A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues

J. R. Dimmock, M. P. Padmanilayam, R. N. Puthucode, A. J. Nazarali, N. L. Motaganahalli, G. A. Zello, J. W. Quail, E. O. Oloo, H. B. Kraatz, J. S. Prisciak, T. M. Allen, C. L. Santos, J. Balzarini, E. De Clercq, Elias Kurian Manavathu

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Abstract

A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure - activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -σ relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.

Original languageEnglish (US)
Pages (from-to)586-593
Number of pages8
JournalJournal of Medicinal Chemistry
Volume44
Issue number4
DOIs
StatePublished - Feb 15 2001

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Piperidones
Cytotoxins
Structure-Activity Relationship
Melphalan
Jurkat Cells
X Ray Crystallography
Antineoplastic Agents
Inhibitory Concentration 50
Nitrogen
RNA
Apoptosis
Cell Line
DNA
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Dimmock, J. R., Padmanilayam, M. P., Puthucode, R. N., Nazarali, A. J., Motaganahalli, N. L., Zello, G. A., ... Manavathu, E. K. (2001). A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. Journal of Medicinal Chemistry, 44(4), 586-593. https://doi.org/10.1021/jm0002580

A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. / Dimmock, J. R.; Padmanilayam, M. P.; Puthucode, R. N.; Nazarali, A. J.; Motaganahalli, N. L.; Zello, G. A.; Quail, J. W.; Oloo, E. O.; Kraatz, H. B.; Prisciak, J. S.; Allen, T. M.; Santos, C. L.; Balzarini, J.; De Clercq, E.; Manavathu, Elias Kurian.

In: Journal of Medicinal Chemistry, Vol. 44, No. 4, 15.02.2001, p. 586-593.

Research output: Contribution to journalArticle

Dimmock, JR, Padmanilayam, MP, Puthucode, RN, Nazarali, AJ, Motaganahalli, NL, Zello, GA, Quail, JW, Oloo, EO, Kraatz, HB, Prisciak, JS, Allen, TM, Santos, CL, Balzarini, J, De Clercq, E & Manavathu, EK 2001, 'A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues', Journal of Medicinal Chemistry, vol. 44, no. 4, pp. 586-593. https://doi.org/10.1021/jm0002580
Dimmock, J. R. ; Padmanilayam, M. P. ; Puthucode, R. N. ; Nazarali, A. J. ; Motaganahalli, N. L. ; Zello, G. A. ; Quail, J. W. ; Oloo, E. O. ; Kraatz, H. B. ; Prisciak, J. S. ; Allen, T. M. ; Santos, C. L. ; Balzarini, J. ; De Clercq, E. ; Manavathu, Elias Kurian. / A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 4. pp. 586-593.
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AU - Dimmock, J. R.

AU - Padmanilayam, M. P.

AU - Puthucode, R. N.

AU - Nazarali, A. J.

AU - Motaganahalli, N. L.

AU - Zello, G. A.

AU - Quail, J. W.

AU - Oloo, E. O.

AU - Kraatz, H. B.

AU - Prisciak, J. S.

AU - Allen, T. M.

AU - Santos, C. L.

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AU - De Clercq, E.

AU - Manavathu, Elias Kurian

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