title: 1-Aryl-2-dimethylaminomethyl-2-propen-1-one hydrochlorides and related adducts: A quest for selective cytotoxicity for malignant cells.
abstract: The primary objective of this study was to discover one or more clusters of compounds which are not equitoxic but display cytoselectivity toward different malignant cells. Furthermore a most important consideration is that such molecules should also display greater cytotoxic potencies to tumors than normal tissues. Two series of compounds are described which meet these criteria, namely the 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochlorides 1a-e and 1-aryl-3-dimethylamino-2-hydroxymethyl-1-propanone hydrochlorides 2a-e. A number of these compounds possess marked cytotoxic potencies (IC(50) and CC(50) values within the 10(-6) and 10(-7) molar range) which are greater than these of the reference drug melphalan. Statistical analyses demonstrated that cytotoxic potencies are influenced by the size of the aryl substituents in series 1 and to some extent by the electronic properties of the aryl groups in series 2. The mode of action of a representative compound 1e in HL-60 cells included inducing apoptosis and activation of caspases -3, -8, and -9.
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
authors.forename: Hari N
authors.initials: HN
authors.lastname: Pati
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011427:Propiophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C472747:2-dimethylaminomethyl-1-phenyl-2-propen-1-one; D000970:Antineoplastic Agents; D011427:Propiophenones; D020169:Caspases