electrosynthèse Organiques, Institut de Chimie, Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
Carreaux
François
F
Carboni
Bertrand
B
Pethe
Stephanie
S
Goff
Sandrine Vadon-Le
SV
Mansuy
Daniel
D
Boucher
Jean-Luc
JL
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001896:Boron Compounds / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000596:Amino Acids; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D001119:Arginase