title: DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain.
abstract: Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.
authors.affiliation: School of Medicine, Department of Pathology, University of Auckland, New Zealand.
authors.forename: K K
authors.initials: KK
authors.lastname: Valu
authors.forename: T A
authors.initials: TA
authors.lastname: Gourdie
authors.forename: T J
authors.initials: TJ
authors.lastname: Boritzki
authors.forename: G L
authors.initials: GL
authors.lastname: Gravatt
authors.forename: B C
authors.initials: BC
authors.lastname: Baguley
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: L P
authors.initials: LP
authors.lastname: Wakelin
authors.forename: P D
authors.initials: PD
authors.lastname: Woodgate
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000477:Alkylating Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000478:Alkylation; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D004247:DNA / Q000187:drug effects*; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000477:Alkylating Agents; D007364:Intercalating Agents; D004247:DNA; D000816:Aniline Mustard