Discovery of stereospecific cytotoxicity of (8R,8'R)-trans-arctigenin against insect cells and structure-activity relationship on aromatic ring.

One of the arctigenin stereoisomers, (8R,8'R)-trans-form 1, showed stereospecific cytotoxicity against insect cells, Sf9 and NIAS-AeAl-2 cells. By the comparison with other stereoisomers, the most importance of the 8'R stereochemistry for the higher activities was clarified. On the other hand, the wider range of activity level among stereoisomers against cancer cells, HL-60, was not observed. The structure-activity relationship research using derivatives bearing (8R,8'R)-trans-form was performed to show the same level of activities of 3-iodo, 4-iodo, and 3,4-methylenedioxy derivatives 28, 29, and 36 as (8R,8'R)-trans-arctigenin 1. In the examination of thiono derivatives, 4-iodo thiono and 3,4-methylenedioxy thiono derivatives 66, 67 showed similar level of activities to that of (8R,8'R)-trans-arctigenin 1. The expression of ribosomal 28S rRNA gene of Sf9 cells was increased by (8R,8'R)-trans-arctigenin 1, whereas a degradation of DNA was not observed.

Design of 92 New 9-Norlignan Derivatives and Their Effect on Cell Viabilities of Cancer and Insect Cells.

Ninety-two new 9-norlignan derivatives containing more effective compounds against both cancer and insect cells than lead compounds were synthesized. Against HeLa cells, 7-(3,4-dimethoxyphenyl)-7'-(3'-hydroxy-4'-methoxyphenyl) derivative 63 (IC50 = 0.9 ± 0.2 µM) was to be around 6-fold more potent than lead compound 5. Moreover, against HL-60 cells, 7-(4-trifluoromethylphenyl)-7'-(3'/4'-hydroxyphenyl) derivatives 78 and 79 (IC50 = 2.2 ± 0.4 µM and 2.4 ± 0.6 µM) were 3-fold more potent than lead compound 5. Furthermore, against Sf9 cells from the common cutworm, the 7-(4-trifluoromethylphenyl) derivatives bearing electron-withdrawing groups 76-96 showed a wider range of activity (around 20-fold difference), giving valuable information on the structure-activity relationship. The 7-(4-trifluoromethylphenyl)-7'-(2'/3'-hydroxyphenyl) derivatives 77 and 78 (IC50 = 4.7 ± 0.6 µM and 4.9 ± 0.9 µM) had around 2-fold higher activity against Sf9 cells than lead compound 5. The 7-(4-trifluoromethylphenyl)-7'-(3'-hydroxyphenyl) derivative 78 was also effective against mosquito NIAS-AcAl-2 cells with an IC50 value of 5.4 ± 0.3.

Effects of Substituents on the Aromatic Ring of Lignano-9,9'-lactone on Plant Growth Inhibitory Activity.

The relationship between the structure of lignano-9,9'-lactone (2,3-dibenzylbutyrolactone) and its activity as a plant growth regulator has been clarified. Derivatives with higher plant growth inhibitory activity than natural dimethylmatairesinol 4 were synthesized. The 2-hydroxy-7- Z-ene derivative 42 displayed growth inhibitory activity against both the shoots (IC50 = 0.65 mM) and roots (IC50 = 0.43 mM) of lettuce seedlings. Regiospecific activity was observed. The 2,3-dihydroxy derivative 24 showed the highest growth inhibitory activity against both the shoots (IC50 = 0.36 mM) and roots (IC50 = 0.13 mM) of Italian ryegrass seedlings. A similar level of activity to 24 against just the roots of Italian ryegrass seedlings was maintained when the hydroxy group at position 3 of the 2,3-dihydroxy derivative 24 was replaced by a fluorine atom. The (2-hydroxy,4-fluoro)-derivative 33 also showed growth inhibitory activity against both the shoots (IC50 = 0.79 mM) and roots (IC50 = 0.14 mM) of Italian ryegrass seedlings. The level of activity was found to depend on the positions of the two hydroxy groups or the hydroxy group and fluorine atom on the aromatic ring. The importance of the lignano-9,9'-lactone structure was also shown.