Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones and related compounds

Jonathan R. Dimmock, Amitabh Jha, Gordon A. Zello, J. Wilson Quail, Eliud O. Oloo, Kurt H. Nienaber, Earl S. Kowalczyk, Theresa M. Allen, Cheryl L. Santos, Erik De Clercq, Jan Balzarini, Elias Kurian Manavathu, James P. Stables

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC50 values of 54% of the enones were less than 10 μM when all four screens were considered and less than 1 μM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett σ, Hansch π and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.

Original languageEnglish (US)
Pages (from-to)961-972
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume37
Issue number12
DOIs
StatePublished - Dec 1 2002

Fingerprint

Piperidones
Toxicity
X Ray Crystallography
Tumor Cell Line
Amides
Antineoplastic Agents
Inhibitory Concentration 50
T-cells
X ray crystallography
Cytotoxicity
Bioactivity
T-Lymphocytes
Torsional stress
Tumors
Assays
Refractive index
Cells

Keywords

  • 4-Piperidones
  • Cytotoxicity
  • Murine toxicity
  • Structure-activity relationships

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones and related compounds. / Dimmock, Jonathan R.; Jha, Amitabh; Zello, Gordon A.; Quail, J. Wilson; Oloo, Eliud O.; Nienaber, Kurt H.; Kowalczyk, Earl S.; Allen, Theresa M.; Santos, Cheryl L.; De Clercq, Erik; Balzarini, Jan; Manavathu, Elias Kurian; Stables, James P.

In: European Journal of Medicinal Chemistry, Vol. 37, No. 12, 01.12.2002, p. 961-972.

Research output: Contribution to journalArticle

Dimmock, JR, Jha, A, Zello, GA, Quail, JW, Oloo, EO, Nienaber, KH, Kowalczyk, ES, Allen, TM, Santos, CL, De Clercq, E, Balzarini, J, Manavathu, EK & Stables, JP 2002, 'Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones and related compounds', European Journal of Medicinal Chemistry, vol. 37, no. 12, pp. 961-972. https://doi.org/10.1016/S0223-5234(02)01414-9
Dimmock, Jonathan R. ; Jha, Amitabh ; Zello, Gordon A. ; Quail, J. Wilson ; Oloo, Eliud O. ; Nienaber, Kurt H. ; Kowalczyk, Earl S. ; Allen, Theresa M. ; Santos, Cheryl L. ; De Clercq, Erik ; Balzarini, Jan ; Manavathu, Elias Kurian ; Stables, James P. / Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones and related compounds. In: European Journal of Medicinal Chemistry. 2002 ; Vol. 37, No. 12. pp. 961-972.
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abstract = "A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC50 values of 54{\%} of the enones were less than 10 μM when all four screens were considered and less than 1 μM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett σ, Hansch π and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.",
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AU - Dimmock, Jonathan R.

AU - Jha, Amitabh

AU - Zello, Gordon A.

AU - Quail, J. Wilson

AU - Oloo, Eliud O.

AU - Nienaber, Kurt H.

AU - Kowalczyk, Earl S.

AU - Allen, Theresa M.

AU - Santos, Cheryl L.

AU - De Clercq, Erik

AU - Balzarini, Jan

AU - Manavathu, Elias Kurian

AU - Stables, James P.

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N2 - A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4- piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC50 values of 54% of the enones were less than 10 μM when all four screens were considered and less than 1 μM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett σ, Hansch π and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.

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