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

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.

where R is CH2CH2N(CH3)2; CH2CH(CH3)N(CH3)2; CH2CH2N(CH2CH3)2; CH2CH2N(–CH2CH2CH2CH2–); CH2CH2N(–CH2(CH2)3CH2–); CH2CH2N(–CH2CH2OCH2CH2–); CH2CH2CH2N(CH3)2; CH2CH2(–CHN(CH3)CH2CH2CH2–); CH2CH2N(Bn)2; CH2CH2N(CH3)Bn; CH2CH2NH2; CH2CH2NHCH3.Figure optionsDownload as PowerPoint slide