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The new lignano-9,9'-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC 50 =12μM), however, it was inactive against HeLa cells (EC 50 >100μM). The synthesized (3,4-dichloro, 2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the lignano-9,9'-lactone structures showed the EC 50 values of 10μM and 9.4μM against HL-60 cells, respectively. Against HeLa cells, the EC 50 value of the derivative 66 was 27μM. By comparing the activities with the corresponding 9,9'-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold difference., (Copyright © 2017. Published by Elsevier Ltd.)

The structure-activity relationship of the antifungal fluorinated dihydroguaiaretic acid derivatives was evaluated. Some of the newly synthesized lignan compounds were found to show higher antifungal activity against phytopathogenic fungi such as Alternaria alternata (Japanese pear and apple pathotypes) and A. citri than the lead compound, 3-fluoro-3'-methoxylignan-4'-ol (3). The broad antifungal spectrum of 3'-hydroxyphenyl derivative 16 was observed, and the 3'-fluoro-4'-hydroxyphenyl derivative 38 was found to show the highest activity against the A. alternata Japanese pear pathotype, with an EC 50 value of 11 μM. The preventive effect of the potent lignan on the infection of A. alternata in the Japanese pear's leaves was also shown.

We compared the cytotoxic activities of dietary epoxylignans and their stereoisomers and found (-)-verrucosin, which is (7S,7'R,8R,8'R)-7,7'-epoxylignan, to be the most cytotoxic epoxylignan against HeLa cells (IC50 = 6.6 μM). On the other hand, the activity was about a factor of 10 less against HL-60. In this research on the relationship between the structure and cytotoxic activity of (-)-verrucosin 13, the 7-(4-methoxyphenyl)-7'-(3,4-dimethoxyphenyl) derivative 60, for which the activity (IC50 = 2.4 μM) is three times greater than (-)-verrucosin 13, was discovered. The induction of apoptosis by caspase 3/7 was observed upon treatment with the (-)-verrucosin derivative.

All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7'-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC50=16-20 μM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (-)-Kadangustin J showed stereospecific cytotoxic activity (IC50=47-67 μM). Since (R)-9'-fluoro derivative 23 was most potent (IC50=19 μM) among the corresponding fluoro stereoisomers, (R)-9'-alkyl derivatives were synthesized, hydrophobic 9'-heptyl derivative 27 showing highest activity (IC50=3.7 μM against HL-60, IC50=3.1 μM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9'-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cytotoxic activities of synthesized lignan derivatives were estimated by WST-8 reduction assay against HL-60 and HeLa cells to show the structure-activity relationship. The activities of some effective compounds were examined against Colon 26 and Vero cells. Dietary secoisolariciresinol (SECO, 1) and its metabolite, 9,9'-anhydrosecoisolariciresinol (2), did not show the cytotoxic activity. On the other hand, all stereoisomers of dihydroguaiaretic acid (DGA, 9,9'-dehydroxysecoisolariciresinol, 3-5) exhibited the activity (IC50: around 30 μM). The IC50 value of (8R,8'R)-9-butyl DGA derivative 13 was around 6 μM. This fact means that the hydrophobic group was advantageous for higher activity at 9- and 9'-positions. By the evaluation of the effect of 7and 7'-aryl group on the activity, we discovered the highest activity of (8R,8'R)-7-(3-hydroxy-4-methoxyphenyl)-7'-(2-ethoxyphenyl) DGA derivative 47 showing around 1 μM of IC50 value, which is about 24-fold higher activity than that of natural (8R,8'R)-DGA. The derivative of dietary lignan showed the high cytotoxic activity.

The relationship between antifungal activity against Alternaria alternata and structure on the 7-phenyl group of (+)-dihydroguaiaretic acid ((+)-DGA) was clarified by employing 38 synthesized (+)-DGA derivatives. The results were identified by quantitative structure-activity relationship (QSAR) analysis employing the Hansch-Fujita method. Some compounds showed higher activity than (+)-DGA. The compound showing highest activity was 3,5-difluorophenyl derivative 37. It was suggested that the small electron-withdrawing group at the meta-position of the 7-phenyl group is important for the higher activity by antifungal test and Hansch-Fujita analysis. The whitening activity of 3-hydroxy-4-methoxyphenyl derivative 28, 3-hydroxy-4-ethoxyphenyl derivative 29, and 3-hydroxy-4-isopropoxyphenyl derivative 30 against A. alternata Japanese pear pathotype was also discovered.

