title: Cytotoxic and topographical properties of 6-arylidene-2-dimethylaminomethylcyclohexanone hydrochlorides and related compounds.
abstract: A number of 2-arylidenecyclohexanones (1a-h) were converted into the corresponding Mannich bases (2a-h) and (3a,f). Evaluation against murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed the marked cytotoxicity of the Mannich bases and also the fact that almost invariably these compounds were more potent than the precursor enones (1a-h). Further evaluation of most of the Mannich bases towards a panel of nearly 60 human tumour cell lines confirmed their utility as potent cytotoxins. In this assay, the compounds showed growth-inhibiting properties greater than the anticancer alkylator melphalan. QSAR studies revealed that in some cell lines compounds possessing small electron-attracting aryl substituents showed the greatest potencies. Molecular modeling and X-ray crystallography demonstrated that various interatomic distances and torsion angles correlated with cytotoxicity. A representative compound (2a) demonstrated weak inhibiting properties towards human N-myristoyltransferase and stimulated a tyrosine protein kinase. A single dose of 100 mg/kg of most of the compounds did not prove to be lethal in mice.
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. dimmock@skyway.usask.ca
authors.forename: J R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: M
authors.initials: M
authors.lastname: Chamankhah
authors.forename: U
authors.initials: U
authors.lastname: Das
authors.forename: G A
authors.initials: GA
authors.lastname: Zello
authors.forename: J W
authors.initials: JW
authors.lastname: Quail
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: K H
authors.initials: KH
authors.lastname: Nienaber
authors.forename: R K
authors.initials: RK
authors.lastname: Sharma
authors.forename: P
authors.initials: P
authors.lastname: Selvakumar
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J P
authors.initials: JP
authors.lastname: Stables
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008352:Mannich Bases / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003512:Cyclohexanones; D008352:Mannich Bases; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; D011505:Protein-Tyrosine Kinases