Discovery of pyridine-2-ones as novel class of multidrug resistance (MDR) modulators: first structure-activity relationships.

A novel facile synthesis led to pyridine-2-one target structures of which first series with varying substituents have been yielded and biologically characterized as novel multidrug resistance (MDR) modulators inhibiting P-glycoprotein (P-gp). Structure-activity relationships prove a dependency of the MDR-modulating properties from the kind and positioning of hydrogen bond acceptor functions within the molecular skeleton. Cyano functions turned out as biologically effective substituents for a potential hydrogen bonding to the protein target structure.

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.

Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors.

OBJECTIVES: P-Glycoprotein (P-gp) plays a central role in the development of resistance against cytostatics in anticancer therapy and against human immunodeficiency virus (HIV) therapeutics of the HIV-1 protease inhibitor type. An approach to reverse the so-called multidrug resistance (MDR) phenomenon by the use of P-gp inhibiting agents is a challenge in the therapy of cancer and AIDS. Effective in-vitro inhibitors have P-gp substrate properties so that the expected in-vivo effects have been disappointing so far. Consequent higher dosages cause toxic effects. METHODS: Novel HIV-1 protease inhibitors (H17, JW41, JW33 and JW46) have been evaluated in comparison with ritonavir as P-gp inhibiting agents, in the exclusively P-gp overexpressing model cell line mouse T lymphoma using flow cytometry. The cytotoxic properties against various cell lines were characterized in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay to estimate potential toxic effects in therapeutically relevant concentrations in metabolically active HepG2 cells, drug-sensitive Jurkat cells and in gastric carcinoma cells. KEY FINDINGS: Concentration-dependent effective reversal properties have been discussed in context and proved to be mainly influenced by the number of potential hydrogen bond acceptor functions. The compounds showed no cytotoxic properties in P-gp inhibiting concentration ranges. Ritonavir, a known P-gp substrate, proved to be less toxic in the P-gp expressing cell line than in the nonexpressing cell line at the cell-exposed concentrations and thus showed P-gp substrate properties. Two compounds, H17 and JW41, showed no P-gp substrate properties, with higher toxicity in the P-gp expressing cell line compared with the nonexpressing cell line. CONCLUSIONS: The novel compounds have been shown to be prospective AIDS therapeutics, acting as effective and nontoxic P-gp inhibitors compared with ritonavir, which is a known P-gp inhibitor with unfavourable toxic and P-gp substrate properties.

Impact of novel MDR modulators on human cancer cells: reversal activities and induction studies.

PURPOSE: Novel multidrug resistance (mdr) modulators have been proved as inhibitors of P-glycoprotein (P-gp). We first investigated the in vitro effects of selected compounds in human cancer cells on multidrug resistance reversal effects compared to drug standards and on P-gp induction to characterize the potential of the compounds as clinical candidates. METHODS: The uptake of daunorubicin into a parental cancer cell line and P-gp expressing subcell line in presence of the modulators was characterized by flow cytometry. Induction of P-gp was investigated in P-gp expressing and non-expressing cancer cell lines on the RNA level by real-time quantitative polymerase chain reaction (RTQ-PCR) and protein quantification. Results were additionally confirmed by northern blot techniques and functionality assays in selected cell lines. RESULTS: The novel modulators showed activities as mdr reversers in a P-gp specific human cancer cell model with mainly increased uptake rates of daunorubicin into the drug-resistant cell line. H17 proved to be more active than cyclosporine A as a known strong mdr modulator. The induction studies revealed practically no induction potential of the compounds in usual short-time drug application regimes in all cell lines. Furthermore, the novel modulators did not increase the efflux of a P-gp model substrate in the functionality model assay. This confirmed the results of non-P-gp induction which was observed on both the RNA and the protein levels. CONCLUSIONS: The novel mdr modulators proved as perspective candidates for further clinical studies because they turned out to be highly active in human cancer cell models. Furthermore, they showed no potential to induce the transmembrane efflux pump P-gp. This is a significant advantage compared to modulators which failed in clinical trials because of induction-effects that increase cellular resistances and, moreover, side effects in normal cells.

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.

Structure-activity relationships of novel N-acyloxy-1,4-dihydropyridines as P-glycoprotein inhibitors.

Series of novel N-acyloxy-1,4-dihydropyridines have been synthesized and evaluated as P-glycoprotein inhibitors in an in vitro assay to estimate their potential to act as multidrug resistance modulators in cancer cells. Structure-activity relationships are discussed and prove a significant and regiospecific influence of certain functional groups.