The cytotoxic activities of sesquilignans, (7S,8S,7'R,8'R)- and (7R,8R,7'S,8'S)-morinol A and (7S,8S,7'S,8'S)- and (7R,8R,7'R,8'R)-morinol B were compared, showing no significant difference between stereoisomers (IC50=24-35 μM). As a next stage, the effect of substituents at 7, 7', and 7"-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7'R,8'R)-7,7',7"-phenyl derivative 18 (IC50=6-7 μM). In the research on the structure-activity relationship of 7"-position of (7S,8S,7'R,8'R)-7,7',7"-phenyl derivative 18, the most potent compounds were 7,7',7"-phenyl derivative 18 (IC50=6 μM) against HeLa cells. Against HL-60 cells, 7"-(4-nitrophenyl)-7,7'-phenyl derivative 33 and 7"-hexyl-7,7'-phenyl derivative 37 (IC50=5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7'R,8'R)-morinol A. It was also confirmed that the 7'-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Using 21 newly synthesized 7,7'-dioxo-9,9'-epoxylignane derivatives having a modified 7-phenyl group, we examined the relationship between their structure and antifungal activity against plant pathogens such as Bipolaris oryzae to determine the effects of various substituents on the antifungal activity. Compared with the lead compound having a 4-OH-3-CH(3)O-phenyl moiety, several analogs showed higher antifungal activity against B. oryzae, including the compound having an unsubstituted phenyl group and those having either of the following phenyl substituents: 2-OH, 4-CH(3)O, 4-C(2)H(5)O, 4-n-C(3)H(7)O, 4-n-C(4)H(9)O, 4-CF(3)O, 4-C(2)H(5), or 4-Cl. On the other hand, the activity of compounds having a branched substituent, such as 4-i-C(3)H(7)O or 4-i-C(3)H(7), on the 7-phenyl group or a multi-substituted phenyl group was equipotent or inferior to that of the lead compound. These results as well as correlations between the antifungal activity of the test compounds and the physicochemical parameters of the varied substituents suggest that the position of substitution on the 7-phenyl group and the incorporation of substituents with optimal physicochemical properties are important for exerting the antifungal activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Flaxseed lignan, secoisolariciresinol has been reported to possess health benefits. We previously synthesized each stereoisomer of secoisolariciresinol and found that (-)-secoisolariciresinol reduces lipid accumulation and induces adiponectin production in 3T3-L1 adipocytes. Here we show the effects of (-)-secoisolariciresinol on high-fat diet-induced obesity in C57BL/6 male mice. Oral administration of (-)-secoisolariciresinol for 28 consecutive days significantly suppressed the gain of body weight. Increased serum adiponectin level and decreased gene expression of fatty acid synthase and sterol regulatory element-binding protein-1c in liver, which are related to fatty acid synthesis, were observed in the mice orally administered with (-)-secoisolariciresinol. In addition, subcutaneous injection of (-)-secoisolariciresinol also significantly suppressed the gain of body weight. Serum leptin levels were significantly increased by treating with (-)-secoisolariciresinol or (-)-enterolactone. Subcutaneous injection of (-)-secoisolariciresinol, (-)-enterolactone, or (-)-enterodiol promoted gene expression of acyl-CoA oxidase, carnitine palmitoyl transferase-1, and peroxisome proliferator-activated receptor α, which are related to β-oxidation. Overall results suggest that (-)-secoisolariciresinol exerts a suppressive effect on the gain of body weight of mice fed a high-fat diet by inducing gene expression of adiponectin, resulting in the altered expression of various genes related to the synthesis and β-oxidation of fatty acids.

