Electron-deficient DNA-intercalating agents as antitumor drugs: aza analogues of the experimental clinical agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.
Chen
Q
Q
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Deady
L W
LW
Baguley
B C
BC
Denny
W A
WA
D000166:Acridines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism*; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D009287:Naphthyridines; C086210:N-(2-(dimethylamino)ethyl)benzo(b)(1,5)naphthyridine-6-carboxamide; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D004247:DNA