Dihydroguaiaretic Acid Research Articles

Phytochemical and Gene Network Analysis Elucidating the Key Genes Involved in the Biosynthesis of Gomisin J in Schisandra sphenanthera

The biosynthesis and distribution of lignans in medicinal plants, particularly in Schisandra sphenanthera, hold significant pharmacological importance. This study bridges the knowledge gap in understanding the tissue-specific biosynthesis and distribution of these compounds, with a focus on Gomisin J. Our phytochemical analysis revealed a distinct accumulation pattern of Gomisin J, predominantly in the roots, contrasting with the distribution of Pregomisin and Dihydroguaiaretic acid. This finding highlights the roots’ unique role in lignan storage and biosynthesis. Further, differential gene expression analysis across various tissues illuminated the biosynthetic pathways and regulatory mechanisms of these lignans. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA), we identified the MEtan module as a key player, strongly correlated with Gomisin J levels. This module’s in-depth examination revealed the crucial involvement of four cytochrome P450 (CYP) enzymes and eight transcription factors. Notably, the CYP genes DN6828 and DN2874-i3 exhibited up-regulation in roots across both male and female plants, while DN51746 was specifically up-regulated in male roots, indicating a potential gender-specific aspect in Gomisin J biosynthesis. Comparative analysis with functionally characterized CYP71A homologs suggests these CYP genes might be involved in distinct biosynthetic pathways, including terpenoids, alkaloids, and phenylpropanoids, and potentially in lignan biosynthesis. This hypothesis, supported by their more than 55% identity with CYP71As and strong correlation with Gomisin J concentration, opens avenues for novel discoveries in lignan biosynthesis, pending further functional characterization. Our research provides a comprehensive understanding of the genetic and metabolic mechanisms underlying the tissue-specific distribution of lignans in Schisandra sphenanthera, offering valuable insights for their pharmacological exploitation.

Understanding apoptotic induction by Sargentodoxa cuneata-Patrinia villosa herb pair via PI3K/AKT/mTOR signalling in colorectal cancer cells using network pharmacology and cellular studies

Ethnopharmacological relevanceSargentodoxa cuneata (Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson, DXT)-Patrinia villosa(Patrinia villosa (Thunb.) Dufr, BJC) constitutes a commonly employed herb pair in Chinese medicine for colorectal cancer (CRC) treatment. Modern pharmacological investigations have revealed the anticancer activities of both Sargentodoxa cuneata and Patrinia villosa. Nevertheless, comprehensive studies are required to discern the specific antitumor active ingredients and mechanism of action when these two herbs are used in combination. Aim of the studyThrough the integration of network pharmacology, molecular docking techniques, experimental assays, and bioinformatics analysis, our study aims to forecast the active ingredients, potential targets, and molecular mechanisms underlying the therapeutic efficacy of this herb pair against CRC. Materials and methodsPlant names (1, Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson; 2, Patrinia villosa (Thunb.) Dufr.) have been verified through WorldFloraOnline (www.worldFloraonline.org) and MPNs (http://mpns.kew.org). The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were utilized for screening the active ingredients of the herb pair. The PharmMapper database was employed to predict the target proteins for each active ingredient. CRC-related targets were obtained from the Genecards database, Online Mendelian Inheritance in Man (OMIM) database, Disease Gene Network (DisGeNET) database, and Therapeutic Target Database (TTD). Common targets were identified by intersecting the target proteins of all active ingredients with CRC-related targets. Protein-protein interactions (PPI) for the common target proteins were constructed using the String database and Cytoscape 3.9.1 software. Network topology analysis facilitated the identification of core targets. These core targets were subjected to enrichment analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) using the Metascape database. Molecular docking was performed using Discovery Studio 2019 to investigate the interactions between the active ingredients and core target proteins. The core targets were validated through bioinformatics analysis using GEPIA, HPA, and the cBioPortal database. Finally, a series of experiments were conducted to further validate the results in vitro. ResultA total of 15 active ingredients and 255 herb targets were identified, resulting in 66 common targets in conjunction with 6113 disease targets. The PPI analysis highlighted AKT1, EGFR, CASP3, SRC, and ESR1 as core targets. KEGG enrichment analysis indicated significant enrichment in the PI3K-AKT signaling pathway, a pathway associated with cancer. Molecular docking experiments confirmed favorable interactions between dihydroguaiaretic acid and the core target proteins (AKT1, EGFR, CASP3, and ESR1). Bioinformatics analysis revealed differential expression of EGFR and CASP3 in normal and CRC tissues. Cellular experiments further verified that dihydroguaiaretic acid induces apoptosis in colorectal cancer cells through the PI3K-AKT signaling pathway. ConclusionOur network pharmacology study has elucidated that the Sargentodoxa cuneata-Patrinia villosa herb pair exerts the negative regulation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the induction of apoptosis in colorectal cancer cells. This research has predicted and validated the active ingredients, potential targets, and molecular mechanisms of Sargentodoxa cuneata-Patrinia villosa in the treatment of CRC, providing scientific evidence for the use of traditional Chinese medicine in managing CRC.