Matairesinol is one of the lignan compounds found in a variety of plant foodstuffs. We investigated the immunomodulatory effects of (-)-matairesinol in vivo and ex vivo by using mice. Although we found no significant differences in the IgG, IgA and IgM levels in the serum, the IgE level was strongly suppressed by the uptake of (-)-matairesinol in both intact and ovalbumin-immunized mice. The immunoglobulin produced by lymphocytes from the spleen was not activated by the intake of (-)-matairesinol. However, lymphocytes in such gut-associated lymphatic tissues as Peyer's patches and mesenteric lymph nodes were activated by the administration of (-)-matairesinol.

We have found that (-)-virgatusin and related compounds have antimicrobial and antifungal activity. To identify further biological activities of these compounds, we tested the activity of acridine orange efflux, which shows ionophore-like disruption of cellular ion homeostasis activity. After testing 31 compounds, we found that verrucosin and a related compound had disruption activity.

The relationship between the structure of naturally occurring (7R,7'R,8R,8'R)-morinol B and its antifungal activity was examined. 3-Demethoxy morinol B showed much higher activity than the natural compound. The activity of the 4-butoxy-3-demethoxy derivative was higher than that of 3-demethoxy morinol B.

The IgE-suppressive activity of (-)-matairesinol is demonstrated, and the structure-activity relationship of (-)-matairesinol clarified. 3',4-Dihydroxy-3,4'-dimethoxylignano-9,9'-lactone showed higher IgE-suppressive activity than (-)-matairesinol without any cytotoxic activity. Some derivatives bearing a longer and more bulky alkoxy group at the 3 or 4 position showed IgE-accelerative activity.

The relationship between the stereochemistry and antimicrobial activity of butane-type lignans was clarified. All stereoisomers of dihydroguaiaretic acid (DGA) showed both antibacterial and antifungal activity. The (+)- and (-)-7,7'-dioxodihydroguaiaretic acid (ODGA) also showed both antibacterial and antifungal activity, while meso-ODGA did not show antibacterial activity, but showed antifungal activity. No activity of any stereoisomer of secoisolariciresinol (SECO) was apparent.

The syntheses of all stereoisomers of tetrasubstituted tetrahydrofuran lignan were accomplished, and the antimicrobial activity was examined. The 9,9'-diol compound bearing (7R,7'R,8R,8'R) and (7R,7'S,8R,8'R) stereochemistry showed the strongest antibacterial activity against Listeria denitrificans and Bacillus subtilis, respectively. It was also found that (-)-virgatusin bearing (7S,7'R,8S,8'S) stereochemistry had strongest antifungal activity.

As we have reported, flaxseed lignan, (+)-secoisolariciresinol (SECO), (-)-SECO, and meso-SECO were stereoselectively synthesized and their biological functions were evaluated. In the present study, we focused on the effects of SECOs on the regulation of 3T3-L1 adipocytes, and identified the structure-activity relationships. Optically active SECO and meso-SECO were tested for their effects on lipid metabolism in 3T3-L1 adipocytes. (-)-SECO accelerated adiponectin production of 3T3-L1 adipocytes. On the other hand, (+)- and meso-SECO suppressed the production of adiponectin. In addition, triglyceride (TG) accumulation in 3T3-L1 adipocytes was significantly suppressed by all three SECOs tested here, as was 17beta-estradiol, when the SECOs were added to the medium during induction of 3T3-L1 preadipocytes to adipocytes. Especially, (-)-SECO strongly reduced TG accumulation. It is well-known that SECO has estrogen-like activity. Hence the estrogen-like activity of each SECO compound was assessed. Only (-)-SECO had estrogen-like activity.

The antimicrobial activity of all stereoisomers of morinols A and B was tested. All stereoisomers of morinols A and B showed antifungal activity against Alternaria alternata, especially (-)-morinol B which showed the strongest activity. The natural component, (+)-morinol A, and unnatural stereoisomer, (7S,7'S,8R,8'R)-morinol B, showed antibacterial activity against the gram-positive bacteria, Bacillus subtilis and Listeria denitrificans.

