title: 6-Substituted 6H-dibenzo[c,h][2,6]naphthyridin-5-ones: reversed lactam analogues of ARC-111 with potent topoisomerase I-targeting activity and cytotoxicity.
abstract: 6-Substituted 8,9-dimethoxy-2,3-methylenedioxy-6H-dibenzo[c,h][2,6]naphthyridin-5-ones were synthesized and evaluated for topoisomerase I-targeting activity and cytotoxicity. Several of these reversed lactam analogues of ARC-111 exhibited exceptional cytotoxicity with IC50 values ranging from 0.5 to 3.0 nM. In contrast to topotecan, no resistance was observed with several of these reversed lactam analogues in tumor cell lines that overexpressed the efflux transporters MDR1 or BCRP.
authors.affiliation: Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
authors.forename: Shejin
authors.initials: S
authors.lastname: Zhu
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Ruchelman
authors.forename: Nai
authors.initials: N
authors.lastname: Zhou
authors.forename: Angela
authors.initials: A
authors.lastname: Liu
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
mesh_terms: D000577:Amides / Q000737:chemistry; D001554:Benzene / Q000737:chemistry*; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007769:Lactams; D009287:Naphthyridines; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D001554:Benzene; D002166:Camptothecin