Molecular Docking Study of Nutmeg (Myristica Fragrans) Constituents as Anti-Skin Cancer Agents

<p>Molecular docking analysis was carried out to understand better the interaction between DHODH and inhibitor from nutmeg in this series. The nutmeg constituent binding orientations in the active site of DHODH was seen in a molecular docking analysis and helped design a potentially new inhibitor. This work aimed to study the molecular docking of nutmeg constituents with the DHODH inhibitor using a computer-aided drug design. Molecular docking using AutoDock 4.2 was done to explore the models of binding complexes. The 3D structure was derived using Discovery Studio to investigate the essential chemical interaction of complex structures. Dihydroguaiaretic acid was the most potent ligand having a docking score of -9.3 kcal/mol. This value was better than the standard drug 5-FU. The dihydroguaiaretic acid structure interacted with Tyr365 and Thr63 through a hydrogen bond similar to the native ligand. These results suggest that nutmeg seed could serve as the lead compound for potent DHODH inhibitors against skin.</p>

Matrix Solid-Phase Dispersion Combined with HPLC-DAD for Simultaneous Determination of Nine Lignans in Saururus chinensis.

A simple and rapid method, based on matrix solid-phase dispersion (MSPD) and high-performance liquid chromatography (HPLC) was developed for simultaneous determination of nine lignans, including (-)-(7R,8R)-machilin D (Wang, C., Wang, P., Chen, X., Wang, W., Jin, Y.; Saururus chinensis (Lour.) Baill blocks enterovirus 71 infection by hijacking MEK1-ERK signaling pathway; Antiviral Research, (2015); 119:47-56), dihydroguaiaretic acid (Quan, Z., Lee, Y.J., Yang, J.H., Lu,Y., Li,Y., Lee,Y.K., et al.; Ethanol extracts of Saururus chinensis suppress ovalbumin-sensitization airway inflammation; Journal of Ethnopharmacology, (2010); 132:143-149.), sauchinone (Zhuang, T., Liang, J.Y., Sun, J.B., Wu, Y., Huang, L.R., Qu, W.; Secondary metabolites from Saururus chinensis and their chemotaxonomic significance; Biochemical Systematics and Ecology, (2014); 56:95-98.), rel-(7S,8S,7'R,8'R)-3,3',4,4',5,5'-hexamethoxy-7.O.7',8.8'-lignan (Tsai, W.J., Shen, C.C., Tsai, T.H., Lin, L.C.; Lignans from the aerial parts of Saururus chinensis: isolation, structural characterization, and their effects on platelet aggregation; Journal of Natural Products, (2014); 77:125-131), licarin A (Cui, H., Xu, B., Wu, T., Xu, J., Yuan, Y., Gu, Q.; Potential antiviral lignans from the roots of Saururus chinensis with activity against Epstein-Barr virus lytic replication; Journal of Natural Products, (2014); 77:100-110.), manassantin A (Lu, Y., Piao, D., Zhang, H., Li, X., Chao, G.H., Park, S.J., et al.; Saucerneol F inhibits tumor necrosis factor-alpha and IL-6 production by suppressing Fyn-mediated pathways in FcepsilonRI-mediated mast cells; Food and Chemical Toxicology, (2013); 59:696-702.), saurucinol I (Kwon, O.E., Lee, H.S., Lee, S.W., Chung, M.Y., Bae, K.H., Rho, M.C., et al.; Manassantin A and B isolated from Saururus chinensis inhibit TNF-α-induced cell adhesion molecule expression of human umbilical vein endothelial