Design, Synthesis and Biological Activity of New Polyenolic Inhibitors of Matrix Metalloproteinases: A Focus on Chemically-Modified Curcumins

Title:Design, Synthesis and Biological Activity of New Polyenolic Inhibitors of Matrix Metalloproteinases: A Focus on Chemically-Modified Curcumins

Volume: 19 Issue: 25

Author(s): Yu Zhang, Ying Gu, Hsi-Ming Lee, Elena Hambardjieva, Kveta Vrankova, Lorne M. Golub and Francis Johnson

Affiliation:

Keywords: Matrix metalloproteinases, chemically-modified-curcumin, connective tissue degradation, zinc-binding, enolic β-diketone moiety

Abstract: Matrix metalloproteinases (MMPs) are essential for the degradation and turnover of components of the extracellular matrix (ECM) and, when pathologically elevated, mediate connective tissue loss (including bone destruction) in various inflammatory and other diseases. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of Doxycycline are FDA-approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. Because the C-11/ C-12 diketonic moiety of the tetracyclines is primarily responsible, through zinc-binding, for MMP inhibition, we have uniquely modified curcumin as a “core” molecule, since it contains a similar enolic system and is known to have beneficial effects in diseases where connective-tissue loss occurs. Specifically we have developed new congeners which exhibit improved zinc-binding and solubility, and potent reduction of excessive MMP levels and activity. We now describe a series of curcuminoid bi- and tri-carbonylmethanes in which all of these properties are substantially improved. An N-phenylaminocarbonyl derivative of bis-demethoxycurcumin (CMC2.24) was selected as the “lead” substance because it showed superior potency in vitro (i.e., the lowest IC50) against a series of neutral proteases (MMPs) associated with tissue erosion. Moreover, CMC2.24 administered to diabetic rats orally (30mg/kg), reduced the secretion of pathologically-excessive levels of MMP-9 to normal in cultured peritoneal macrophages with no evidence of toxicity. Thus, this (and other similar novel) compound(s) may be useful in various diseases of connective-tissue loss.

Cite this article as:

Zhang Yu, Gu Ying, Lee Hsi-Ming, Hambardjieva Elena, Vrankova Kveta, M. Golub Lorne and Johnson Francis, Design, Synthesis and Biological Activity of New Polyenolic Inhibitors of Matrix Metalloproteinases: A Focus on Chemically-Modified Curcumins, Current Medicinal Chemistry 2012; 19 (25) . https://dx.doi.org/10.2174/092986712802884295