A New Lignan from Annona squamosa L. (Annonaceae) Demonstrates Vasorelaxant Effects In Vitro.

Esquamosan, a new furofuran lignan, has been isolated by bio-guided assays from the methanolic extract of the leaves of Annona squamosa L., and its structure was elucidated by spectroscopic methods. Esquamosan inhibited the rat aortic ring contraction evoked by phenylephrine in a concentration-dependent manner and showed an inhibitory effect on vasocontraction of the depolarized aorta with high-concentration potassium. The vasorelaxant effect by esquamosan could be attributed mainly to the inhibition of calcium influx from extracellular space through voltage-dependent calcium channels or receptor-operated Ca2+ channels and also partly mediated through the increased release of NO from endothelial cells. The ability of esquamosan to modify the vascular reactivity of rat aortic rings incubated with high glucose (D-glucose 55 mM) was then evaluated, and this furofuran lignan reverted the endothelium-dependent impairment effect of high glucose in rat aortic rings. The antioxidant capacity of esquamosan was assessed using DPPH and FRAP assays. Esquamosan exhibited a similar antioxidant capacity compared to ascorbic acid, which was used as a positive control. In conclusion, this lignan showed a vasorelaxant effect, free radical scavenging capacity, and potential reductive power, suggesting its potential beneficial use to treat complex cardiometabolic diseases due to free radical-mediated diseases and its calcium antagonist effect.

Thioether and Ether Furofuran Lignans: Semisynthesis, Reaction Mechanism, and Inhibitory Effect against α-Glucosidase and Free Radicals.

The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study, the semisynthesis of 28 furofuran lignans using samin (5) as the starting material is described. Our methodology involved the protonation of samin (5) to generate an oxocarbenium ion followed by the attack from two different nucleophiles, namely, thiols (RSH) and alcohols (ROH). The highly diastereoselective thioether and ether furofuran lignans were obtained, and their configurations were confirmed by 2D NMR and X-ray crystallography. The mechanism underlying the reaction was studied by monitoring 1H NMR and computational calculations, that is, the diastereomeric α- and ß-products were equally formed through the SN1-like mechanism, while the ß-product was gradually transformed via an SN2-like mechanism to the α-congener in the late step. Upon evaluation of the inhibitory effect of the synthesized lignans against α-glucosidases and free radicals, the lignans 7f and 7o of the phenolic hydroxyl group were the most potent inhibitors. Additionally, the mechanisms underlying the α-glucosidase inhibition of 7f and 7o were verified to be of a mixed manner and noncompetitive inhibition, respectively. The results indicated that both 7f and 7o possessed promising antidiabetic activity, while simultaneously inhibiting α-glucosidases and free radicals.

Two new furofuran lignan glycoside derivatives from the fruit of Forsythia suspensa.

Phytochemical investigation of 95% ethanol extract of the fruit of Forsythia suspensa resulted in the isolation of two new furofuran lignan glycoside derivatives pinoresinoside A (1) and phillyrigeninside A (2), along with three known ones. Their structures were established based on extensive spectroscopic data analyses and comparison with literature data. Absolute configuration of 1 was determined by CD method. In addition, compounds 1 and 2 were revealed to show in vitro cytotoxicity against human tumor cell lines (SGC-7901, MCF-7 and HepG2), with IC50 values ranging from 16.77 to 37.35 µM. [Formula: see text].

Furofuran lignans as a new series of antidiabetic agents exerting α-glucosidase inhibition and radical scarvenging: Semisynthesis, kinetic study and molecular modeling.

A new series of furofuran lignans containing catechol moiety were prepared from the reactions between lignans and a variety of phenolics. All 22 products obtained were evaluated against three different α-glucosidases (maltase, sucrase and Baker's yeast glucosidase) and DPPH radical. Of furofuran lignans evaluated, ß-14, having two catechol moieties and one acetoxy group, was the most potent inhibitor against Baker's yeast, maltase, and sucrase with IC50 values of 5.3, 25.7, and 12.9 µM, respectively. Of interest, its inhibitory potency toward Baker's yeast was 28 times greater than standard drug, acarbose and its DPPH radical scavenging (SC50 11.2 µM) was 130 times higher than commercial antioxidant BHT. Subsequent investigation on mechanism underlying the inhibitory effect of ß-14 revealed that it blocked Baker's yeast and sucrase functions by mixed-type inhibition while it exerted non-competitive inhibition toward maltase. Molecular dynamics simulation of the most potent furofuran lignans (4, α-8b, α-14, and ß-14) with the homology rat intestinal maltase at the binding site revealed that the hydrogen bond interactions from catechol, acetoxy, and quinone moieties of furofuran lignans were the key interaction to bind tightly to α-glucosidase. The results indicated that ß-14 possessed promising antidiabetic activity through simultaneously inhibiting α-glucosidases and free radicals.

