title: Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N.
abstract: Tertiary amine N-oxides of DNA intercalators with alkylamino sidechains are a new class of bioreductive drugs. N-oxidation masks the cationic charge of the amines, forming prodrugs with low DNA binding affinity and low toxicity which can be activated selectively by metabolic reduction under hypoxic conditions. This study compares three intercalator N-oxides (NC-NO, DACA-NO and AQ4N), which, respectively, give nitracrine (NC), DACA and AQ4 on reduction. In aerobic cell culture all three N-oxide were much less toxic than the corresponding amines, and showed large increases in cytotoxicity under hypoxia. The topoisomerase poisons DACA and AQ4 (and their N-oxides) were less active against non-cycling than cycling cells. However, only AQ4N was active against the mouse mammary tumour MDAH-MCa-4. This dialkylaminoanthraquinone-di-N-oxide has activity at least as great as the reference bioreductive drug RB 6145 against this tumour, both with and without radiation and when combined with the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA). It is suggested that the high in vivo activity of AQ4N relative to the other topoisomerase-targeted N-oxide, DACA-NO, may be in part due to release in hypoxic cells of an intracalator with sufficiently high DNA binding affinity that it is retained long enough to kill non-cycling cells when they eventually re-enter the cell cycle.
authors.affiliation: Department of Pathology, University of Auckland, New Zealand.
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: S M
authors.initials: SM
authors.lastname: Pullen
authors.forename: K M
authors.initials: KM
authors.lastname: Thompson
authors.forename: A E
authors.initials: AE
authors.lastname: Li
authors.forename: L H
authors.initials: LH
authors.lastname: Patterson
authors.forename: H H
authors.initials: HH
authors.lastname: Lee
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D009564:Nitracrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000494:pharmacology*; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
chemical_list: D000166:Acridines; D000880:Anthraquinones; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011355:Prodrugs; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C001815:C 684; C094428:AQ4N; D009564:Nitracrine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide