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Synthesis and In Vitro Evaluation of 2‐Aminoquinazolin‐4(3 H )‐one‐Based Inhibitors for tRNA‐Guanine Transglycosylase (TGT)
Author(s) -
Meyer Emmanuel A.,
Furler Maya,
Diederich François,
Brenk Ruth,
Klebe Gerhard
Publication year - 2004
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200490122
Subject(s) - chemistry , stereochemistry , guanine , crystal structure , active site , transfer rna , residue (chemistry) , hydrogen bond , carboxylate , enzyme , nucleotide , crystallography , rna , molecule , biochemistry , organic chemistry , gene
Abstract tRNA‐Guanine transglycosylase (TGT) plays a key role in the post‐transcriptional modification of tRNA. It has been linked with the pathogenicity of shigellae , the causative agents of bacillary dysentery (shigellosis). Here, we report structureactivity relationships (SARs) for a new series of 2‐aminoquinazolin‐4(3 H )‐one‐based inhibitors of TGT, resulting from structure‐based design ( Fig. 2 ). Versatile synthetic protocols allow selective functionalization of the 2‐aminoquinazolin‐4(3 H )‐one core ( Schemes 1 – 6 ) with H‐bond‐donor groups in position 6 (for H‐bonding to the C=O group of Leu231) and lipophilic residues in position 8 for reaching into a shallow, newly discovered lipophilic pocket lined by Val282, Val45, and Leu68. The binding mode of several of these ligands in the active site of TGT was established by crystal structure analyses ( Figs. 4 and 6 ). A dramatic S effect was observed, with the replacement of the S‐atom in the (phenylsulfanyl)methyl residue in position 8 of inhibitor 1c ( K i =100 n M ) by the O‐atom (in 1h , K i =5.6 μ M ) or CH 2 (in 1i , K i =3.6 μ M ), resulting in a massive loss of activity ( Fig. 3 ). Crystal structure analysis showed that the lipophilic Me group points into a highly polar region of the active site encompassed by the side chains of Asp280 and Asp102 and collides directly ( d (C⋅⋅⋅O)=3.1 Å) with one of the O‐atoms of the carboxylate of Asp102. Similarly, lipophilic linkers departing from position 8 and orienting residues in the shallow hydrophobic pocket presumably encounter analogous unfavorable contacts, accounting for the modest contribution to the binding free enthalpy upon introduction of these residues. These findings provide a valuable starting point for future structure‐based lead optimization cycles leading to TGT inhibitors with increased in vitro potency.