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Sulindac sulfide (SS) and indomethacin are NSAIDs that have shown an ability to reduce the incidence and mortality from colon cancer, although the pathway by which they exert these actions remains the subject of investigation. Analysis of the crystal structure of the COX-2/indomethacin complex reveals a hydrophobic depression in the active site, which binds the 2-methyl group on the indole ring of indomethacin. Removal of the 2-methyl group abolishes the ability of indomethacin to inhibit COX-1 or COX-2 in a time-dependent fashion. Interestingly, 2-des-methyl analogs of indomethacin and SS are equipotent to the parent drugs at inhibiting proliferation of RKO and HCT116 colon cancer cell lines. Derivatization of 2-des-methyl SS to a benzyl amide resulted in a significant increase in potency (ED50 of 1 μM in RKO cells). Structure-activity analysis indicated that substitutions were tolerated at the para-position of the benzyl amide and at the para-position of the benzylidene ring of 2-des-methyl SS. The most potent derivative prepared exhibited an ED50 of 40 nM in RKO cells. Hoechst staining indicated that all compounds induced cell death through apoptotic pathways. Furthermore, a reduction in PARP cleavage, caspase-3 activation and p53 induction was demonstrated in RKO-E6 cells indicating that these derivatives exert their actions through a p53-dependent pathway. The ability to synthesize NSAID derivatives that retain their anti-proliferative properties while eliminating their COX inhibitory activity may provide a new approach for the identification of anticancer agents.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]