Anticancer Research 2004-01-01

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

Tohru Nakayachi, Eiji Yasumoto, Kensuke Nakano, Sufi Reza Md Morshed, Ken Hashimoto, Hirotaka Kikuchi, Hirofumi Nishikawa, Masami Kawase, Hiroshi Sakagami

文献索引：Anticancer Res. 24(2B) , 737-42, (2004)

全文：HTML全文

摘要

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.