Phenolic Lignans Research Articles

Biological Evaluation of Phellinsin A Analogues as Chitin Synthase II Inhibitors

Chitin is the β-1,4-linked homopolymer of N-acetyl-Dglucosamine (GlcNAc) that constitutes an important structural component of the cell walls of nearly all zoopathogenic and phytopathogenic fungi, and plays a crucial role in the determination of cell morphology. Chitin have been known to be synthesized by chitin synthase I, II, and III in Saccharomyces cerevisiae. Chitin synthase II is an essential enzyme for the formation of primary septum between mother and daughter cells, and chitin synthase III is responsible for the formation of chitin ring at bud emergence, whereas chitin synthase I is a repair enzyme of the damaged cells on cell division. Accordingly, specific inhibitors of chitin synthase II and III are expected to be an attractive target for the development of antifungal agents. In the course of exploring a chitin synthase II inhibitor from microbial sources, we isolated a new phenolic lignan bearing a γ-lactone ring from the cultured broth of Phellinus sp. PL3. The lignan compound named phellinsin A (3a) exhibited inhibition of chitin synthase II with an IC50 value of 27 μg/mL and showed 2.5 times stronger inhibitory activity than polyoxin D, and its structure was established by NMR analysis and synthesis. Our efforts toward the development of a potent antifungal agent have focused on examining structure-activity relationships for phellinsin A. We have modified the aryl group in phellinsin A by changing the number of phenolic OH groups in order to investigate the effect of the number of free phenolic OH groups in γ-lactone analogues of phellinsin A (3a) on chitin synthase II inhibitory activity. Herein, we describe the biological evaluation of phellinsin A analogues 3. The γ-lactone analogues 3c-f of phellinsin A were prepared by oxidative dimerization of cinnamic acid derivatives 1 into the corresponding dilactones 2, followed by monohydrolysis of the dilactones as shown in Scheme 1. The γlactones 3a and 3b were prepared by demethylation of compounds 3d and 3e using BBr3, respectively. The γ-lactone analogues 3 of phellinsin A were examined for structure-activity relationships of phellinsin A (3a). Inhibitory activities of the compounds against chitin synthase II were evaluated by measurement of the formation of chitin with UDP-[C]-N-acetyl-D-glucosamine. Table 1 showed the inhibitory activities of phellinsin A analogues at 140 and 280 μg/mL concentrations. The activities were largely dependent on the presence of free phenolic OH substituents in γ-lactone analogues 3. Generally, the compound 3f with non-phenolic OH groups did not show

Antigenotoxic effect of nordihydroguaiaretic acid against chlormadinone acetate-induced genotoxicity in mice bone-marrow cells

Nordihydroguaiaretic acid (NDGA), a phenolic lignan, was tested for its antigenotoxic potential against chlormadinone acetate (CMA)-induced genotoxic damage in mice bone-marrow cells. Doses of about 22.50 mg/kg body weight of CMA were given along with 1, 5 and 10 mg/kg body weight of NDGA intraperitoneally. The treatment resulted in the reduction of sister chromatid exchanges and chromosomal aberrations induced by CMA, suggesting an antigenotoxic potential of NDGA. Earlier studies show that CMA generates reactive oxygen species, responsible for genotoxic damage. The free radical-scavenging property of NDGA is responsible for the reduction of genotoxic damage induced by CMA in mice bone-marrow cells.

Effect of Benzylic Oxygen on the Cytotoxic Activity for Colon 26 Cell Line of Phenolic Lignans

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.

A Simple Synthesis of Nordihydroguaiaretic Acid and Its Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Effect of Benzylic Oxygen on the Antioxidant Activity of Phenolic Lignans

It has been clarified in the present investigation that a high degree of oxidation at the benzylic position of phenolic lignans bearing a 4-hydroxy-3-methoxybenzyl group reduces their antioxidant activity and that the antioxidant activity of the bis(4-hydroxy-3-methoxybenzyl)tetrahydrofuran lignan 2 is higher than that of the corresponding gamma-butyrolactone lignan 1. This was demonstrated by comparing the antioxidant activities of compounds 1 and 2 with those of the (benzyl)(hydroxybenzyl)tetrahydrofurans 3 and 4, the bis(hydroxybenzyl)tetrahydrofurans 7 and 8, the (benzoyl)(benzyl)tetrahydrofuran 6, and the dibenzoyltetrahydrofuran 9. The activity level of compound 2 was approximately the same potency as that of the tetrahydronaphthalene-tetrahydrofuran 5. These compounds possess either a 4-hydroxy-3-methoxybenzyl group or a 4-hydroxy-3-methoxybenzoyl group as the benzyl or benzoyl group. An examination of radical scavenging activity showed differences of activity between diastereomers. To make this comparison possible, compounds 1-9 were synthesized using new synthetic routes for several of these lignans. In this investigation, stereoisomers of the (benzyl)(hydroxybenzyl)tetrahydrofurans 3 and 4 and liovils 7 and 8 were synthesized for the first time.

