Cytotoxic 1,4-bis(2-oxo-1-cycloalkylmethylene)benzenes and related compounds.
A series of 1,4-bis(2-oxo-1-cycloalkylmethylene)benzenes 2a-c and 4 and a related acyclic analogue 6a were synthesised and converted to the corresponding Mannich bases 3a-c, 5 and 6b. Evaluation of these compounds against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed that the Mannich bases were more cytotoxic than the corresponding unsaturated ketones. 1,4-bis(3-Dimethylaminomethyl-2-oxo-1-cyclohexylmethylene)benzene dihydrochloride (3a) had lower IC(50) values than melphalan against the four cell lines and was 15 times more potent than this drug when examined against a panel of human tumours.
Dimmock
Jonathan R
JR
College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9. dimmock@skyway.usask.ca
Jha
Amitabh
A
Kumar
Praveen
P
Zello
Gordon A
GA
Quail
J Wilson
JW
Oloo
Eliud O
EO
Oucharek
Jennifer J
JJ
Pasha
Mohammed K
MK
Seitz
Dallas
D
Sharma
Rajendra K
RK
Allen
Theresa M
TM
Santos
Cheryl L
CL
Manavathu
Elias K
EK
De Clercq
Erik
E
Balzarini
Jan
J
Stables
James P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D008352:Mannich Bases