Arylnaphthalene Lignan Research Articles

Isolation of Novel Compounds from Lepidium sativum Seeds and Evaluation of Their Potential Anti-Tumor Activity.

Four undescribed compounds including a pair of enantiomers of a dihydroarylnaphthalene lignan [(±)-1], an arylnaphthalene lignan (2), and an indoleacetic acid ester (3), together with four known compounds (4-7), were isolated from the seeds of Lepidium sativum. Their structures were identified by HRMS and NMR spectroscopic data, and the absolute configuration of these compounds were assigned by ECD data in combination with quantum chemical calculations. Compound (-)-1 had weak inhibitory activity against HeLa cell line with an IC50 value of 60.23±3.51 μM, and compound (+)-1 presented moderate inhibitory effect against HeLa cell line with an IC50 value of 19.99±1.00 μM (IC50 value of the positive control was 0.40±0.02 μM).

Potential of 6′‑hydroxy justicidin B from Justicia procumbens as a therapeutic agent against coronavirus disease 2019

BackgroundSince the onset of the coronavirus disease 2019 (COVID-19) pandemic, remarkable advances have been made in vaccine development to reduce mortality. However, therapeutic interventions for COVID-19 are comparatively limited despite these intensive efforts. Furthermore, the rapid mutation capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a characteristic of its RNA structure, has led to the emergence of multiple variants, necessitating a shift from a predominantly vaccine-centric approach to one that encompasses therapeutic strategies. 6′-Hydroxy justicidin B (6′-HJB), an arylnaphthalene lignan isolated from Justicia procumbens, a traditional Chinese medicine, is known for its antiviral properties. Hypothesis/PurposeThe aim of the present study was to assess the effectiveness and safety of 6′-HJB against SARS-CoV-2 in order to determine its potential as a therapeutic agent against COVID-19. MethodsThe efficacy of 6′-HJB was evaluated both in vitro using Vero and Calu-3 cell lines and in vivo using ferrets. The safety assessment included toxicokinetics, safety pharmacology, and Good Laboratory Practice (GLP)-compliant toxicity evaluations following single- and repeated-dose toxicity studies in dogs. ResultsThe anti-SARS-CoV-2 efficacy of 6′-HJB was evaluated through dose-response curve (DRC) analysis using immunofluorescence; 6′-HJB demonstrated superior inhibition of SARS-CoV-2 growth and lower cytotoxicity than remdesivir. In SARS-CoV-2-infected ferret, 6′-HJB showed efficacy comparable to that of the positive control, Truvada. Further GLP toxicity studies corroborated the safety profile of 6′-HJB. Single-dose and 4-week repeated oral toxicity studies in Beagle dogs demonstrated minimal harmful effects at the highest dosages. The lethal dose of 6′-HJB exceeded 2,000 mg kg-1 in Beagle dogs. Toxicokinetic and GLP safety pharmacology studies demonstrated no adverse effects of 6′-HJB on metabolic processes, respiratory or central nervous systems, or cardiac functions. ConclusionThis research highlights both the antiviral efficacy and safety profile of 6′-HJB, underscoring its potential as a novel COVID-19 treatment option. The potential of 6′-HJB was demonstrated using modern scientific methodologies and standards.

Comparative quantitative profiling of rare justicidin B in in vitro cultivated Linum species

This research investigates the production and optimization of justicidin B from L. austriacum and L. alpinum in vitro cultures, aiming for high yields of this pharmacologically significant arylnaphthalene lignan. Various cultivation techniques were employed, including shoot, root, and callus cultures, with different media formulations to induce justicidin B biosynthesis. In vitro shoots, callus, and root cultures of both Linum species were successfully established to enhance justicidin B production. Quantification of the lignan was performed using LC-HRESI-MS analysis, comparing the quantities to those of isolated and identified justicidin B from L. leonii hairy root extract. The results show that the in vitro root cultures of L. alpinum produced 1.3 times more justicidin B than those of L. austriacum (7.24 μg/mg DW and 5.31 μg/mg DW, respectively). Additionally, the shoot cultures of L. alpinum yielded 4.5 times more justicidin B than those of L. austriacum (4.34 μg/mg DW and 0.96 μg/mg DW, respectively).

