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

Amitabh Jha, Chandrani Mukherjee, Ashok K. Prasad, Virinder S. Parmar, Erik De Clercq, Jan Balzarini, James P. Stables, Elias Kurian Manavathu, Anuraag Shrivastav, Rajendra K. Sharma, Kurt H. Nienaber, Gordon A. Zello, Jonathan R. Dimmock

Research output: Contribution to journalArticle

33 Scopus citations

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 IC50 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 μM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.

Original languageEnglish (US)
Pages (from-to)5854-5865
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number17
DOIs
StatePublished - Sep 1 2007

Keywords

  • 3,5-Bis(arylidene)-4-piperidones
  • Cytostatic activity
  • Human N-myristoyltransferase
  • Molecular modeling
  • Murine toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Jha, A., Mukherjee, C., Prasad, A. K., Parmar, V. S., Clercq, E. D., Balzarini, J., Stables, J. P., Manavathu, E. K., Shrivastav, A., Sharma, R. K., Nienaber, K. H., Zello, G. A., & Dimmock, J. R. (2007). E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: A topographical study of some novel potent cytotoxins. Bioorganic and Medicinal Chemistry, 15(17), 5854-5865. https://doi.org/10.1016/j.bmc.2007.05.065