[Show abstract][Hide abstract] ABSTRACT: Novel N- and 4-substituted 1,4-dihydropyridines with a C2-symmetric molecular scaffold have been profiled as highly active modulators of the transmembrane efflux pump P-glycoprotein (P-gp, ABCB1) in an exclusively P-gp overexpressing cell line model. Structure–activity relationships have been discussed for varied substituents of both the N- and the 4-residue. The influence of potential hydrogen bond acceptor functions has been characterized in relation to the number and position of the substituents. Cellular toxicity has been closely considered and the P-gp substrate properties are suggested as the limiting molecular properties of known P-gp modulators. The non-toxicity and non-substrate properties of our novel inhibitors qualify this novel compound class as a prospective tool to effectively combat the efflux pump-mediated cellular resistance of anticancer drug substrates, as could be demonstrated in the first in vitro studies.
Preview · Article · Feb 2015 · Medicinal Chemistry Communication
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Nov 2012 · Medicinal chemistry (Shāriqah (United Arab Emirates))
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Nov 2012 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Feb 2010 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jun 2009 · Anti-cancer agents in medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Sep 2008 · Journal of Medicinal Chemistry