Arylnaphthalene lignans with a focus Linum species: a review on phytochemical, biotechnological and pharmacological potential

Lignans are a large group of dimeric phenylpropanoids with a long and distinguished history of medicinal use in the ancient cultures of many peoples. The two main groups, -aryltetralin and arylnaphthalene lignans, are leading compounds with important pharmacological properties and a wide range of biological activities. While the first group is well studied mainly for the production of podophyllotoxin, for arylnaphthalene lignans, the data on the availability of a sustainable resource for their production is are still insufficient. The Linum genus, comprising approximately 180 species, is notable for its arylnaphthalene lignans production like justicidin B and isojusticidin B. The pharmacological potential of arylnaphthalene lignans includes cytotoxic, antiviral, anti-inflammatory and antiprotozoal effects. The review highlights the use of biotechnology by in vitro cultures for optimising lignan production. Structural elucidation of novel lignans underscores the ongoing diversity and potential discoveries in this botanical domain, providing an important additional information of arylnaphthalene lignans.

Steglich Esterification of Activated Cinnamyl Cinnamate Derivatives and Computational Studies of Intramolecular Diels-Alder for Lignan Synthesis

A ryltetralin and arylnaphthalene lignans consisting of methylenedioxy or trimethoxy groups, such as podophyllotoxin and phyllanthusmin C, are known to have effective anticancer properties. The synthesis of these compounds can be achieved through intramolecular Diels-Alder reactions on cinnamyl cinnamate ester derivatives. Furthermore, this ester is commonly synthesized through an esterification reaction between cinnamoyl halide and cinnamyl alcohol. In this study, cinnamyl cinnamate only produced a 41% yield, while a nearly quantitative yield of 98% was obtained using the Steglich reaction with N,N’-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. This reaction was used to synthesize eight cinnamyl cinnamate ester derivatives, which consisted of methylenedioxy and trimethoxy groups, following a combinatorial synthesis. 3,4-Methylenedioxy- and 3,4,5-trimethoxycinnamyl alcohols were obtained by reducing methyl 3,4-methylenedioxycinnamate and 3,4,5-trimethoxycinnamic acid, respectively. The results showed that the ester yields were excellent, except for the ester derivatives of 3,4,5-trimethoxycinnamyl alcohol. This alcohol was unstable during column chromatography, leading to the direct esterification of the crude reduction products. A side product with Rf adjacent to the ester was obtained, thereby reducing the ester yield. The identification of this by-product and the intramolecular Diels-Alder reaction on the products obtained were described in this study. Computational studies showed that transforming reactants into products led to the production of one intermediate compound and two transition states (TS). Each TS represented the intramolecular Diels-Alder cycloaddition reaction and migration of [1,3]-hydrogen. Thermodynamic studies consistently revealed that a solvent environment could effectively reduce the activation energy associated with a chemical process.

Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review.

Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.

Justicidin B and related lignans from two South African Monsonia species with potent activity against HeLa cervical cancer cells

Cervical cancer is a deadly malignancy, one of the most common for women, evidencing the need for effective new chemotherapeutic agents to treat the disease. Lignans are widely occurring natural products with important pharmacological effects, including anticancer activities. Five arylnaphthalene lignans, isolated from Monsonia angustifolia and M. glauca (Geraniaceae), were investigated for their cytotoxicity against HeLa human cervical cancer cells. The best activity (IC50 1.2 μM) was exerted by justicidin B (4). The presence of additional methoxy groups in the “northern part” of the arylnaphthalene scaffold, at C-6 and/or C-7, lowered the cytotoxicity. Even more significantly, a free hydroxy group at C-7, leads to a drastic decrease in potency, by two orders of magnitude. Live-cell imaging experiments revealed that 4 induces changes in cancer cells morphology, effecting their elongation and eventual death. Justicidin B (4) inhibited formation of HeLa cell colonies in a dose-dependent manner. Mechanistic investigations showed that 4 modulates the expression of key proteins involved in apoptosis, suggesting that it induces cell death through several mechanisms.

Identification of an Arylnaphthalene Lignan Derivative as an Inhibitor against Dengue Virus Serotypes 1 to 4 (DENV-1 to -4) Using a Newly Developed DENV-3 Infectious Clone and Replicon.

