Recognition of pharmacophore of ar-turmerone for its anticancer activity

For the analysis of structure activity relationship of ar-turmerone analogues, the compounds containing the various substituents on the phenyl ring and 1(or 2)-naphthyl group in the place of phenyl of ar-turmerone were prepared and tested their cytotoxicity against HL-60, K-562, and L1210 leukemia cellsin vitro. The substituents at para position are methoxy, phenoxy, methyl, trifluoromethyl, fluoro, and chloro. Atmeta position methoxy, methyl, trifluoromethyl, or chloro groups and atortho position methoxy or chloro group were introduced. Against HL-60 and K-562 cells, ED₅₀ values of the analogues are ranged from 0.8 to 30.0 μg/ml. Against L1210 cell, these are located more than 20.0 μg/ml. However, 5-carboethoxy-2-methyl-6-(1-naphthyl)-2-octen-4-one (5n) possesses ED50 valuses 0.8, 2.1, 6.5 μg/ml against HL-60, K-562, L1210 cells, respectively. The electronic nature of the subsituents on phenyl ring of ar-turmerone dose not affect the biological activity. Therefore the flat structure of aromatic portion of ar-turmerone analogues is the more important factor for their activity rather than its electronic nature. The potentiation of the cytotoxicity with the enlargement of aromatic ring region also supports the importance of the plane structure of this area. The restriction of the single bond rotation between C-6 and aromatic ring through the introduction of substituents at theortho position of phenyl ring and the increment of size of alkyl group at C-6 position enhances the activity. Therefore the effective conformation should be the one having the orthogonal arrangement between the aromatic ring and the side chain.