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Structure-activity relationships of alpha, beta-unsaturated ketones as assessed by their cytotoxicity against oral tumor cells.

Abstract
A series of simple alpha, beta-unsaturated carbonyl compounds (1-26) was characterized for their cytotoxic profiles against oral human normal and tumor cells. Several cycloalkenones showed potent cytotoxic activities against human oral squamous cell carcinoma HSC-2 cell line. Among them, 4,4-dimethyl-2-cyclopenten-1-one (12) exhibited low cytotoxic activity against a normal human cell, gingival fibroblast HGF, and displayed higher tumor-specific cytotoxicity (SI value = CC50 (HGF)/CC50 (HSC-2) = 4.0). The cytotoxicities of the unsaturated lactones were moderately tumor-specific (SI = 1.5-1.9). Agarose gel electrophoresis showed that the induction of internucleosomal DNA fragmentation in human promyelocytic leukemia cell HL-60 is dependent on the structure of alpha, beta-unsaturated carbonyl compounds. Fluorometric protease assay showed that some, but not all compounds, activated the caspase 3 in a dose-dependent manner. All alpha, beta-unsaturated carbonyl compounds studied did not activate caspases 8 and 9. The cytotoxic activity of alpha, beta-unsaturated carbonyl compounds was profoundly reduced in the presence of N-acetylcysteine. The study suggests that the presence of a non sterically hindered Michael acceptor seems to be an essential structural requirement for the cytotoxic activity in alpha, beta-unsaturated ketones.
AuthorsTohru Nakayachi, Eiji Yasumoto, Kensuke Nakano, Sufi Reza Md Morshed, Ken Hashimoto, Hirotaka Kikuchi, Hirofumi Nishikawa, Masami Kawase, Hiroshi Sakagami
JournalAnticancer research (Anticancer Res) 2004 Mar-Apr Vol. 24 Issue 2B Pg. 737-42 ISSN: 0250-7005 [Print] Greece
PMID15161020 (Publication Type: Journal Article)
Chemical References
  • Alkenes
  • Ketones
  • Caspases
Topics
  • Alkenes (chemistry, pharmacology)
  • Carcinoma, Squamous Cell (drug therapy)
  • Caspases (metabolism)
  • Cells, Cultured
  • DNA Fragmentation (drug effects)
  • Drug Screening Assays, Antitumor
  • Enzyme Activation
  • HL-60 Cells
  • Humans
  • Ketones (chemistry, pharmacology)
  • Mouth Neoplasms (drug therapy)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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