Nitric oxide releasing acridone carboxamide derivatives as reverters of doxorubicin resistance in MCF7/Dx cancer cells

• Published in: Bioorganic chemistry 2016-02, Vol.64, p.51-58
• Main Authors: Rajendra Prasad, V.V.S., Deepak Reddy, G., Kathmann, Ietje, Amareswararao, M., Peters, G.J.
• Format: Article
• Language: English
• Subjects: Acridone; Acridones - chemical synthesis; Acridones - chemistry; Acridones - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Humans; MCF-7 Cells; Mitoxantrone - pharmacology; Molecular Docking Simulation; Nitric oxide; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2015.11.007

Effect of nitric oxide releasing acridone (compound 14) over drug efflux in drug resistant cancer cell lines. [Display omitted] •NO donating acridones were designed for exogenous release of NO into the cellular environment.•Intracellular release of nitrite from NO donating acridones was substantial.•Nitric oxide release enhanced the accumulation of doxorubicin in MCF7/Dx cell lines.•Nitric oxide releasing group potentiates the cytotoxic effect of the acridones. A series of nitric oxide donating acridone derivatives are synthesized and evaluated for in vitro cytotoxic activity against different sensitive and resistant cancer cell lines MCF7/Wt, MCF7/Mr (BCRP overexpression) and MCF7/Dx (P-gp expression). The results showed that NO-donating acridones are potent against both the sensitive and resistant cells. Structure activity relationship indicate that the nitric oxide donating moiety connected through a butyl chain at N10 position as well as morpholino moiety linkage through an amide bridge on the acridone ring system at C-2 position, are required to exert a good cytotoxic effect. Further, good correlations were observed when cytotoxic properties were compared with in vitro nitric oxide release rate, nitric oxide donating group potentiated the cytotoxic effect of the acridone derivatives. Exogenous release of nitric oxide by NO donating acridones enhanced the accumulation of doxorubicin in MCF7/Dx cell lines when it was coadministered with doxorubicin, which inhibited the efflux process of doxorubicin. In summary, a nitric oxide donating group can potentiate the anti-MDR property of acridones.