Dengue virus (DENV) is the most widespread arbovirus, causing symptoms ranging from dengue fever to severe dengue, including hemorrhagic fever and shock syndrome. Four serotypes of DENV (DENV-1 to -4) can infect humans; however, no anti-DENV drug is available. To facilitate the study of antivirals and viral pathogenesis, here we developed an infectious clone and a subgenomic replicon of DENV-3 strains for anti-DENV drug discovery by screening a synthetic compound library. The viral cDNA was amplified from a serum sample from a DENV-3-infected individual during the 2019 epidemic; however, fragments containing the prM-E-partial NS1 region could not be cloned until a DENV-3 consensus sequence with 19 synonymous substitutions was introduced to reduce putative Escherichia coli promoter activity. Transfection of the resulting cDNA clone, plasmid DV3syn, released an infectious virus titer of 2.2 × 102 focus-forming units (FFU)/mL. Through serial passages, four adaptive mutations (4M) were identified, and addition of 4M generated recombinant DV3syn_4M, which produced viral titers ranging from 1.5 × 104 to 6.7 × 104 FFU/mL and remained genetically stable in transformant bacteria. Additionally, we constructed a DENV-3 subgenomic replicon and screened an arylnaphthalene lignan library, from which C169-P1 was identified as exhibiting inhibitory effects on viral replicon. A time-of-drug addition assay revealed that C169-P1 also impeded the internalization process of cell entry. Furthermore, we demonstrated that C169-P1 inhibited the infectivity of DV3syn_4M, as well as DENV-1, DENV-2, and DENV-4, in a dose-dependent manner. This study provides an infectious clone and a replicon for the study of DENV-3 and a candidate compound for future development against DENV-1 to -4 infections. IMPORTANCE Dengue virus (DENV) is the most prevalent mosquito-transmitted virus, and there is no an anti-dengue drug. Reverse genetic systems representative of different serotype viruses are invaluable tools for the study of viral pathogenesis and antiviral drugs. Here, we developed an efficient infectious clone of a clinical DENV-3 genotype III isolate. We successfully overcame the instability of flavivirus genome-length cDNA in transformant bacteria, an unsolved issue for construction of cDNA clones of flaviviruses, and adapted this clone to efficiently produce infectious viruses following plasmid transfection of cell culture. Moreover, we constructed a DENV-3 subgenomic replicon and screened a compound library. An arylnaphthalene lignan, C169-P1, was identified as an inhibitor of virus replication and cell entry. Finally, we demonstrated that C169-P1 exhibited a broad-spectrum antiviral effect against the infections with DENV-1 to -4. The reverse genetic systems and the compound candidate described here facilitate the study of DENV and related RNA viruses.

Arylnaphthalene Lignans with Anti-SARS-CoV-2 and Antiproliferative Activities from the Underground Organs of Linum austriacum and Linum perenne.

Diphyllin (1) and justicidin B (2) are arylnaphthalene lignans with antiviral and antiproliferative effects. Compound 1 is also known as an effective inhibitor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To evaluate the in vitro antiviral and cytotoxic potency of both lignans in SARS-CoV-2 -infected cells and various cancer cell lines, respectively, 1 and 2 were isolated from the underground organs of Linum austriacum and Linum perenne. Two previously undescribed arylnaphthalene lignans, denominated linadiacin A and B (3 and 4), were also isolated and identified. In acidic media, 3 was converted by a two-step reaction into 2 via the intermediate 4. Optimum acid treatment conditions were determined to isolate lignans by one-step preparative high-performance liquid chromatography (HPLC). The results of the conversion, HPLC-tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and molecular modeling studies allowed complete structure analysis. Compounds 1 and 2 were the most effective against SARS-CoV-2 with a 3-log reduction in the viral copy number at a 12.5 μM concentration. Ten human cancer cell lines showed sensitivity to at least one of the isolated lignans.