cells; Archives of Pharmacal Research, (2005); 28:55-60.), manassantin B (Hwang, B.Y., Lee, J.H., Jung, H.S., Kim, K.S., Nam, J.B., Hong, Y.S., et al.; Sauchinone, a lignan from Saururus chinensis, suppresses iNOS expression through the inhibition of transactivation activity of RelA of NF-κB; Planta Medica, (2003); 69:1096-01.) and licarin B (Hwang, B.Y., Lee, J.H., Nam, J.B., Hong, Y.S., Lee, J.J.; Lignans from Saururus chinensis inhibiting the transcription factor NF-κB; Phytochemistry, (2003); 64:765-771.) in Saururus chinensis. The parameters of MSPD were optimized to be that 0.2 g of sample, blended with 0.4 g silica gel, and eluted with 5 mL of methanol. The separation was carried out on a C18 column with acidified aqueous acetonitrile gradients. The established method was fully validated in terms of linearity (r2 ≥ 0.9994), sensitivity, precision (RSD ≤ 3.18%), repeatability (RSD ≤ 3.02%) as well as recovery (93.49-103.52%), and subsequently applied to six samples of S. chinensis from different areas. The MSPD extraction promoted higher extraction yields of nine lignans, lower solvent sample and solvent consumption.

Synergistic effect of abscisic acid and ethylene on color development in tomato ( Solanum lycopersicum L.) fruit

Abstract In order to investigate the synergistic effect of abscisic acid and ethylene on tomato color development during ripening, mature green tomato fruit were harvested and treated with abscisic acid (ABA), 1-methylcyclopropene (1-MCP), alone or in combination, and dihydroguaiaretic acid (NDGA), and then were stored at 20 °C and 90% RH for fourteen days. Endogenous ethylene production, color development and the expression profiles of major related genes in treated fruits were examined. Furthermore, 2000 bp sequences upstream of major related genes were analyzed. Results indicated that ABA significantly up-regulated the expression levels of major genes related to carotenoids and flavonoids biosynthesis (ranging from 2.08 to 35 folds) and initiated the accumulation of carotenoids, phenolics and flavonoids by 2 or 4 days earlier than that in control. However, results demonstrated that the exogenous ABA could not significantly affect tomato color development without ethylene. The outcome of gene promoter analysis revealed that, besides single existence of ABRE or ERE motifs, 10 of 23 genes involved in carotenoids biosynthetic pathway, and 10 of 40 genes involved in flavonoid biosynthesis pathway possess both ABRE and ERE motifs in their 2000 bp upstream sequences, suggesting that ABA and ethylene may affect fruit color development via the collaborative regulation of these genes.

Chemical Constituents of Kadsura coccinea

Two new dibenzocyclooctadiene lignans, named schisantherin R (3) and schisantherin S (4), and six known compounds, named kadsuralignan I, kadsuralignan J, binankadsurin A, kadsuralactone B, acetyl-binankadsurin A, and dihydroguaiaretic acid, were isolated from the chloroform fraction of the ethanol extract of Kadsura coccinea (Lem.) A. C. Sm. The structures of the compounds were elucidated by spectroscopic analysis, including MS, CD, and 1D and 2D NMR spectra.

