Novel naphthalimide-indomethacin hybrids as potential antitumor agents: effects of linkers on hypoxic/oxic cytotoxicity and apoptosis-inducing activity

A series of novel naphthalimide-indomethacin hybrids with different linkers were designed and synthe- sized. Their antitumor activity was evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, and A375 cancer cell lines in vitro. Preliminary results showed that the hybrids had moderate cytotoxic activity with 50% inhibition con- centration (IC50) values of *10 -5 M, and could effectively induce apoptosis in HeLa cells. More importantly, the amide derivatives had better cytotoxic and proapoptotic activity than their ester counterparts, whereas the ester derivatives had hypoxic preferred cytotoxicity and might be used as promising candidates of prodrug in hypoxic tumor cells. This work provides a novel class of naphthalimide-indo- methacin hybrids with unique antitumor activity for further optimization.