Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds

Umashankar Das, H. Inci Gul, Jane Alcorn, Anuraag Shrivastav, Theresa George, Rajendra K. Sharma, Kurt H. Nienaber, Erik De Clercq, Jan Balzarini, Masami Kawase, Noriyuki Kan, Toru Tanaka, Satoru Tani, Karl A. Werbovetz, Adam J. Yakovich, Elias Kurian Manavathu, James P. Stables, Jonathan R. Dimmock

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienyl pharmacophore was incorporated into four series of compounds 1-4. Compounds 1a-g comprised a cluster of 3-arylidene-1-(4-nitrophenylmethylene)-2-oxo-3,4-dihydro-1H-naphthalenes while the analogues 2a-g consisted of a group of 6-arylidene-2-(4-nitrophenylmethylene)cyclohexanones. Three other compounds prepared in this study were 1-(4-nitrophenylmethylene)-3-(3,4,5-trimethoxyphenylmethylene)-2-oxo-2,3-dihydro-1H-indene 3a as well as two 5-arylidene-2-(4-nitrophenylmethylene)cyclopentanones 4a, b. The compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. In general, the compounds in series 1 displayed marked cytotoxicity having IC50 values in the 1-5 μM range while the related cyclohexyl analogues in series 2 were slightly less potent (IC50 figures were mainly 5-10 μM). The relative locations of two aryl rings present in all four series were considered to contribute significantly to bioactivity and may have accounted for the virtual absence of cytotoxic properties in series 3 and 4. Most of the compounds were administered intraperitoneally to mice using doses up to and including 300 mg/kg. No mortalities were noted. The inhibiting effect of most of the compounds towards Helicobacter pylori is noteworthy. The modes of action of representative compounds include the induction of apoptosis while some compounds weakly inhibited tubulin polymerisation and human N-myristoyltransferase.

Original languageEnglish (US)
Pages (from-to)577-585
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume41
Issue number5
DOIs
StatePublished - May 1 2006

Fingerprint

Cyclohexanones
Alkadienes
Naphthalenes
T-cells
Tubulin
Cytotoxicity
Bioactivity
Scaffolds
Inhibitory Concentration 50
Polymerization
Apoptosis
Helicobacter pylori
T-Lymphocytes
Mortality
4-nitrophenyl
glycylpeptide N-tetradecanoyltransferase
indene
cyclopentanone

Keywords

  • Apoptosis
  • Conjugated unsaturated ketones
  • Cytotoxicity
  • Molecular modelling
  • Rodent toxicity
  • Structure-activity relationships

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Das, U., Gul, H. I., Alcorn, J., Shrivastav, A., George, T., Sharma, R. K., ... Dimmock, J. R. (2006). Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds. European Journal of Medicinal Chemistry, 41(5), 577-585. https://doi.org/10.1016/j.ejmech.2005.12.014

Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds. / Das, Umashankar; Gul, H. Inci; Alcorn, Jane; Shrivastav, Anuraag; George, Theresa; Sharma, Rajendra K.; Nienaber, Kurt H.; De Clercq, Erik; Balzarini, Jan; Kawase, Masami; Kan, Noriyuki; Tanaka, Toru; Tani, Satoru; Werbovetz, Karl A.; Yakovich, Adam J.; Manavathu, Elias Kurian; Stables, James P.; Dimmock, Jonathan R.

In: European Journal of Medicinal Chemistry, Vol. 41, No. 5, 01.05.2006, p. 577-585.

Research output: Contribution to journalArticle

Das, U, Gul, HI, Alcorn, J, Shrivastav, A, George, T, Sharma, RK, Nienaber, KH, De Clercq, E, Balzarini, J, Kawase, M, Kan, N, Tanaka, T, Tani, S, Werbovetz, KA, Yakovich, AJ, Manavathu, EK, Stables, JP & Dimmock, JR 2006, 'Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds', European Journal of Medicinal Chemistry, vol. 41, no. 5, pp. 577-585. https://doi.org/10.1016/j.ejmech.2005.12.014
Das, Umashankar ; Gul, H. Inci ; Alcorn, Jane ; Shrivastav, Anuraag ; George, Theresa ; Sharma, Rajendra K. ; Nienaber, Kurt H. ; De Clercq, Erik ; Balzarini, Jan ; Kawase, Masami ; Kan, Noriyuki ; Tanaka, Toru ; Tani, Satoru ; Werbovetz, Karl A. ; Yakovich, Adam J. ; Manavathu, Elias Kurian ; Stables, James P. ; Dimmock, Jonathan R. / Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds. In: European Journal of Medicinal Chemistry. 2006 ; Vol. 41, No. 5. pp. 577-585.
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AU - Alcorn, Jane

AU - Shrivastav, Anuraag

AU - George, Theresa

AU - Sharma, Rajendra K.

AU - Nienaber, Kurt H.

AU - De Clercq, Erik

AU - Balzarini, Jan

AU - Kawase, Masami

AU - Kan, Noriyuki

AU - Tanaka, Toru

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