title: Cytotoxic evaluation of some 3,5-diarylidene-4-piperidones and various related quaternary ammonium compounds and analogs.
abstract: A number of 3,5-diarylidene-4-piperidones (1) and some related quaternary ammonium salts (5) as well as closely related analogs were prepared principally as candidate cytotoxic agents in two screens. The first test system used an average of 54 human tumor cell lines from eight neoplastic diseases, namely leukemia, melanoma, colon, non-small-cell lung, small-cell lung, central nervous system, ovarian, and renal cancers. Selective toxicity was demonstrated by some of the compounds, especially toward leukemia. The second screen used L1210 lymphoid leukemia cells. In general, the compounds were less cytotoxic than the reference drug melphalan in both screens. Linear plots were made between the Hammett (sigma), fragment (f), and molar refractivity (MR) constants of the nuclear substituents in series 1 and 5 with the IC50 figures of both the human tumor cell lines and L1210 cells. Evaluation against the human tumor cell lines revealed that increases in the f values were correlated with elevation of cytotoxicity in both series 1 and 5; MR constants were also important in series 5. In the L1210 screen, sigma and MR constants were positively correlated with cytotoxicity. X-ray crystallography was undertaken on 3,5-bis-[[4'-(methylthio)phenyl]methylene]-1-methyl-4-piperidone methiodide (5d), which had significant cytotoxicity, and 3,5-bis(4-pyridylmethylene)-1-methyl-4-piperidone methiodide (6), which was virtually inactive in both screens.(ABSTRACT TRUNCATED AT 250 WORDS)
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: J W
authors.initials: JW
authors.lastname: Quail
authors.forename: U
authors.initials: U
authors.lastname: Pugazhenthi
authors.forename: T M
authors.initials: TM
authors.lastname: Allen
authors.forename: G Y
authors.initials: GY
authors.lastname: Kao
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014780:Viruses / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D010880:Piperidines; D000644:Quaternary Ammonium Compounds