LARVICIDAL ACTIVITY OF THE SYNTHESISED LIGNANS, NEOLIGNANS, AND COUMARIN AGAINST Crocidolimia binotalis 2nd INSTAR LARVAE

Five compounds comprising 8-O-4’-neolignan (7), two arylnaphthalene lignans (5, 8), aryldihydrobenzofuran neolignan (4), and lignan (6) were synthesised by enzymatic coupling reaction using horseradish peroxidase (HRP) between vanillin (1) with methyl ferulate (2) or methyl sinapate (3). All of these compounds, as well as previously synthesised palladium-catalysed coupling products of neolignan (9), 8-O-4'-neolignan (10), arylcoumarin (11), and lignan (12), were examined for larvicidal activity against Crocidolomia binotalis 2nd instar larvae. It revealed that seven out of nine synthesised compounds had a mortality rate of more than 90% after 24 hours of exposure. Neolignan (10) and lignan (6) demonstrated the strongest larvicidal activity with LD50 = 2.218 mg/L and LD50 = 1.678 mg/L, respectively compared to the standard azadirachtin (LD50 =2.818 mg/L). The results showed that the synthesised compounds have a high potential for use in the control of C. binotalis larvae and could be used in the development of new and more effective compounds as larvicides.

Aryltetralin lignans from Hyptis brachiata inhibiting T lymphocyte proliferation

Increased activation and proliferation of T lymphocytes plays an essential role in the development of chronic inflammation and autoimmune diseases. Currently used immunosuppressive drugs often do not provide long-lasting relief of symptoms and show a gradual loss of efficacy over time, and are accompanied by various side effects. Therefore, novel immunosuppressive lead substances are needed. For this purpose, an in-house library consisting of 600 extracts of plants from Panama was screened for inhibition of human T lymphocyte proliferation. As one of the hits, an ethyl acetate extract from the aerial parts of Hyptis brachiata (Lamiaceae) exhibited strong inhibitory effects. Subsequent investigation resulted in the isolation of seven aryltetralin lignans, five arylnaphthalene lignans, two flavonoids, three triterpenes, and cinnamyl cinnamate. Aryltetralin lignans inhibited T lymphocyte proliferation in a concentration-dependent manner without induction of apoptosis. No relevant inhibition was observed for the arylnaphthalene lignans, flavonoids, and triterpenes. Additional cell cycle arrest investigations revealed that isolated aryltetralin lignans potently inhibited cell division in G2/M phase similarly to podophyllotoxin. Multifluorescence panel analyses of the extract also showed weak suppressive effects on the production of IL-2 and TNF-α. Therefore, preparations made out of H. brachiata could be further explored as an interesting herbal alternative in the treatment of autoimmune diseases.

Total Synthesis of Arylnaphthalene Lignans through a Photochemical Key Step

AbstractThe total syntheses of three arylnaphthalene lignans (ANLs) were developed: Vitrofolal E (1), Noralashinol C (2), and Ternifoliuslignan E (3). These natural products have in common a missing substituent in 2‐position of the naphthalene moiety (2H‐ANLs). The key step of these syntheses is a regioselective intramolecular Photo‐Dehydro‐Diels‐Alder (PDDA) reaction with (1,7)naphthalenophanes as primary products. A further improvement of the photochemical step was achieved by triplet sensitization with xanthone, allowing the use of more efficient UVA lamps. It should be noted that this work is a continuation of a previous publication about the total synthesis of lignans using the PDDA reaction.[1]

Linum lewisii Adventitious and Hairy-Roots Cultures as Lignan Plant Factories

Plants synthesize specific secondary metabolites for survival, reproduction, environmental resilience, and defense. Among them, lignans are a class of polyphenols with several bioactive properties: chemopreventive, anti-inflammatory, antiviral, and antioxidant. These compounds are often extracted from field-grown plants with very low yields. To overcome these constraints, in vitro tissue cultures provide a tool to optimize large-scale production. Moreover, the use of elicitation to increase secondary metabolite production is gaining importance. The aim of this work was to develop adventitious (ARL) and hairy roots (HRL) from Linum lewisi, a species able to synthesize arylnaphthalene lignans such as justicidin B. The ARL and HRL were obtained for the first time and characterized for their phenol content, antioxidant activity, and the production of justicidin B after treatments with several elicitors and precursor feeding. Through NMR spectroscopy, other four lignans were highlighted and identified in the roots extracts. A pilot-scale bioreactor was adopted to assess the suitability of the developed root cultures for future large-scale production. The ARL and HRL cultures showed a justicidin B production higher than other Linum species cultures described up to now (75.8 mg/L and 82.2 g/L), and the production more than doubled after elicitation with MeJA.

