期刊
CHEMISTRY-AN ASIAN JOURNAL
卷 7, 期 2, 页码 425-434出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/asia.201100732
关键词
ab initio calculations; enzymes; inhibitors; macrocycles; metathesis
资金
- Interuniversity Attraction Pole (IAP) [P6/19 PROFUSA]
- F.R.S.-FNRS
- UCL
- ULg
As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged beta-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic beta-lactams by the ring-closing metathesis (RCM) of bis-omega-alkenyl-3(S)-aminoazetidinone precursors. The reactivity of 1,3-bridged beta-lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring-opening process by using ab initio calculations. The results predicted that 16-membered cycles should be more reactive. Biochemical evaluations against R39 DD-peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4d, which featured a 16-membered bridge and the N-tert-butyloxycarbonyl chain at the C3 position of the beta-lactam ring. Surprisingly, the corresponding bicycle, 12d, with the PhOCH2CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds.
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