5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ^+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.

Investigating a series of anilinoquinazoline derivatives substituted by carbamic acid esters, we have established the importance of the carbamate functional group and the substitution on the arylamino ring by a donor/acceptor group such as halide or methyl. All the newly-synthesized compounds described were evaluated for both their in vitroEGFR and VEGFR-2 kinase inhibition and antiproliferative activities against various cancer cells. These novel compounds were effective tyrosine kinase inhibitors (TKIs) for these two enzymes with in vitro IC50 values in the submicromolar range, but showed a moderated inhibitory activity on cancer cells. Modification of the ether linkage at the 6- or 7- position of the quinazoline core with a basic or aliphatic side chain (70–80) was investigated and it was demonstrated that introduction of aminoalkyl substituents such as morpholinoethoxy is a key modification that increases antiproliferative activity.