N-ethyl morpholine-deca hydroacridine 1, 8-diones as novel P-gp inhibitors and multidrug resistance reversal agents in cancer cells

• Published in: Journal of molecular structure 2025-03, Vol.1325, p.140953, Article 140953
• Main Authors: Eskandari, Masoomeh, Moosavi, Fatemeh, Nazari, Somayeh, Mardaneh, Pegah, Poustforoosh, Alireza, Zargari, Farshid, Mohabbati, Maryam, Saso, Luciano, Edraki, Najmeh, Firuzi, Omidreza
• Format: Article
• Language: English
• Subjects: Anticancer agents; Cell culture; Drug design; Drug resistance; Transporters
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140953

•Eight novel N-Ethyl morpholine-deca hydroacridine 1, 8-diones were synthesized.•P-glycoprotein-mediated multidrug resistance (MDR) reversal was tested in vitro.•Compounds 4a, 4b, 4c, 4f, and 4h inhibited MDR as measured by rhodamine 123 assay.•Compounds 4a, 4b, and 4c reversed resistance to doxorubicin in MDR cancer cells.•None of the compounds exhibited direct cytotoxicity against 3 tested cancer cells. Cancer remains a substantial cause of global mortality. Multidrug resistance (MDR), often arising from the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp), stands as a major contributor to chemotherapy failure. This study seeks to investigate the impact of a set of novel N-ethyl morpholine-deca hydroacridine 1, 8-diones on the reversal of P-gp-induced MDR. Eight novel deca hydroacridine 1, 8-diones hybrids linked to an N-ethyl morpholine ring and featuring diverse aryl moieties at the C9 position of the acridinone core were synthesized. Accumulation of rhodamine 123 (Rhd123) in P-gp overexpressing MES-SA/DX5 cancer cells was evaluated via flow cytometry. The capacity of the compounds to reverse MDR was also examined in MES-SA-DX5 cells. Cytotoxic effect was tested against MCF-7, K562, A549 cancer cell lines using MTT assay. Moreover, docking studies and molecular dynamic simulations were conducted to explore the interactions of derivatives with the binding site of the P-gp transporter. Rhd123 accumulation test in MES-SA/DX5 cells indicated that compounds 4a, 4b, 4c, 4f, and 4h could potentially serve as potent inhibitors of P-gp. Additionally, compounds 4a, 4b, and 4c, bearing 4‑bromo, 4‑chloro, and 2,4-di‑chloro phenyl groups, effectively reversed resistance to doxorubicin when co-incubated with this chemotherapeutic agent in MDR cells. None of the compounds exhibited direct cytotoxicity against cancer cell lines. In silico investigation revealed that these compounds can form various interactions with P-gp and affect its activity. Our findings suggest that the designed compounds exhibit promising potential as MDR reversal agents. [Display omitted]