Axial Chirality and Antiviral Activity Evaluation of Arylnaphthalene Lignan Glycosides from Justicia procumbens

AbstractOne of the structural uniqueness of arylnaphthalene lignans (ANLs) is their potential atropoisomerism, which may result in bioactivity discrepancy. However, the stable ANL atropisomers rarely exist in nature. In the course of our phytochemical study of Justicia procumbens, we isolated nine ANL glycosides (1–9) with four of them (1–4) being identified as new stable atropisomers. Their absolute configurations were determined based on the analysis of the circular dichroism (CD) and electronic circular dichroism (ECD) data. The ANL compounds were evaluated for their antiviral potential as entry inhibitors against the infections of H5N1 influenza virus, vesicular stomatitis virus (VSV) and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with 5 being the most potent one with IC50 values ranging from 0.0063–1.13 μM. The atropisomers did not display significant antiviral activity, indicating that a free rotation of the biphenyl aryl‐aryl bond could play a significant role in the antiviral activity of ANL compounds.

Antiviral, Anticancer and Hypotensive Potential of Diphyllin Glycosides and their Mechanisms of Action

Diphyllin glycosides (DG) are a type of arylnaphthalene lignans isolated from different plants, and their synthetic derivatives have shown effective antiviral, cytotoxic, hypotensive and diuretic effects at very low concentrations similar to standard drugs that are under clinical use. The biological activities of the DG interfere with signaling pathways of viral infection and cancer induction. The sugar moieties of DG enhance bioavailability and pharmacological activities. The promising results of DG at nanomolar concentrations under in vitro and in vivo conditions should be explored further with clinical trials to determine its toxic effects, pharmacokinetics and pharmacodynamics. This may help identify suitable antiviral and anticancer drugs in the near future. Considering all these activities, the present review is focused on the chemical aspects of DG with a detailed account of the mechanisms of action of DG. An attempt is also made to comment on the status of clinical trials involving DG along with the possible limitations in studies based on available literature till September 2020.

Effective components and mechanism analysis of anti-platelet aggregation effect of Justicia procumbens L.

Ethnopharmacological relevanceJusticia procumbens L. is a traditional Chinese medicine, first recorded in "Shen Nong's Herbal Classic", for the treatment of lumbar pain and fever. As a widely distributed herb, it has also been documented in India, Nepal, and Malaysia. In “Tang Materia Medica”, a famous medicinal book of Tang Dynasty in ancient China, it was first used to treat diseases associated with blood stasis. Blood stasis syndrome is closely related to thrombus formation and platelet aggregation. Although some compounds isolated from this plant have anti-platelet aggregation effects, the main chemical components and mechanism of J. procumbens in terms of these effects are little known. Aims of the studyThrough in vivo and in vitro experiments, this studsy revealed the characteristic components and action mechanism of anti-platelet aggregation by J. procumbens from an overall perspective. Materials and methodsThe effective crude extracts of the whole plant were screened via an in vitro anti-platelet aggregation test. After incubating these extracts with apheresis platelets, high affinity compounds were detected by HPLC-MS and regulatory genes were detected using gene chips. The effective components and potential target proteins were analyzed using computational docking technology. Furthermore, the compound with the strongest predicted activity was evaluated in vivo via an anti-thrombotic test. ResultsIntegrin aⅡbβ3, PKCα, PI3Kγ, and mitogen-activated protein kinase 14 were found to be potential targets. Justicidin B, tuberculatin, chinensinaphthol methyl ether, and neojusticin B were effective compounds that inhibited human platelet aggregation by suppressing Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways. Among the compounds that bind to platelets, justicidin B showed the strongest virtual binding force. The test of carotid artery thrombosis induced by ferric chloride in SD rats confirmed that justicidin B inhibited thrombus formation. ConclusionExperimental investigation showed that arylnaphthalene lignan aglycones with one methylenedioxy group and two methoxy groups are effective components for anti-platelet aggregation by J. procumbens. These compounds inhibit Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways by suppressing the expression of genes such as ITGB3, PRKCA, PIK3CG, and MAPK14. These results reflected the characteristics of multi-component and multi-target synergistic treatment of Chinese medicine.

Studies toward the Total Synthesis of Arylnaphthalene Lignans via a Photo-Dehydro-Diels-Alder (PDDA) Reaction.

An efficient method for the preparation of arylnaphthalene lignans (ANLs) was developed, which is based on the Photo-Dehydro-Diels-Alder (PDDA) reaction. While intermolecular PDDA reactions turned out to be inefficient, the intramolecular variant using suberic acid as tether linking two aryl propiolic esters smoothly provided naphthalenophanes. The irradiations were performed with a previously developed annular continuous-flow reactor and UVB lamps. In this way, the natural products Alashinol D, Taiwanin C, and an unnamed ANL could be prepared.

Synthesis, Cytotoxicity, Anti-Migration and Anti-Invasion Activity of Diphyllin Heterocyclic Derivatives.

Diphyllin, an arylnaphthalene lignan lactone, isolated from many traditional medicinal plants, has been reported to possess anticancer and antiviral activities. Natural diphyllin and its glycosides were identified as potent vacuolar H+-ATPase (V-ATPase) inhibitors. The aim of this study was to design and synthesize a series of heterocyclic derivatives of diphyllin as novel anticancer agents. The targeted heterocyclic derivatives of diphyllin were synthesized from diphyllin employing etherification reaction and N-substitution reaction. Cytotoxicity of these compounds on four cancer cells was assessed by MTT assay. The inhibitory activity of V-ATPase of compound 3n was measured on MGC-803 cells. Anti-migration and anti-invasion abilities were assessed by transwell invasion assay and scratch wound assay. Most of these derivatives displayed potent cytotoxicity on four cancer cells at submicromolar concentrations. The most potent derivative 3n has been shown to inhibit V-ATPase activity, migration and invasion abilities on MGC-803 cells at 0.75 μM. The collective results clearly indicate that heterocyclic derivatives of diphyllin inhibit the viability, V-ATPase activity, migration and invasion of the MGC803 cells. The current findings provide valuable insights for the future development of novel diphyllin derivatives as anticancer agents.

Plant-derived lignans as potential antiviral agents: a systematic review.

Medicinal plants are one of the most important sources of antiviral agents and lead compounds. Lignans are a large class of natural compounds comprising two phenyl propane units. Many of them have demonstrated biological activities, and some of them have even been developed as therapeutic drugs. In this review, 630 lignans, including those obtained from medicinal plants and their chemical derivatives, were systematically reviewed for their antiviral activity and mechanism of action. The compounds discussed herein were published in articles between 1998 and 2020. The articles were identified using both database searches (e.g., Web of Science, Pub Med and Scifinder) using key words such as: antiviral activity, antiviral effects, lignans, HBV, HCV, HIV, HPV, HSV, JEV, SARS-CoV, RSV and influenza A virus, and directed searches of scholarly publisher’s websites including ACS, Elsevier, Springer, Thieme, and Wiley. The compounds were classified on their structural characteristics as 1) arylnaphthalene lignans, 2) aryltetralin lignans, 3) dibenzylbutyrolactone lignans, 4) dibenzylbutane lignans, 5) tetrahydrofuranoid and tetrahydrofurofuranoid lignans, 6) benzofuran lignans, 7) neolignans, 8) dibenzocyclooctadiene lignans and homolignans, and 9) norlignans and other lignoids. Details on isolation and antiviral activities of the most active compounds within each class of lignan are discussed in detail, as are studies of synthetic lignans that provide structure–activity relationship information.

Stable Axially Chiral Isomers of Arylnaphthalene Lignan Glycosides with Antiviral Potential Discovered from Justicia procumbens.

Arylnaphthalene lignans (ANLs) were known to have axial chirality due to the biphenyl skeleton with hindered rotation at the single bond. However, the stable ANL atropisomers have not been isolated from nature until the present study. Phytochemical separation of the methanol extract of the stems and barks of Justicia procumbens led to the isolation of 11 ANL glycosides including four pairs of new atropisomers with stable confirmations at room temperature. Their structures were deduced from elucidation of the extensive spectral data, and their absolute configurations were determined by the circular dichroism, electronic circular dichroism, and X-ray methods as well as the total synthesis of one pair of the atropisomers. The ANL compounds were evaluated for their antiviral potential, and it was found that they displayed great antiviral activity discrepancy between a pair of atropisomers due to the geometric orientation. The 1'P-oriented atropisomers showed much more significant antiviral potency than their corresponding 1'M-oriented counterparts. The biological activity discrepancy caused by the axial chirality will not only inspire synthetic design of novel ANL atropisomers to enrich the structural diversity, but also provide important hints to direct the synthetic approaches toward the antiviral drug development of ANL compounds.