Design, Synthesis And Antitumor Activities Study Of Quinoxaline-1,4-dioxide Derivatives

Hypoxic regions exist in 90%of solid tumors, which were related with tumor proliferation, progression and resistance to radiotherapy and chemotherapy. Despite the cancer treatment difficulties caused by presence of hypoxic regions, it also makes the tumor treatment of selective targeting hypoxia possible. Bioreductive agents are the most promising hypoxia-selective anti-tumor strategies, and aromatic nitrogen-oxide derivatives have been extensive and in-depth studied in the field of solid tumors therapeutics.3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39) showed good hypoxic anti-tumor activity in vitro and in vivo in our previous research, which was used as the lead compound. The hypoxia related quinoxaline 1,4-dioxide scaffold was remained,2-ethyl sulfone was replaced by substituted benzenesulfonyl amino, or 3-phenyl was replaced by substituted aminomethyl moiety, two series new quinoxaline 1,4-dioxide were designed to improve the physical and chemical properties of molecules as well as remain hypoxia anti-tumor activity.After retro-synthetic analysis of the target compounds, a reasonable synthetic route have been proposed, and 36 new quinoxaline 1,4-dioxide derivatives were synthesized, which was confirmed by 1H NMR and MS. In vitro anti-tumor evaluation revealed that most of the compounds showed moderate to strong inhibitory activity in four tumor cell lines both in hypoxic and normoxic conditions.