Protective effect of nordihydroguaiaretic acid (NDGA) against norgestrel induced genotoxic damage

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan and possesses antioxidant and number of properties potentially useful to man. The effect of NDGA was studied against norgestrel induced genotoxic damage, using sister chromatid exchanges (SCEs), chromosomal aberrations (CAs), mitotic index (MI) and replication index (RI) as parameters. Amounts of 5, 10 and 20 μM of norgestrel was tested for its genotoxic effect in the absence as well as presence of S9 mix, and was found to be genotoxic at 10 and 20 μM in the presence of S9 mix. Again, 10 μM of norgestrel was treated with 0.5 and 1 μM of NDGA, separately, in the presence of S9 mix. Similar treatment was given with 20 μM of norgestrel. Treatments given with NDGA result in the reduction of SCE, CA and increase of MI as well as RI, suggesting its protective action on human lymphocytes in vitro against the norgestrel induced genotoxic damage.

A Simple Synthesis of Nordihydroguaiaretic Acid and Its Analogues

Nordihydroguaiaretic acid (NDGA, 1aa) is a non-toxic phenolic lignan isolated from the resinous exudations of the North American creosote bush such as Larrea divaricata Cav. (Zygophyllaceae). In addition to the usage as an antioxidant in food, interests in NDGA have been continuously increased due to its intriguing pharmacological properties including the inhibitory activity on lipoxygenase, inflammation-inducing systems, herpes simples, HIV, and human papillomavirus, as well as hyperglycemic activity. As a family of NDGA, related compound tetra-O-methylNDGA (1ea) showed tumoricidal activity, and compounds 1ca and 1eb (machillin A) showed strong inhibitory activity on melanin biosynthesis.

In vivo and in vitro antigenotoxic effect of nordihydroguaiaretic acid against SCEs induced by methyl methanesulfonate

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan which has shown to cause a variety of actions potentially useful for human health; therefore, in this investigation we determined its capacity for inhibiting the rate of sister chromatid exchanges (SCEs) induced by methyl methanesulfonate (MMS). We tested the effect of 0.25, 0.50, 1.0, and 2.0 μM of NDGA on the damage exerted by 55 μM of MMS. Cultured human lymphocytes from two female donors were used for the experiment. The best result concerning its modulatory action was obtained with 1.0 μM of NDGA; with this dose the mean inhibitory index including both donors reached 68.2%. The values obtained for the mitotic and proliferative indexes were not significantly modified with respect to the basal data. We also used the mouse bone marrow in vivo system to evaluate the inhibitory effect of the chemical. In this study we tested 1.0, 6.0, and 11.0 mg/kg of NDGA intraperitoneally (i.p.) administered 1 h before an i.p. injection of MMS (40 mg/kg). The best inhibitory index in this model corresponded to the dose of 11 mg/kg of NDGA (86.9%). The mitotic index and the average generation time showed no significant variation with respect to the control data. Our study established that NDGA produces antigenotoxic action in mammalian cells in vitro and in vivo.

In vivo and in vitro induction of sister-chromatid exchanges by nordihydroguaiaretic acid

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan previously used as an antioxidant in commercial products, and with a number of properties potentially useful to man. As its genotoxic capacity has been poorly evaluated, in this investigation we determined its effect on the production of sister-chromatid exchanges (SCEs), and on the level of mitotic index (MI) in cultured human lymphocytes and in mouse bone marrow cells in vivo. The proliferative index (PI), and the average generation time (AGT) were also determined for human lymphocytes and in mouse bone marrow cells respectively. The in vitro study was made in two donors using NDGA doses of 1.1, 3.6, 6.7, 13.5, and 27.0 μM; and for the in vivo study the tested doses were 8.8, 17.6, 35.3, and 70.7 mg/kg of body weight. The results concerning SCE induction in human lymphocytes showed a dose-dependent response with a maximum mean increase of 5.52 SCE in relation to the control level, and with respect to MI and PI a decrement of more than 50% and a cell cycle delay was detected only with the high dose. In the study with bone marrow cells, a statistically significant difference was determined with the high two doses (an increase of 1.06 SCEs with 70.7 mg/kg in relation to the control level). The MI decreased only with the high dose and no modification was observed with respect to AGT. In conclusion, in both used models the study demonstrated that NDGA produced genotoxic and cytotoxic effects.

Phenolic lignans from flower buds of Magnolia fargesii

Three phenolic lignans were isolated from flower buds of Magnolia fargesii. One was a new lignan named (+)-de- O-methylmagnolin and the other two were the newly found lignans from this plant, (+)-phillygenin and (+)-pinoresinol. The structures of these lignans were determined by spectroscopic studies. The structure of (+)-magnolin isolated from this plant was also investigated in detail by spectral data.

