Synthesis and activity of analogues of the isoleucyl tRNA synthetase inhibitor SB-203207.
Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
Crasto
Curtis F
CF
Research School of Chemistry, Institute of Advanced Studies, Australian National University, Canberra, ACT 0200, Australia.
Forrest
Andrew K
AK
Karoli
Tomislav
T
March
Darren R
DR
Mensah
Lucy
L
O'Hanlon
Peter J
PJ
Nairn
Michael R
MR
Oldham
Mark D
MD
Yue
Weimin
W
Banwell
Martin G
MG
Easton
Christopher J
CJ
D000596:Amino Acids / Q000737:chemistry; D000604:Amino Acyl-tRNA Synthetases; D000818:Animals; D007192:Indenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D051381:Rats; D013211:Staphylococcus aureus / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D000596:Amino Acids; D007192:Indenes; C410786:SB 203207; D013449:Sulfonamides; D000604:Amino Acyl-tRNA Synthetases; D007533:Isoleucine-tRNA Ligase