Masafumi Maruyama

Antifungal activity of tetra-substituted tetrahydrofuran lignan, (-)-virgatusin, and its structure-activity relationship.

Antifungal activities of the optically pure (>99%ee) (−)- and (+)-virgatusin, a tetra-substituted tetrahydrofuran lignan, were tested. (−)-Virgatusin, which is a natural product, showed highest antifungal activity against Colletotrichum lagenarium. Research on its structure-activity relationship was also performed. It was shown that two methoxy groups on 9 and 9′ positions and a 3,4-methylenedioxyphenyl group on the 7 position of virgatusin were essential for high fungal growth inhibition. The part on 7′-phenyl group was not essential for activity. The 7′-(4-methoxyphenyl) derivative showed higher activity than that of (−)-virgatusin.

Antioxidant Activity of Butane Type Lignans, Secoisolariciresinol, Dihydroguaiaretic Acid, and 7,7′-Oxodihydroguaiaretic Acid

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.

Antimicrobial Activity of Stereoisomers of Butane-Type Lignans

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 Effect of Secoisolariciresinol on 3T3-L1 Adipocytes and the Relationship between Molecular Structure and 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 17β-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.

Effect of the benzylic structure of lignan on antioxidant 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.

Antibacterial Activity of a Virgatusin-Related Compound

The relationship between antibacterial activity of tetra-substituted tetrahydrofuran lignans (1–4) and their absolute configurations was tested. Only compound 4 among two virgatusins and two related compounds exhibited growth inhibitory activity against the Gram-positive bacteria Bacillus subtilis, Staphylococcus aureus and Listeria denitrificans. Compound 4 affected the growth of B. subtilis in a bactericidic manner, and its ability to dissipate the cytoplasmic membrane potential was investigated using the fluorescence probe 3,3′-dipropylthiadicarbocyanine iodide. These results suggested that compound 4 damages cells by causing the loss of the proton motive force and disruption of the cellular integrity of the membrane, leading to cell death. In addition, it was shown that the antibacterial activity of a lignan was closely related to its absolute configuration and functional groups.

Antimicrobiological activity of lignan: effect of benzylic oxygen and stereochemistry of 2,3-dibenzyl-4-butanolide and 3,4-dibenzyltetrahydrofuran lignans on activity.

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.

First Stereoselective Synthesis of meso-Secoisolariciresinol and Comparison of Its Biological Activity with (+) and (−)-Secoisolariciresinol

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.

Syntheses and Antimicrobial Activity of Tetrasubstituted Tetrahydrofuran Lignan Stereoisomers

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.

Antimicrobial Activity of Stereoisomers of Morinols A and B, Tetrahydropyran Sesquineolignans

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.