Synthetic studies on optically active furofuran and diarylbutane lignans.

Lignans are a large class of naturally occurring secondary metabolites which are widely spread within the plant kingdom. Their diverse structures and variety of biological activities have fascinated organic chemists. For synthesizing optically active lignans, we have developed the novel asymmetric dimerization of cinnamic acid derivatives, and applied it to the enantioselective syntheses of furofuran lignans (yangambin, sesamin, eudesmin, caruilignan A) and diarylbutane lignans (sauriols A and B). This review summarizes the methodology of our asymmetric dimerization of cinnamic acid derivatives, and efficient total syntheses of furofuran and diarylbutane lignans reported by our and other groups.

Six new compounds from Atractylodes lancea and their hepatoprotective activities.

Two new phenolic glycosides with a rare ß-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl moiety (1, 2), one new dihydrobenzofuran derivative (3), one new pyrazine derivative (4), two new furofuran lignan glycosides (5, 6), and six known compounds (7-12) were isolated from the rhizomes of Atractylodes lancea. The structures of these compounds were elucidated by extensive spectroscopic analyses combined with the experimental and calculated electronic circular dichroism and the Rh2(OCOCF3)4-induced circular dichroism for configurational assignments. Notably, compounds 1-3 showed significant hepatoprotective activities against N-acetyl-p-aminophenol-induced HepG2 cell injury. This study is also the first Letter on the isolation of furofuran lignans and pyrazine derivatives (4-7) from the genus Atractylodes.

Intermedianin, a new furofuran lignan from the leaves of Knema intermedia Warb.

Phytochemical investigation of the leaves of Knema intermedia has led to the isolation of a new furofuran lignan, intermedianin 1 together with five known lignans, α-cubebin 2, ß-cubebin 3, bicubebin A 4, bicubebin B 5, and bicubebin C 6. The characterisation and structural elucidation of the isolated compounds were established by extensive spectroscopic data analysis and comparison with literature data. The antifungal activity was tested using the broth microdilution assay, whereas the microbial biofilms were determined using a semi-quantitative static biofilm. Compound 1 exhibited activity against C. albicans, C. lusitanae, and C. auris, (each with MIC/MFC value 250 µg/mL) and increased the biofilm of C. auris (64.07 ± 3.83%) and Candida lusitanae (62.90 ± 3.41%) when treated with 500 µg/mL.

Furofuran Lignans for Plant Protection: Discovery of Sesamolin and Its Derivatives as Novel Anti-Tobacco Mosaic Virus and Antibacterial Agents.

Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0-A31 and B0-B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC50 value of 130.4 µg/mL, which was superior to that of commercial ningnanmycin (EC50 = 202.0 µg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC50 value of 43.8 µg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper. This research lays a solid foundation for the utilization of furofuran lignans in crop protection.

Naturally occurring furofuran lignans: structural diversity and biological activities.

Furofuran lignans containing the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane skeleton, represent one of the major subclasses of the lignan family of natural products. Furofuran lignans feature a wide variety of structures due to different substituents at aryl groups and diverse configurations at furofuran ring. Moreover, they exhibit a wide range of significant biological activities, including antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities. This review summarizes source, phytochemistry, and biological activities of 137 natural furofuran lignans isolated from 53 species in 41 genera of 27 plant families for the last 20 years, which provides a comprehensive information for further research of these furofuran lignans as potential pharmaceutical agents.

A new furofuran lignan from Piper terminaliflorum Tseng.

