Synthesis and SAR Study of Anticancer Protoflavone Derivatives: Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters

Abstract

There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7 and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux.

The Effects of Synthetically Modified Natural Compounds on ABC Transporters

“…Ko143 showed highly potent inhibition of BCRP in vitro however in vivo Ko143 exhibited a short plasma half-life of approximately 1 h [ 81 ]. Thereafter, natural compounds including flavonoid scaffolds, aurones, marine products, quinazoline and chalcone moieties and protoflavones have all been modified to investigate BCRP reversibility [ 77 , 78 , 82 , 83 , 84 , 85 ].…”

“…Protoflavones exhibit collateral sensitivity in MDR cells as they exhibited higher cytotoxicity against MDR cell lines MCF-7/dox and KB-V1 cells that overexpress P-gp and BCRP, respectively [ 85 ]. With the exception of protoapigenone the 51 remaining protoflavones showed no response to the overexpression of BCRP/P-gp [ 85 ].…”

“…Protoflavones exhibit collateral sensitivity in MDR cells as they exhibited higher cytotoxicity against MDR cell lines MCF-7/dox and KB-V1 cells that overexpress P-gp and BCRP, respectively [ 85 ]. With the exception of protoapigenone the 51 remaining protoflavones showed no response to the overexpression of BCRP/P-gp [ 85 ]. The bypassing of ABC transport by designing anticancer drugs that aren’t transported by ABC transporters could also be a viable strategy to overcome MDR resistance [ 85 ].…”

“…With the exception of protoapigenone the 51 remaining protoflavones showed no response to the overexpression of BCRP/P-gp [ 85 ]. The bypassing of ABC transport by designing anticancer drugs that aren’t transported by ABC transporters could also be a viable strategy to overcome MDR resistance [ 85 ]. The evaluation of less potent ABC inhibitors in models where ABC transporter expression are closer to the clinical levels should be investigated further.…”

Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

“…However, the clinical relevance of such inhibitors remains questionable despite the existence of compounds with potent in vitro activity [2]. Alternatively, recent reports revealed several compounds selectively killing cells overexpressing ATPase efflux pumps, such as P-glycoprotein (P-gp/MDR1) and Multidrug resistance associated protein 1 (MRP1/ABC1) [5][6][7][8][9][10]. These molecules were shown to target MDR cancer cells, offering an emerging strategy for anticancer agent development [11,12].…”