E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: a topographical study of some novel potent cytotoxins.

Abstract

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 microM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.

• Authors: Amitabh Jha, Chandrani Mukherjee, Ashok K Prasad, Virinder S Parmar, Erik De Clercq, Jan Balzarini, James P Stables, Elias K Manavathu, Anuraag Shrivastav, Rajendra K Sharma, Kurt H Nienaber, Gordon A Zello, Jonathan R Dimmock
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 17 Pg. 5854-65 (Sep 01 2007) ISSN: 0968-0896 [Print] England
• PMID: 17562365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytotoxins
• Piperidones

Topics

• Amination
• Animals
• Cell Line
• Cell Survival (drug effects)
• Cytotoxins (chemical synthesis, chemistry, toxicity)
• Humans
• Inhibitory Concentration 50
• Mice
• Models, Molecular
• Molecular Structure
• Piperidones (chemical synthesis, chemistry, toxicity)
• Structure-Activity Relationship