title: Design, synthesis, and DNA sequence selectivity of formaldehyde-mediated DNA-adducts of the novel N-(4-aminobutyl) acridine-4-carboxamide.
abstract: A novel derivative of the anti-tumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) was prepared by reduction of 9-oxoacridan-4-carboxylic acid to acridine-4-carboxylic acid with subsequent conversion to N-(4-aminobutyl)acridine-4-carboxamide (C4-DACA). Molecular modeling studies suggested that a DACA analogue comprising a side chain length of four carbons was optimal to form formaldehyde-mediated drug-DNA adducts via the minor groove. An in vitro transcription assay revealed that formaldehyde-mediated C4-DACA-DNA adducts selectively formed at CpG and CpA dinucleotide sequences, which is strikingly similar to that of formaldehyde-activated anthracenediones such as pixantrone.
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ankers
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Benny J
authors.initials: BJ
authors.lastname: Evison
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia.
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia.
authors.forename: Robert T C
authors.initials: RTC
authors.lastname: Brownlee
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia. Electronic address: s.cutts@latrobe.edu.au.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000378:metabolism*; D018899:CpG Islands; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D004202:Disinfectants / Q000494:pharmacology; D015195:Drug Design; D005557:Formaldehyde / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000166:Acridines; D018736:DNA Adducts; D004202:Disinfectants; D007546:Isoquinolines; D059005:Topoisomerase II Inhibitors; D005557:Formaldehyde; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; C086548:pixantrone
keywords: Acridine-4-carboxamide; DNA adducts; Energy minimized 3D model; Formaldehyde activation; Transcription assay