title: 4-Alkyliden-beta-lactams conjugated to polyphenols: synthesis and inhibitory activity.
abstract: A series of compounds combining the beta-lactam and polyphenol scaffold have been prepared and evaluated for inhibition of human leukocyte elastase and matrix metallo-proteases MMP-2 and MMP-9. The design of these compounds has been based on the 'overlapping-type' strategy where two pharmacophores are linked in a single molecule. The most powerful compound against elastase was an N-galloyl-4-alkyliden beta-lactam, [3-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-1-(3,4,5-tris-benzyloxy-benzoyl)-azetidin-2-ylidene]-acetic acid ethylester, with an IC50 of 0.5 microM; while the most powerful against MMP-2 was a 4-alkyliden beta-lactam arylated on the C-3 hydroxy side chain (3,5-bis-benzyloxy-4-hydroxy-benzoic acid 1-(2-benzyloxycarbonylmethylene-4-oxo-azetidin-3-yl)-ethyl ester) with an IC50 of 4 microM. Of the total 35 compounds tested, high levels of inhibition of elastase and of MMPs were separately exerted by distinct molecules.
authors.affiliation: Department of Chemistry G. Ciamician, University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cainelli
authors.forename: Paola
authors.initials: P
authors.lastname: Galletti
authors.forename: Spiridione
authors.initials: S
authors.lastname: Garbisa
authors.forename: Daria
authors.initials: D
authors.lastname: Giacomini
authors.forename: Luigi
authors.initials: L
authors.lastname: Sartor
authors.forename: Arianna
authors.initials: A
authors.lastname: Quintavalla
mesh_terms: D045744:Cell Line, Tumor; D005419:Flavonoids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D059808:Polyphenols; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D010636:Phenols; D059808:Polyphenols; D047090:beta-Lactams; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases