Structure-Activity Relationships of α, β-Unsaturated Ketones as Assessed by their Cytotoxicity against Oral Tumor Cells

A series of simple α, β-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 = CC 50 (HGF)/CC 50 (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 α, β-unsaturated carbonyl compounds. Fluorometric protease assay showed that some, but not all compounds, activated the caspase 3 in a dose-dependent manner. All α, β-unsaturated carbonyl compounds studied did not activate caspases 8 and 9. The cytotoxic activity of α, β-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 α, β-unsaturated ketones.