title: Nitric oxide releasing acridone carboxamide derivatives as reverters of doxorubicin resistance in MCF7/Dx cancer cells.
abstract: 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 N(10) 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.
authors.affiliation: Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India; Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: rajendraprasad.vvs@viper.ac.in.
authors.forename: V V S
authors.initials: VV
authors.lastname: Rajendra Prasad
authors.affiliation: Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India.
authors.forename: G
authors.initials: G
authors.lastname: Deepak Reddy
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ietje
authors.initials: I
authors.lastname: Kathmann
authors.affiliation: Clinical Research Department, Emcure Pharmaceuticals Ltd., Pune, India.
authors.forename: M
authors.initials: M
authors.lastname: Amareswararao
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D054831:Acridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008942:Mitoxantrone / Q000494:pharmacology; D062105:Molecular Docking Simulation; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054831:Acridones; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D004317:Doxorubicin; D008942:Mitoxantrone
keywords: Acridone; Breast cancer; Doxorubicin; Nitric oxide