Structure-activity relationships of alpha, beta-unsaturated ketones as assessed by their cytotoxicity against oral tumor cells.
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.
Nakayachi
Tohru
T
Department of Dental Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan.
Yasumoto
Eiji
E
Nakano
Kensuke
K
Morshed
Sufi Reza Md
SR
Hashimoto
Ken
K
Kikuchi
Hirotaka
H
Nishikawa
Hirofumi
H
Kawase
Masami
M
Sakagami
Hiroshi
H
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000475:Alkenes; D007659:Ketones; D020169:Caspases