N-alkylated aminoacyl sulfamoyladenosines as potential inhibitors of aminoacylation reactions and microcin C analogues containing D-amino acids.
Microcin C analogues were recently envisaged as important compounds for the development of novel antibiotics. Two issues that may pose problems to these potential antibiotics are possible acquisition of resistance through acetylation and in vivo instability of the peptide chain. N-methylated aminoacyl sulfamoyladenosines were synthesized to investigate their potential as aminoacyl tRNA synthetase inhibitors and to establish whether these N-alkylated analogues would escape the natural inactivation mechanism via acetylation of the alpha amine. It was shown however, that these compounds are not able to effectively inhibit their respective aminoacyl tRNA synthetase. In addition, we showed that (D)-aspartyl-sulfamoyladenosine (i.e. with a (D)-configuration for the aspartyl moiety), is a potent inhibitor of aspartyl tRNA synthetase. However, we also showed that the inhibitory effect of (D)- aspartyl-sulfamoyladenosine is relatively short-lasting. Microcin C analogues with (D)-amino acids throughout from positions two to six proved inactive. They were shown to be resistant against metabolism by the different peptidases and therefore not able to release the active moiety. This observation could not be reversed by incorporation of (L)-amino acids at position six, showing that none of the available peptidases exhibit endopeptidase activity.
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
Gaston H
GH
Vondenhoff
Ksenia
K
Pugach
Bharat
B
Gadakh
Laurence
L
Carlier
Jef
J
Rozenski
Mathy
M
Froeyen
Konstantin
K
Severinov
Arthur
A
Van Aerschot
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry*; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D049148:Aminoacylation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001226:Aspartate-tRNA Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001430:Bacteriocins / Q000737:chemistry* / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D013449:Sulfonamides; C020411:microcin; D000604:Amino Acyl-tRNA Synthetases; D001226:Aspartate-tRNA Ligase; D000241:Adenosine