4-alkylidene-azetidin-2-ones: novel inhibitors of leukocyte elastase and gelatinase |
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Authors: | Cainelli Gianfranco Galletti Paola Garbisa Spiridione Giacomini Daria Sartor Luigi Quintavalla Arianna |
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Institution: | a Department of Chemistry ‘G. Ciamician’, University of Bologna, Via Selmi 2, I-40126, Bologna, Italy b Department of Experimental Biomedical Sciences, Medical School of Padova, Viale G. Colombo 3, 35121, Padova, Italy |
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Abstract: | In addition to their antibiotic potency, β-lactams have recently been investigated as inhibitors of serine proteinase such as leukocyte elastase (LE), released by inflammatory cells. We describe the synthesis of a series of 4-alkylidene-β-lactams, and investigate how substitutions on C-3, C-4, and N-1 of the β-lactam ring affect the activity of human LE and gelatinases MMP-2 and MMP-9. LE activity was measured using a chromogenic substrate, while gelatin-zymography assay was used to evaluate gelatinase activity. We demonstrate that C-4 unsaturation on the β-lactam ring determines the degree of biological activity, with a selectivity over LE by 3-1-(tert-butyldimethylsilyloxy)-ethyl] derivatives (lowest IC50 was 4 μM), and over gelatinase MMP-2 by C-3-unsubstituted 4-1-ethoxycarbonyl]-ethylidene-β-lactams (lowest IC50 was 60 μM). (3S)-3-(1R)-1-hydroxyethyl]-4-(1-ethoxycarbonyl)-ethylidene-azetidin-2-one inhibits gelatinase MMP-9. The compounds tested showed no cytotoxicity against NIH-3T3 murine fibroblasts. This is the first example of beta-lactams inhibiting metallo-proteinases instrumental in cancer invasion and angiogenesis. These molecules are good candidates for prototype drugs showing selective antibiotic, anti-inflammatory, and anti-invasion properties. |
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