11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine derivatives as novel topoisomerase I-targeting agents

Abstract

Several 11-substituted benzo[i]phenanthridine derivatives were synthesized, and their TOP1-targeting activity and cytotoxicity were assessed. Comparative data indicate that TOP1-targeting was often the primary molecular target associated with their cytotoxicity. Several 11-aminoalkyl derivatives, 11-aminocarboxy derivatives as well as the 11-[(2-dimethylamino)ethyl]carboxamide of 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine were synthesized and did exhibit considerable cytotoxicity with IC 50 values ranging from 20 to 120 nM in the human lymphoblast tumor cell line RPMI8402.

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…These derivatives (such as 65 ) have less than 10% of the activity of 40 , and the Top1 inhibition correlates poorly with the cytotoxicity, although the methylenedioxy group appears to be a requirement for activity . Aminoalkyl, ester, and carboxamide substituents have been placed at positions 11 and 12, and these some of substituents improve Top1 poisoning activity substantially (such as in 66 ), and several derivatives have nanomolar cytotoxicity (IC 50 ) against the human lymphoblast tumor line RPMI8402 . Dibenzo[ c , h ]cinnolines such as 67 were also prepared, which exhibit more potent Top1 inhibition and cytotoxicity than the corresponding benzo[ i ]phenanthridines and do not have diminished cytotoxicity in MDR1‐overexpressing cells, but exhibit cross‐resistance in 1 ‐resistant cell lines .…”

“…324 Aminoalkyl, ester, and carboxamide substituents have been placed at positions 11 and 12, and these some of substituents improve Top1 poisoning activity substantially (such as in 66), and several derivatives have nanomolar cytotoxicity (IC 50 ) against the human lymphoblast tumor line RPMI8402. [325][326][327] Dibenzo[c,h]cinnolines such as 67 were also prepared, which exhibit more potent Top1 inhibition and cytotoxicity than the corresponding benzo[i]phenanthridines and do not have diminished cytotoxicity in MDR1-overexpressing cells, but exhibit crossresistance in 1-resistant cell lines. 328 A French group later tried to prepare isomeric derivatives of the benzo[i] phenanthridines (benzo[c]phenanthrolines and -phenanthrolinones) where the nitrogen was moved to the A-ring (either position 7 or 8), although these compounds have only modest Top1 poisoning activity that does not correlate with their cytotoxicity.…”

Novel topoisomerase I-targeting antitumor agents synthesized from the N,N,N-trimethylammonium derivative of ARC-111, 5H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N,N,N-trimethylammonium)ethyl]dibenzo[c,h][1,6]naphthyridin-6-one iodide

“… a Topoisomerase I cleavage values are reported as REC, Relative Effective Concentration, these are concentrations relative to topotecan, whose value is arbitrarily assumed to be 1, that are able to produce 10% cleavage of the plamid DNA in the presence of human topoisomerase I. b The biological data for these compounds listed in this table have been reported previously [22]. …”

“…ARC-111 can be readily prepared in overall yields that exceed 58% from 4-hydoxy-6,7-methylenedioxyquinoline. The utility of employing its N , N , N -trimethylammonium derivative as the electrophile was initially reported by our laboratory as a means for the preparation of end-products that would be otherwise problematic [22]. Methods associated with the direct displacement of the quaternary ammonium group with hydroxide, cyclopropylamine, imidazole, 1 H -1,2,3-triazole, N -alkylethylenediamines, ethanolamine, and polyhydroxylated alkylamines are detailed in the present study as a convenient means for furthering insight into the structure–activity relationships within this series of non-camptothecin TOP1-targeting agents.…”

Dual behavior of 2‐tetralone: A new approach for the synthesis of 5‐aryl‐7,8,13,14‐tetrahydrodibenzo[a,i]phenanthridine

“…The literature preparations of the phenanthridine ring system have disadvantages, such as, lengthy syntheses, low yields, and structurally complicated precursors [8, 15–20]. Even a synthesis involving a few steps from simple precursors such as formaldehyde and 2‐methylbenzonitrile affords benzo[c]phenanthridine in a 6% overall yield [15].…”