Verrucosin

Cytotoxic effects of neolignans from Saururus cernuus (Saururaceae) against prostate cancer cells.[Pubmed:36752700]

Chem Biol Drug Des. 2023 Jun;101(6):1299-1306.

In this study, five neolignans were isolated from Saururus cernuus-threo-dihydroguaiaretic acid (1), threo-austrobailignan-6 (2), threo-austrobailignan-5 (3), Verrucosin (4), and saucernetin (5)-and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood-brain barrier and did not show any alert in PAINS (pan-assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 mumol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 mumol/L and compound 2 showed effects at 100 mumol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni.[Pubmed:36369516]

Sci Rep. 2022 Nov 11;12(1):19320.

Schistosomiasis, a parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, especially in developing countries. Despite the significant economic and public health consequences, only one drug is currently available for treatment of schistosomiasis, praziquantel. Thus, there is an urgent demand for new anthelmintic agents. Based on our continuous studies involving the chemical prospection of floristic biodiversity aiming to discover new bioactive compounds, this work reports the in vitro antiparasitic activity against Schistosoma mansoni adult worms of neolignans threo-austrobailignan-6 and Verrucosin, both isolated from Saururus cernuus L. (Saururaceae). These neolignans showed a significant in vitro schistosomicidal activity, with EC(50) values of 12.6-28.1 microM. Further analysis revealed a pronounced reduction in the number of S. mansoni eggs. Scanning electron microscopy analysis revealed morphological alterations when schistosomes were exposed to either threo-austrobailignan-6 or Verrucosin. These relevant antischistosomal properties were accompanied by low cytotoxicity potential against the animal (Vero) and human (HaCaT) cell lines, resulting in a high selectivity index. Considering the promising chemical and biological properties of threo-austrobailignan-6 and Verrucosin, this research should be of interest to those in the area of neglected diseases and in particular antischistosomal drug discovery.

Degranulation inhibitors from the arils of Myristica fragrans in antigen-stimulated rat basophilic leukemia cells.[Pubmed:29336005]

J Nat Med. 2018 Mar;72(2):464-473.

A methanol extract of mace, the aril of Myristica fragrans (Myristicaceae), was found to inhibit the release of beta-hexosaminidase, a marker of antigen-IgE-stimulated degranulation in rat basophilic leukemia cells (RBL-2H3, IC(50) = 45.7 mug/ml). From the extract, three new 8-O-4' type neolignans, maceneolignans I-K (1-3), were isolated, and the stereostructures of 1-3 were elucidated based on spectroscopic and chemical evidence. Among the isolates, maceneolignans A (5), D (6), and H (8), (-)-(8R)-∆(8')-4-hydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan (13), (-)-(8R)-∆(8')-3,4,5,3',5'-pentamethoxy-8-O-4'-neolignan (14), (-)-erythro-(7R,8S)-∆(8')-7-acetoxy-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (24), Verrucosin (25), and malabaricone C (29) were investigated as possible degranulation inhibitors (IC(50) = 20.7-63.7 muM). These inhibitory activities were more potent than those of the antiallergic agents tranilast (282 muM) and ketotifen fumalate (158 muM). Compounds 5, 25, and 29 also inhibited antigen-stimulated tumor necrosis factor-alpha production (IC(50) = 39.5-51.2 muM), an important process in the late phase of type I allergic reactions.

Labdane-type diterpenoids from Vitex limonifolia and their antivirus activities.[Pubmed:28914420]

J Nat Med. 2018 Jan;72(1):290-297.

Phytochemical investigation of the methanol extract of Vitex limonifolia leaves led to the isolation of three new labdane-type diterpenoids, vitexlimolides A-C (1-3) and eight known compounds, 5,4'-dihydroxy-3,7-dimethoxyflavone (4), vitecetin (5), 5,4'-dihydroxy-7,3'-dimethoxyflavone (6), Verrucosin (7), 2alpha, 3alpha-dihydroxy-urs-12-en-28-oic acid (8), euscaphlic acid (9), 18,19-seco, 2alpha, 3alpha-dihydroxy-19-oxo-urs-11,13(18)-dien-28-oic acid (10), and maslinic acid (11). Their chemical structures were elucidated by physical and chemical methods. All compounds were evaluated for antiviral activities against CVB3, HRV1B, and EV71 viruses. As a result, compounds 4 and 6 showed potent antiviral activity against CVB3 infection with IC(50) values of 0.12 +/- 0.06 and 1.86 +/- 0.18 (microM), respectively.

Neolignans from the Arils of Myristica fragrans as Potent Antagonists of CC Chemokine Receptor 3.[Pubmed:27419473]

J Nat Prod. 2016 Aug 26;79(8):2005-13.

CC chemokine receptor 3 (CCR3) is expressed selectively in eosinophils, basophils, and some Th2 cells and plays a major role in allergic diseases. A methanol extract from the arils of Myristica fragrans inhibited CC chemokine ligand 11-induced chemotaxis in CCR3-expressing L1.2 cells at 100 mug/mL. From this extract, eight new neolignans, maceneolignans A-H (1-8), were isolated, and their stereostructures were elucidated from their spectroscopic values and chemical properties. Of those constituents, compounds 1, 4, 6, and 8 and (+)-erythro-(7S,8R)-Delta(8')-7-hydroxy-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (11), (-)-(8R)-Delta(8')-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (25), Verrucosin (26), and myristicin (27) inhibited CCR3-mediated chemotaxis at a concentration of 1 muM. Among them, 1 (EC50 1.6 muM), 6 (1.5 muM), and 8 (1.4 muM) showed relatively strong activities, which were comparable to that of a synthetic CCR3 selective antagonist, SB328437 (0.78 muM).

