Synthesis and in vitro evaluation of targeted tetracycline derivatives: Effects on inhibition of matrix metalloproteinases

Among other non-antibiotic properties, tetracyclines inhibit matrix metalloproteinases and are currently under study for the treatment of osteoarthritis. Quaternary ammonium conjugates of tetracyclines were synthesized by direct alkylation of the amine function at the 4-position with methyl iodide....

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2007-03, Vol.15 (6), p.2368-2374
Main Authors: Vidal, Aurélien, Sabatini, Massimo, Rolland-Valognes, Gaëlle, Renard, Pierre, Madelmont, Jean-Claude, Mounetou, Emmanuelle
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cartilage, Articular - drug effects
Cartilage, Articular - enzymology
Chondrosarcoma - drug therapy
Chondrosarcoma - enzymology
Chondrosarcoma - pathology
Collagen - drug effects
Collagen - metabolism
Humans
In Vitro Techniques
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases - metabolism
Medical sciences
Metalloproteinases
Osteoarthritis
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Proteoglycans - drug effects
Proteoglycans - metabolism
Quaternary ammonium
Rabbits
Tetracyclines
Tetracyclines - chemical synthesis
Tetracyclines - chemistry
Tetracyclines - pharmacology
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Summary:Among other non-antibiotic properties, tetracyclines inhibit matrix metalloproteinases and are currently under study for the treatment of osteoarthritis. Quaternary ammonium conjugates of tetracyclines were synthesized by direct alkylation of the amine function at the 4-position with methyl iodide. When tested in vitro, they inhibited cytokine-induced MMP expression to a lesser extent than parent tetracyclines. This was compensated by an improved inhibition of MMP catalytic activity. Since inhibition of collagen degradation was maintained these derivatives could be potent drug candidates for cartilage-targeted chondroprotective treatment.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.01.026