1-Aryl-2-dimethylaminomethyl-2-propen-1-one hydrochlorides and related adducts: A quest for selective cytotoxicity for malignant cells.
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.
Pati
Hari N
HN
College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
Das
Umashankar
U
Kawase
Masami
M
Sakagami
Hiroshi
H
Balzarini
Jan
J
De Clercq
Erik
E
Dimmock
Jonathan R
JR
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
C472747:2-dimethylaminomethyl-1-phenyl-2-propen-1-one; D000970:Antineoplastic Agents; D011427:Propiophenones; D020169:Caspases