Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells

Peter Werner; Nikoletta Szemeredi; Gabriella Spengler; Andreas Hilgeroth

doi:10.2174/0118715206314406240502054139

Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells

Anticancer Agents Med Chem. 2024 May 3. doi: 10.2174/0118715206314406240502054139. Online ahead of print.

Authors

Peter Werner¹, Nikoletta Szemeredi², Gabriella Spengler², Andreas Hilgeroth¹

Affiliations

¹ Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
² Department of Medical Microbiology, University of Szeged, Dóm tér 10, 6720 Szeged, Hungary.

PMID: 38706362
DOI: 10.2174/0118715206314406240502054139

Abstract

Background: Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties.

Aim: This study aimed to find Novel MDR modulators to effectively combat multidrug resistance in cancer cells.

Objective: We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells.

Methods: Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate.

Results: Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity or restoration of cancer cell sensitivity towards the used anticancer drug.

Conclusion: Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.

Keywords: ABCB1 modulating activity; Drug development; anticancer drug resistance; anticancer drug toxicity.; small-molecules; substituent effects.