High-affinity inhibitors of tRNA-guanine transglycosylase replacing the function of a structural water cluster.
The tRNA-modifying enzyme tRNA-guanine transglycosylase (TGT) is essential for the pathogenic mechanism of Shigella flexneri, the causing agent of the bacterial diarrheal disease shigellosis. Herein, the synthesis of a new class of rationally designed 6-amino-imidazo[4,5-g]quinazolin-8(7H)-one- (lin-benzoguanine) based inhibitors of TGT are reported. In order to accommodate a small hydrophobic crevice opening near the binding site of ribose-34, 2-aminoethyl substituents were introduced in position 4 of the heterocyclic scaffold. For this purpose, a synthetic sequence consisting of iodination, Suzuki cross-coupling, hydroboration, Mitsunobu reaction, and Gabriel synthesis was employed, furnishing a primary amine that served as a common intermediate for the preparation of a series of derivatives. The resulting ligands displayed very low inhibition constants, down to K(i)=2 nM. Substantial additional inhibitory potency is gained by interaction of terminal lipophilic groups attached to the substituent at position 4 with the hydrophobic crevice shaped by Val45 and Leu68. At the same time, the secondary ammonium center in the substituent displaces a cluster of water molecules, solvating the catalytic residues Asp102 and Asp280, without loss in binding affinity. In addition, a synthetic intermediate with an unusual 3,6,7,8,9,10-hexahydroimidazo[4,5-g][1,3]benzodiazepine core, as confirmed by X-ray analysis, is reported.
Kohler
Philipp C
PC
Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich, Switzerland.
Ritschel
Tina
T
Schweizer
W Bernd
WB
Klebe
Gerhard
G
Diederich
François
F
D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012763:Shigella flexneri / Q000201:enzymology*; D014867:Water / Q000737:chemistry
C545219:6-amino-imidazo(4,5-g)quinazolin-8(7H)-one; D007093:Imidazoles; D011799:Quinazolines; D014867:Water; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase