Abstract
There are two principal reasons why we age: 1) the toxicity of oxygen species; 2) the continuous degradation of collagen by groups of enzymes such as the matrix metalloproteinases (MMPs). The MMPs are a group of more than 25 structurally zinc-containing enzymes that are involved in the degradation of numerous extracellular, pericellular and non-matrix proteins. In many disease conditions their levels and proteinase activity rise, producing pathological and serious structural damage. 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. However, a significant limitation is that the FDA only permits the use of subantimicrobial doses of these antibiotics for these diseases to prevent antibiotic side-effects. Therefore a series of chemically-modified TCs (CMTs), which are no longer anti-bacterial at any dose, were developed, but a significant side-effect was increased photosensitivity. Accordingly, in order to avoid these limitations, a series of chemically-modified curcumins (CMCs) were prepared and evaluated as new MMP inhibitors because they have the same zinc-binding site as the TCs, namely a polyenolic assembly. The current lead compound, CMC2.24 [a bis-(demethoxy) phenylaminocarbonyl derivative of curcumin], exhibits inhibitory IC50 values in vitro, ranging from 2-8 micromolar against two collagenases (MMP-8 and MMP-13), two gelatinases (MMP-2 and MMP-9), MMP-3, MMP-7 and MMP-12. The zinc-binding as well as the acidity constants of these CMCs were evaluated and correlated to their potency as MMP-inhibitors in vitro. An in vitro lipophilicity study and in vivo pharmacokinetics were also carried out for curcumin and CMC2.24. The results show that CMC2.24 is more bioavailable in rat serum, and is retained in organ tissues such as the liver, heart, spleen, lung, kidney and brain in comparison with curcumin, which showed much lower levels of retention in these tissues. It was also found that the production of the pro-inflammatory cytokines and the chemokines including TNF-alpha, IL-1beta; and MCP-1 was significantly reduced by CMC2.24 and a related trione (CMC2.5) in cell culture. Collateral studies with CMC2.24 involving its effects on various disease models are discussed.
Description
298 pg.