Ruthenium dioxide in fluoro acid medium: II. Application to the formation of steganes skeleton by oxidative phenolic coupling.

Ruthenium (IV) dioxide dihydrate in fluoro acidic medium was found to be a very efficient agent for the oxidative coupling of the phenolic lignans (±)-presteganes A and B. Different attempts to oxidise the diphenolic dibenzylbutanolide (±)-HPMF were also carried out, but were unsuccessful. Likely explanation for these failures are given.

Isolation, structure and synthesis of new diarylbutane lignans from Phyllanthus niruri : Synthesis of 5′ -desmethoxy niranthin and an antitumour extractive

The structures of three new lignans (1–3) and a phenolic lignan (4) isolated from Phyllanthus niruri have been determined. The structures (1–3) were confirmed by their total synthesis and that of (4) was by its conversion to (3). The synthesis of (±) 5′ -desmethoxy niranthin (5) and an antitumour extractive (6) is described.

Ruthenium dioxide in fluoro acid medium: I. A new agent in the biaryl oxidative coupling. Application to the synthesis of non phenolic bisbenzocyclooctadiene lignan lactones.

Ruthenium (IV) dioxide dihydrate in fluoro acid medium was found to be a very efficient agent for the oxidative coupling of non phenolic lignans and their derivatives, and this method was applied to the total synthesis of (+/-)-neoisostegane 2a and (+/-)-steganolide A 2b. This procedure was also used to obtain the first stereospecific synthesis of a cis-bisbenzocyclooctadiene lactone, the (+/-)-deoxyschizandrin 17, of which, was afforded by a short reduction sequence.

Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol.

The phenolic lignans enterolactone and enterodiol appear periodically in women's urine, dependent upon synthesis from plant-derived lignans by the intestinal microflora. The phytoestrogen equol is also present in women's urine, and is also derived from a vegetarian diet. Antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. We evaluated the estrogenic and antiestrogenic activity of these compounds using four sensitive assays in tissue culture, including the use of human breast cancer cell lines T47D and MCF-7. Unexpectedly, we found that enterolactone and enterodiol, as well as equol, are weak estrogens, and that enterolactone and equol could stimulate the growth of estrogen-dependent breast cancer cell lines. We suggest that these environmental agents can promote the growth of breast cancer, particularly hormone-dependent metastases that may be located near the gut or in the mesenteries or liver, where the concentration of these intestinally produced compounds would be highest. Treatment with an antiestrogen such as tamoxifen blocks the estrogenic activity of these compounds. In the absence of treatment with an antiestrogen such as tamoxifen, hormonal therapy to block steroidal estrogen synthesis in a patient with breast cancer could conceivably be circumvented by a vegeterian diet rich in the precursors to estrogenic compounds such as enterolactone and equol.

A natural phenolic lignan from Tinospora cordifolia Miers

Systematic chemical investigation of Tinospora cordifolia Miers has yielded a new phenolic lignan along with the known compounds octacosanol, nonacosan-15-one, and β-sitosterol. This lignan has been shown by a combination of spectroscopic and chemical methods to be 3-(α,4-dihydroxy-3-methoxybenzyl)-4-(4-hydroxy-3-methoxybenzyl)tetrahydrofuran (1).

Studies on the alkaloids of rutaceous plants. XIX. The chemical constituents of Xanthoxylum inerme Koidz. (Fagara boninensis Koidz.). 1. Isolation of the chemical constituents from bark and wood

Four compounds were isolated from the wood of Xanthoxylum inerme KOIDZ. (Fagara boninensis KOIDZ.), (Japanese name "Akow-zansho"). One is an alkaloid, 4-methoxy-1-methyl-2-quinolone (III), mp 99-103°, which was isolated for the first time from a natural source. Two others were known coumarins, 6, 7, 8-trimethoxycoumarin (I), mp 107-108°, and aesculetin dimethyl ether (II), mp 147-147.5°. The fourth was a phenolic lignan, dl-syringaresinol (VIII), mp 179-185.5°. On the other hand, seven components were isolated from the bark of the same plant. Four of them were benzo[c]phenanthridine alkaloids, nitidine (XI)(chloride, mp 275-276° : dihydro base (XII), mp 223.5-224°), avicine (XIV)(dihydro base (XIII), mp 223-224°). chelerythrine ψ-cyanide (X), mp 240-245°(decomp.), and oxynitidine (XV), mp 283-285°, assumed to be an artefact alkaloid. One was a water-soluble quaternary tetrahydrobenzylisoquinoline alkaloid, L-(+)-armepavine metho salt (XVIII) (iodide, mp 204-206°), which was isolated from natural source for the first time. The others were an unknown base, X. bon. unknown base I, mp 252-254.5°(decomp.), and aesculetin dimethyl ether (II).