Large ring 1,3-bridged 2-azetidinones: experimental and theoretical studies

The relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a "planar amide" instead of the "twisted amide" typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C=C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the alpha-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH. Indeed, bicycles 11 and 12 are modest inhibitors of PBP2a, while 10 is a good to excellent inhibitor of PBP2a and R39 bacterial enzymes. (C) 2008 Elsevier Masson SAS. All rights reserved

Synthesis and antibacterial activity of monocyclic beta-lactams related to cephalosporin and penicillin sulfones

Starting from the natural Penicillins G and V, a series of monocyclic p-lactams B were prepared, functionalized at N(1) by an acetyl residue and at C(3) and C(4), respectively, by an acylamino side-chain and a sulfone substituent in a cis-stereochemical relationship. The TAL and PIV prodrugs exhibited weak antibacterial activity in vitro

From medicinal chemistry to functionalized biomaterials: development of graftable RGD-peptitomimetics for cell adhesion and cell addressing

Arg-Gly-Asp (RGD) peptidomimetics constructed on the tyrosine scaffold were equipped with an oligoethylene glycol (OEG) spacer-arm for surface grafting. Their in vitro activities as alphaVbeta3 integrin antagonists were in the range of 0.3-0.7 nM. Poly (ethylene terephthalate) (PET) membranes derivatized with peptidomimetics (50-120 pmol/cm2) allowed the adhesion and proliferation of endothelial cells (HSV) in serum-free medium. Iron oxide particles for MR Imaging grafted with peptidomimetics (2-3 molecules/particle of 20 nm diameter) were selectively targeted to activated tumour cells (Jurkat)