Discovery of novel sulfonamide-containing aminophosphonate derivatives as selective COX-2 inhibitors and anti-tumor candidates

As an essential enzyme with a variety of physiological functions, Cyclooxygenase-2 (COX-2) is also closely related to carcinoma due to the observed overexpression. In this work, a novel series of sulfonamide-containing aminophosphonate derivatives ( A1-A25 ) were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity (IC 50  = 0.28 µM) and anti-proliferative capability against several cancer cell lines (IC 50  = 2.34–16.43 µM for HeLa, MCF-7, HCT116 and HepG2 cells). Among them, A23 has the most significant inhibitory effect on HCT116 cells, which were comparable with that of the positive controls respectively (eg: IC 50  = 8.73 µM for HCT116). The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future.