The antioxidant activity of butane-type lignans was evaluated. Secoisolariciresinol (SECO) and dihydroguaiaretic acid (DGA) showed higher radical scavenging activity than that of 7,7'-dioxodihydroguaiaretic acid (ODGA). SECO and DGA inhibited the oxidation of unsaturated fatty acid. Both enantiomers of DGA were also lipoxygenase inhibitors, but neither enantiomer of SECO inhibited the lipoxygenase activity.

The first stereoselective synthesis of meso-secoisolariciresinol is reported. A comparison of the cytotoxic and immunosuppressive activity between meso-secoisolariciresinol and optically active secoisolariciresinols was similarly performed for the first time. Both enantiomers of secoisolariciresinol accelerated IgM production, although meso-secoisolariciresinol did not affect IgM production. Only meso-secoisolariciresinol showed cytotoxic activity.

The effect of the benzylic structure of lignan on antioxidant activity was evaluated. Secoisolariciresinol (1) and 3,4-bis(4-hydroxy-3-methoxybenzyl)tetrahydrofuran (2), which have two secondary benzylic positions without oxygen, showed the highest antioxidant activity. Optically active verrucosin (4) was synthesized for the first time in this experiment.

The benzyl mesylate was employed to construct the tetrasubstituted tetrahydrofuran lignan with avoiding Friedel-Crafts type of reaction. The optically pure 7,8-trans, 7',8'-trans, 7,7'-cis, and 8,8'-cis-virgatusin stereoisomers were synthesized. The enantiomeric excess was >>99%.

The effect of oxidation degree at the benzylic position of 2,3-dibenzyl-4-butanolide and 3,4-dibenzyltetrahydrofuran lignans on the antimicrobiological activity was examined. The highest oxidation degree at the benzylic position of 2,3-dibenzyl-4-butanolide gave the greatest activity, and 3,4-dibenzoyltetrahydrofuran showed the highest antifungal activity. The relationship between stereochemistry and activity was also examined. Both enantiomers of cis-matairesinol were synthesized for the first time, one of the cis-matairesinols showing antibacterial activity.

The 7',8'-stereochemistry of the tetrahydropyran sesquineolignans morinols A and B was determined as threo via synthetic studies and by comparison of NMR data of 7',8'-threo-morinol and 7',8'-erythro-morinol. This study also confirmed that the biosynthetic process produces enantiomeric mixtures of morinols A and B. This was ascertained by comparing the specific rotations of synthesized morinols A and B with those of naturally occurring morinols A and B.

The cytotoxic activity for colon 26 cell line of matairesinol, oxidized matairesinol, 9,9'-epoxylignan and oxidized 9,9'-epoxylignan were examined. (-)-Matairesinol (Mat 1) showed greatest cytotoxic activity (LC(50)=9 microg/ml) of the lactone-type lignans. 7,7'-Oxomatairesinol having same steric configuration as that of (-)-matairesinol showed greater activity (LC(50)=25 microg/ml) than hydroxy or mono-oxomatairesinol. The activities of 9,9'-epoxylignan and 7,7'-oxo-9,9'-epoxylignan having same steric configurations as (-)-matairesinol were weaker than that of corresponding matairesinols. Different activity levels were observed between enantiomers.

The radical and superoxide scavenging activities of oxidized matairesinols were examined. It could be assumed that the free benzylic position was important for higher radical scavenging activity. The different level of activity was observed between 7'-oxomatairesinol (Mat 2) and 7-oxomatairesinol (Mat 3). The activity of 8-hydroxymatairesinol was lower than that of matairesinol (Mat 1). The superoxide scavenging activity of the oxidized matairesinols was also demonstrated for the first time. It is assumed that the pKa value of phenol in the oxidized matairesinols affected this activity.

The first highly enantioselective syntheses of tetra-substituted tetrahydrofuran lignan, (-)- and (+)-virgatusin, were achieved. Hemiacetal was stereoselectively obtained from Evans's syn-aldol product as a single isomer. This hemiacetal was converted to (-)-virgatusin via hydrogenolysis. (+)-Virgatusin was also synthesized through the same process. The enantiomeric excess of the both enantiomers was determined as more than 99% ee.