Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties.

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.

Novel structure-activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators.

Synthesized series of cage dimeric 1,4-dihydropyridines have been systematically evaluated as MDR modulators in in vitro assays to investigate structure-dependent selectivity properties of inhibiting most cancer-relevant efflux pump proteins. Structure-activity relationships of each P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP) 1 and MRP2 inhibition are discussed and prove to be mainly determined by certain aromatic substitution patterns. The characterization of breast cancer resistance protein (BCRP) inhibition results in the discovery of benzyloxy substituted derivatives as selective P-gp inhibitors.

Novel structurally varied N-alkyl 1,4-dihydropyridines as ABCB1 inhibitors: structure-activity relationships, biological activity and first bioanalytical evaluation.

Series of structurally varied N-alkyl 1,4-dihydropyridines and novel benzo-annelated derivatives as 1,4- dihydroquinolines have been characterized as ABCB1 inhibitors. Structure-activity relationships (SARs) are discussed. Cytotoxic activities of selected compounds have been determined. A first bioanalysis of ABCB1 substrate properties has been carried out in a cell-based model. Compounds with highest ABCB1 inhibiting activities were no substrates of ABCB1 and not transported by the efflux pump, thus profiling the new ABCB1 inhibitors.

First biological evaluation of developed 3-benzyloxyfluorenes as novel class of MDR modulators.

A series of 3-benzyloxy-1-aza-9-oxafluorenes has been synthesized and biologically evaluated as novel MDR modulators. The concentration dependent inhibition of the efflux pump ABCB1 (P-glycoprotein) has been characterized and is discussed in relation to calculated lipophilicity data. Instead of the molecular lipophilicity the exact positioning of functional groups was found decisive for the biological activities.

Recent advances in the development of P-gp inhibitors.

During the last decades multidrug resistance (MDR) emerged as main problem in the anti-cancer therapy with cytostatically active agents. Classical as well as recently developed cytostatics develop the phenomenon of loosing activity in former drug-sensitive cells. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. As the attempt to overcome MDR by the use of inhibitors of the efflux pump activities turned out as most promising effect, the development of P-gp inhibitors has been a challenge for medicinal chemists. The article reviews the advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements. The success has been the reduction of cytotoxic properties. The undesired activities could be much lowered in the case of compound classes that were derived from pharmacologically active drugs. Undesired drug interactions and limited in vivo activities are still a problem.

Novel insight in structure-activity relationship and bioanalysis of P-glycoprotein targeting highly potent tetrakishydroxymethyl substituted 3,9-diazatetraasteranes.

Novel 3,9-diazatetraasteranes have been synthesized with varied aromatic substitution patterns and evaluated as P-glycoprotein (P-gp) inhibitors. Structure-activity relationships (SAR) are discussed in relation to determined physicochemical properties. The potential to induce P-gp expression has been evaluated in cancer cell lines. The bioanalytical results indicate favorable noninducing properties compared to P-gp inducing drug standard.