Structure-Antifungal Activity Relationship of Fluorinated Dihydroguaiaretic Acid Derivatives and Preventive Activity against Alternaria alternata Japanese Pear Pathotype.

The structure-activity relationship of the antifungal fluorinated dihydroguaiaretic acid derivatives was evaluated. Some of the newly synthesized lignan compounds were found to show higher antifungal activity against phytopathogenic fungi such as Alternaria alternata (Japanese pear and apple pathotypes) and A. citri than the lead compound, 3-fluoro-3'-methoxylignan-4'-ol (3). The broad antifungal spectrum of 3'-hydroxyphenyl derivative 16 was observed, and the 3'-fluoro-4'-hydroxyphenyl derivative 38 was found to show the highest activity against the A. alternata Japanese pear pathotype, with an EC50 value of 11 μM. The preventive effect of the potent lignan on the infection of A. alternata in the Japanese pear's leaves was also shown.

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2.

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure–activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.

Enantioselective syntheses of both enantiomers of 9′-dehydroxyimperanene and 7,8-dihydro-9′-dehydroxyimperanene and the comparison of biological activity between 9-norlignans and dihydroguaiaretic acids

To estimate the effect of methyl group of dihydroguaiaretic acid, which shows many kinds of biological activities, on biological activity, both enantiomers of 9′-dehydroxyimperanene (5, 6) and 7,8-dihydro-9′-dehydroxyimperanene (7, 8) lacking one of the methyl groups of dihydroguaiaretic acid were synthesized. (S)-7,8-Dihydro-9′-dehydroxyimperanene (7) showed 4–6-fold higher cytotoxic activity than all stereoisomers of dihydroguaiaretic acid (2–4). The IC50 values of (S)-7,8-dihydro-9′-dehydroxyimperanene (7) against HL-60 and HeLa cells were 6.1μM and 5.6μM, respectively. Though only one of three stereoisomers of dihydroguaiaretic acid showed antibacterial activity against a gram negative bacterium, both enantiomers of 5–8 showed antibacterial activity against a gram negative bacterium. This is a Letter on biological activity of 9-norlignan, in which one of methyl groups of lignan is absent.

Acute larvicidal activity against mosquitoes and oxygen consumption inhibitory activity of dihydroguaiaretic acid derivatives.

(-)-Dihydroguaiaretic acid (DGA) and its derivatives having 3-hydroxyphenyl (3-OH-DGA) and variously substituted phenyl groups instead of 3-hydroxy-4-methoxyphenyl groups were synthesized to measure their larvicidal activity against the mosquito Culex pipiens Linnaeus, 1758 (Diptera: Culicidae). Compared with DGA and 3-OH-DGA (LC50 (M), 3.52 × 10(-5) and 4.57 × 10(-5), respectively), (8R,8'R)-lignan-3-ol (3) and its 3-Me (10), 2-OH (12), 3-OH (13), and 2-OMe (15) derivatives showed low potency (ca. 6-8 × 10(-5) M). The 4-Me derivative (11) showed the lowest potency (12.1 × 10(-5) M), and the 2-F derivative (4) showed the highest (2.01 × 10(-5) M). All of the synthesized compounds induced an acute toxic symptom against mosquito larvae, with potency varying with the type and position of the substituents. The 4-F derivative (6), which killed larvae almost completely within 45 min, suppressed the O2 consumption of the mitochondrial fraction, demonstrating that this compound inhibited mitochondrial O2 consumption contributing to a respiratory inhibitory activity.

Lignans from Saururus chinensis with Antiplatelet Aggregation and Neuroprotective Activities

A new natural product, meso-2,3-bis-(3,4,5-trimethoxybenzoyl)butane (1), together with six known lignans, saucernetin diol (2), licarin A (3), di-O-methyltetrahydrofuriguaiacin (4), ent-sauchinone (5), (–)-dihydroguaiaretic acid (6), and licarin B (7), were isolated from Saururus chinensis. