Discovery of substituted 1,4-dihydroquinolines as novel promising class of P-glycoprotein inhibitors: First structure-activity relationships and bioanalytical studies.

Multidrug resistance (mdr) is the most important problem in the therapeutical treatment of cancer. One central problem in the resistance proceeding is the expression of transmembrane efflux pumps which transport drugs out of the cells. We developed novel substituted 1,4-dihydroquinolines as inhibitors of the transmembrane efflux pump P-glycoprotein. Structure-activity relationships are discussed for this first series. Promising active inhibitors have been identified and first bioanalytical studies have been carried out to address questions of cellular toxicity, P-gp substrate as well as mdr reversal properties.

Discovery of substituted 1,4-dihydroquinolines as novel class of ABCB1 modulators.

Transmembrane efflux pumps are one main cause for multidrug resistance (mdr) of cancer. One hopeful approach to combate the mdr has been the development of inhibitors of the efflux pump activity. A novel class of small-molecule inhibitors of the most important efflux pump ABCB1 (P-glycoprotein) has been discovered. Inhibitory activities are discussed in relation to substituent effects. Most active compounds have been evaluated in first bioanalytical studies to reverse the mdr of an anticancer drug. Cellular toxicity and ABCB1 substrate properties of the compounds were investigated. A cellular induction of relevant efflux pump protein expressions was not observed under inhibitor application, so that our compounds are perspective candidates for further preclinical studies.