The Blood-Brain Barrier Permeability of Lignans and Malabaricones from the Seeds of Myristica fragrans in the MDCK-pHaMDR Cell Monolayer Model.[Pubmed:26805808]

Molecules. 2016 Jan 22;21(2):134.

The blood-brain barrier (BBB) permeability of twelve lignans and three phenolic malabaricones from the seeds of Myristica fragrans (nutmeg) were studied with the MDCK-pHaMDR cell monolayer model. The samples were measured by high-performance liquid chromatography and the apparent permeability coefficients (Papp) were calculated. Among the fifteen test compounds, benzonfuran-type, dibenzylbutane-type and arylnaphthalene-type lignans showed poor to moderate permeabilities with Papp values at 10(-8)-10(-6) cm/s; those of 8-O-4'-neolignan and tetrahydrofuran-lignan were at 10(-6)-10(-5) cm/s, meaning that their permeabilities are moderate to high; the permeabilities of malabaricones were poor as their Papp values were at 10(-8)-10(-7) cm/s. To 5-methoxy-dehydrodiisoeugenol (2), erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol acetate (6), Verrucosin (8), and nectandrin B (9), an efflux way was involved and the main transporter for 6, 8 and 9 was demonstrated to be P-glycoprotein. The time and concentration dependency experiments indicated the main transport mechanism for neolignans dehydrodiisoeugenol (1), myrislignan (7) and 8 was passive diffusion. This study summarized the relationship between the BBB permeability and structure parameters of the test compounds, which could be used to preliminarily predict the transport of a compound through BBB. The results provide a significant molecular basis for better understanding the potential central nervous system effects of nutmeg.

Effect of the structure of dietary epoxylignan on its cytotoxic activity: relationship between the structure and the activity of 7,7'-epoxylignan and the introduction of apoptosis by caspase 3/7.[Pubmed:26786026]

Biosci Biotechnol Biochem. 2016;80(4):669-75.

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 muM). 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 muM) 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.

Structure-plant phytotoxic activity relationship of 7,7'-epoxylignanes, (+)- and (-)-verrucosin: simplification on the aromatic ring substituents.[Pubmed:25248684]

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4798-803.

The synthesized 7-aryl derivatives of (7R,7'S,8S,8'S)-(+)-Verrucosin were applied to growth inhibitory activity test against ryegrass at 1mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-Verrucosin against the root (-95%) and the shoot (-60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7'R,8R,8'R)-(-)-Verrucosin at 1mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (-)-Verrucosin against the root (-95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (-80%) than that of (-)-Verrucosin (-60%). As the next step, (7S,7'R,8R,8'R)-7-(3-hydroxyphenyl)-7'-aryl-(-)-Verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7'-(2-hydroxyphenyl) derivative 37 and 7'-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7'-aryl structures of 7,7'-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7'-aryl structures were simplified to show comparable activity to or higher activity than that of (-)-Verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C3b, was estimated as -80% inhibition at 1mM against ryegrass roots.

Disruption of ion homeostasis by verrucosin and a related compound.[Pubmed:21597167]

Biosci Biotechnol Biochem. 2011;75(5):1000-2.

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.

AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect.[Pubmed:20541406]

Bioorg Med Chem Lett. 2010 Jul 15;20(14):4128-31.

AMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPK activators from plants, this study found that the total extract of Myristica fragrans (nutmeg) activated the AMPK enzyme in differentiated C2C12 cells. As active constituents, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), Verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C(1) (6), and galbacin (7) were isolated from this extract. Among the isolates, compounds 1, 4, and 5 at 5 microM produced strong AMPK stimulation in differentiated C2C12 cells. In addition, the preventive effect of a tetrahydrofuran mixture (THF) on weight gain in a diet-induced animal model was further examined. These results suggest that nutmeg and its active constituents can be used not only for the development of agents to treat obesity and possibly type-2 diabetes but may also be beneficial for other metabolic disorders.

Effect of the benzylic structure of lignan on antioxidant activity.[Pubmed:17827687]

Biosci Biotechnol Biochem. 2007 Sep;71(9):2283-90.

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.

O-demethylation of 7,7'-epoxylignans by Aspergillus niger.[Pubmed:8987506]

Phytochemistry. 1996 Sep;43(1):111-3.

Biotransformation of the 7,7'-epoxylignans, (+)-veraguensin, (+)-galbelgin and galgravin by Aspergillus niger has been investigated. These lignans were converted to their corresponding 4,4'-O-demethyl derivatives, (+)-Verrucosin, (+)-fragransin A2 and nectandrin B.

The effect of diterpenoidic diacylglycerols on tentacle regeneration in Hydra vulgaris.[Pubmed:1687559]

Comp Biochem Physiol C Comp Pharmacol Toxicol. 1991;100(3):603-7.

1. The effect of two ichthyotoxic diterpenoid diacylglycerols, Verrucosins A and B, previously isolated from the mantle of a marine nudibranch mollusc, were studied on Hydra vulgaris tentacle regeneration. 2. A potent effect was found for both Verrucosins in the low nanomolar range; the rank of potency observed was analogous to that reported for diglycerid activation of protein kinase C and to that found for Verrucosin activation of this enzyme. 3. In the high nanomolar range, the two Verrucosins were found to be toxic to Hydra vulgaris. 4. Verrucosin B-induced toxicity and tentacle regeneration were found to be dependent on [Ca2+] in the assay medium.