The chemical investigation of whole plants Piper terminaliflorum Tseng led to the isolation of one new furofuran lignan, 7-methoxyasarinin (1), along with three known amide alkaloids (2-4) as N-3,5-dimethoxy-4-hydroxycinnamoylpyrrole (2), dihydropipercide (3) and 1-[(2E,4E,9E)-10-(3,4-Methylenedioxyphenyl)-2,4,9-undecatrienoyl]pyrrolidine (4). Their structures were elucidated by extensive spectroscopic analyses, including 1D, 2D NMR and HR-ESI-MS, and by comparison with the literature. Compounds (2-4) were isolated from Piper terminaliflorum Tseng for the first time. All isolated compounds (1-4) were evaluated for their cytotoxic activities against five human cancer cell lines (including A-549, SMMC-7721, HL-60, MCF-7 and SW-480).

Isolation and characterization of wound-induced compounds from the leaves of Citrus hassaku.

Citrus plants are world widely cultivated as horticultural tree crops, and nowadays their pharmacological activities have been well studied. Since research of defense responses in citrus plants have been mainly focused on the post-harvested fruits because of their commercial importance, defense mechanisms during their developmental stages have not been well understood. In the present study, two wound-induced compounds were isolated from leaves of Citrus hassaku, and their structures were elucidated by high-resolution electron spray ionization mass spectra (HRESIMS) and nuclear magnetic resonance (NMR) analyses. One of these compounds was identified as a known flavanone, hesperetin. The other was characterized as a novel furofuran lignan, and was named 'biscitrusnin-A'. Their antimicrobial activities were also evaluated.

Evaluation of plant growth regulatory activity of furofuran lignan bearing a 7,9':7',9-diepoxy structure using optically pure (+)- and (-)-enantiomers.

The plant growth regulatory activity of furofuran lignan (7,9':7',9-diepoxylignan) was evaluated by employing optically pure synthesized (+)- and (-)-enantiomers. (+)-Sesamin possessing a 3,4-methylenedioxy group on the aromatic rings and 7-aryl structure showed growth promotion activity against lettuce roots (EC50 = 0.50 mM); on the other hand, growth inhibitory activity was observed against lettuce shoots (EC50 = 0.38 mM). Against ryegrass shoots, (-)-sesamolin, which has 3,4-methylenedioxy groups on the aromatic rings and a 7-acetal structure, was effective in showing growth inhibitory activity (EC50 = 0.23 mM). Different activity levels were observed between (+)- and (-)-enantiomers. It was assumed that the 3,4-methylenedioxy group on the aromatic ring was more potent for the plant growth regulatory activity.

Furofuran lignans display schistosomicidal and trypanocidal activities.

Parasitic diseases continue to be a major worldwide health problem, and there is an urgent need for development of therapeutic drugs. This paper describes synthesis of dehydrodiferulic acid dilactone 1 and dehydrodisinapic acid dilactone 2 furofuran lignans by oxidative coupling of ferulic and sinapic acids, respectively. Their schistosomicidal, trypanocidal, and leishmanicidal activities were evaluated in vitro against Schistosoma mansoni adult worms, trypomastigote and amastigotes forms of Trypanosoma cruzi, and promastigote forms of Leishmania amazonensis. Compound 1 did not display significant schistosomicidal activity, but it presented potent trypanocidal activity, since it induced death of trypomastigotes and amastigotes with IC50/24h of 9.3µM and 7.3µM, respectively. Compound 2 had slight trypanocidal and schistosomicidal activities. None of the compounds were active against L. amazonensis. These results demonstrated that furofuran lignans are potentially useful for anti-parasitic drugs development and should be further investigated.

Stereoselective Synthesis of Optically Active Methylene Lactone, Key Intermediate for the Synthesis of 1,2-Oxidized Furofuran Lignan, from L-Glutamic Acid.

(4R)-[(1S)-1-[(tert-Butyldimethylsilyl)oxy]-1-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-3-methylenedihydro-2(3H)-furanone and (4R)-[(1R)-1-[(tert-butyldimethylsilyl)oxy]-1-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-3-methylenedihydro-2(3H)-furanone, which are key intermediates for the synthesis of 1,2-oxidized furofuran lignan, were each stereoselectively synthesized from L-glutamic acid.