Derivatives of aryl amines containing the cytotoxic 1,4-dioxo-2-butenyl pharmacophore.
Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N-myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies.
Department of Chemistry, Acadia University, Wolfville, NS, Canada B4P 2R6. ajha@acadiau.ca
Amitabh
A
Jha
Chandrani
C
Mukherjee
Ashok K
AK
Prasad
Virinder S
VS
Parmar
Manjula
M
Vadaparti
Umashankar
U
Das
Erik
E
De Clercq
Jan
J
Balzarini
James P
JP
Stables
Anuraag
A
Shrivastav
Rajendra K
RK
Sharma
Jonathan R
JR
Dimmock
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000447:Aldehydes / Q000737:chemistry*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000447:Aldehydes; D000588:Amines; D004791:Enzyme Inhibitors; C015977:malealdehyde; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase