Structure-activity relationship in potentially anti-tumor promoting benzalacetone derivatives, as assayed by the epstein-barr virus early antigen activation.
The in vitro anti-tumor promoting activities of antimutagenic benzalacetone (4-phenyl-3-buten-2-one), its monosubstituted derivatives and related compounds, cinnamaldehydes and cinnamic acids, were evaluated by determining the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. In this short-term assay, benzalacetone, which is the basic structure of dehydrozingerone (one-half analog of curcumin) inhibited the EBV-EA activation; the IC(50) value, the molar ratio of benzalacetone to TPA needed for inhibiting 50% of positive cells activated with 32 pmol TPA, was 129. IC(50) values of 2- and 4-methoxybenzalacetones were about one-half of that of benzalacetone and the methoxy compounds were more effective than hydroxybenzalacetones. IC(50) values of chloro- and trifluoromethyl-benzalacetones were higher than that of benzalacetone, indicating that these compounds are weaker inhibitors. In addition, the position of a substituent on the benzene ring affected the inhibitory effect. In benzalacetone derivatives substituted by a hydroxy-, methoxy-, chloro- or trifluoromethyl group, the 2-substituted derivatives exhibited the strongest inhibitory effect, followed by the 3- and the 4-substituents. Cinnamic acid derivatives also decreased the inhibitory effects in the same order. In the side chain of benzalacetone, the terminal group adjacent to the carbon-carbon double bond also affected the inhibitory effect. The conversions of the methylketone to aldehyde and carboxyl groups, i.e., cinnamaldehyde and cinnamic acid, increased the inhibitory effect: the IC(50) values were about one-third of that of benzalacetone. beta-Methyl styrene, which in the side chain has no carbonyl group adjacent to the double bond, inhibited the EBV-EA activation at the concentration of about one-third of that of benzalacetone, indicating that the carbonyl group negatively affects the inhibitory effect. This agreed with the previous observation between isoeugenol and dehydrozingerone, 4-hydroxy-3-methoxy derivatives of beta-methyl styrene and benzalacetone, respectively. The mechanism of the EBV-EA activation inhibition was discussed by being compared with the inhibition of mutagenesis for which the unsaturated bonded-carbonyl system is necessary.
Motohashi
N
N
Department of Radiopharmacy, Kobe Pharmaceutical University, Motoyamakita-machi 4-19-1, Higashinada-ku, Kobe, Japan. motohasi@kobepharma-u.ac.jp
Yamagami
C
C
Tokuda
H
H
Okuda
Y
Y
Ichiishi
E
E
Mukainaka
T
T
Nishino
H
H
Saito
Y
Y
D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000956:Antigens, Viral / Q000032:analysis / Q000096:biosynthesis*; D016587:Antimutagenic Agents / Q000494:pharmacology; D002074:Butanones / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects*
D000956:Antigens, Viral; D016587:Antimutagenic Agents; D002074:Butanones; D002934:Cinnamates; C033305:Epstein-Barr virus early antigen; C029010:cinnamic acid; D000171:Acrolein; C025383:benzylideneacetone; D013755:Tetradecanoylphorbol Acetate; C012843:cinnamaldehyde