title: 3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells.
abstract: 3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.
authors.affiliation: College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
authors.forename: J R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: V K
authors.initials: VK
authors.lastname: Arora
authors.forename: S L
authors.initials: SL
authors.lastname: Wonko
authors.forename: N W
authors.initials: NW
authors.lastname: Hamon
authors.forename: J W
authors.initials: JW
authors.lastname: Quail
authors.forename: Z
authors.initials: Z
authors.lastname: Jia
authors.forename: R C
authors.initials: RC
authors.lastname: Warrington
authors.forename: W D
authors.initials: WD
authors.lastname: Fang
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008968:Molecular Conformation; D009691:Nucleic Acid Denaturation; D010881:Piperidones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D004273:DNA, Neoplasm; D008298:Maleates; D010881:Piperidones; C014476:diethyl maleate; D005978:Glutathione