Evaluation of Novel Diaza Cage Compounds as MRP Modulators in Cancer Cells.

AIM: Novel MRP modulators are needed to combat MRP-mediated multidrug resistance (MDR) in cancer cells. BACKGROUND: Anticancer drug resistance is the main problem in cancer therapy. Causative multidrug efflux pumps are attractive target structures for the development of inhibitors of their activity. OBJECTIVE: We synthesized novel cage dimeric 1,4-dihydropyridines to evaluate them as MRP modulators in cancer cells targeting MRP1, MRP2, and MRP4. METHOD: Cage compounds were synthesized by solution dimerization of monomeric 1,4-dihydropyridines and a final functionalization reaction. The MRP modulation was determined in cellular efflux assays by the use of the flow cytometry technique as well as cellular fluorescent measurements with each fluorescent substrate of the efflux pumps. RESULTS: Difluoro phenyl and methoxy or dimethoxy benzyl substitutions were most favourable for the MRP1 and MRP2 inhibition, whereas monofluor phenyl and dimethoxy benzyl substitutions were most favourable for the MRP4 inhibition. CONCLUSION: Effective inhibitors were identified that were demonstrated to restore the respective cancer cell line sensitivity for the anticancer drug as a proof-of-concept that encourages further preclinical studies.

Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in S. aureus Strains Including MRSA.

BACKGROUND: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance.

Correction: Döring et al. Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy. Molecules 2021, 26, 18.

The authors would like to correct an error made through no fault of their own in the title paper [...].

Discovery of a novel class of small-molecule antibacterial agents against Staphylococcus aureus.

Background: With constantly increasing resistance against the known antibiotics, the search for novel antibacterial compounds is a challenge. The number of synthetic antibacterial agents is limited. Materials & methods: We discovered novel small-molecule antibacterial agents that are accessible via a simple two-step procedure. The evaluation against Staphylococcus aureus showed antibacterial effects depending on the substituent positioning at the residues of the molecular scaffold. Additionally, we investigated the potential of the compounds to increase the antibacterial activity of tetracycline. Results: The most effective antibacterial compounds possessed a 3-methoxy function at an aromatic residue. In combination with tetracycline, we found a strong effect for a few compounds in boosting the antibacterial activity, so the first promising lead compounds with dual activities could be identified.

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy.

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy.

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

Novel Nonsymmetrical 1,4-Dihydropyridines as Inhibitors of Nonsymmetrical MRP-Efflux Pumps for Anticancer Therapy.

Cancer is a strong global burden with increasing numbers of diseases and ongoing anticancer drug resistance. The number of structurally novel anticancer drugs is strongly limited. They cause high costs for the social health systems. Most critical so-called multidrug resistances (MDR) are caused by transmembrane efflux pumps that transport drugs with various structures out of the cancer cells. Multidrug resistance proteins (MRPs) type 1 and 2 are found overexpressed in various kinds of cancer. There is a strong need for inhibitors of those efflux pumps. We developed novel nonsymmetrical 1,4-dihydropyridines as novel inhibitors of cancer relevant MRP types 1 and 2. The structure-dependent activities of the differently substituted derivatives were evaluated in cellular assays of respective cancer cells and are discussed. Promising candidates were identified. One candidate was demonstrated to resensitize a cisplatin resistant cancer cell line and thus to overcome the anticancer drug resistance.