Development of prospective non-toxic inhibitors of ABCB1 activity and expression in a series of selenophenoquinolinones

Abstract

Cancer multidrug resistance (MDR) mediated by overexpression of an ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. Herein, we report the design and synthesis of 12 novel selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells, as well as the mechanism of action. It was found that [3,2-c]selenophenoquinolinones 5b, 5d, and 5e were the most potent chemosensitizers among the studied compounds, however, homopiperazinylmethyl substituted selenopheno[3,2-c]quinolinone 5e had a better cytotoxicity profile. 5e attenuates cell resistance to doxorubicin by inhibiting ABCB1 transporter activity, which was confirmed by the reduced intracellular accumulation of Rhodamine-123, and by suppressing ABCB1 expression, which was proved by the reduced ABCB1 (MDR1) gene expression. These results demonstrate that selenophenoquinolinone is a prospective scaffold for the development of ABCB1 inhibitors for the treatment of MDR cancers.