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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

Nakayachi T,Yasumoto E,Nakano K,Morshed SR,Hashimoto K,Kikuchi H,Nishikawa H,Kawase M,Sakagami H

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

737-42

issue

2B

eissn

0250-7005

issn

1791-7530

journal_volume

24

pub_type

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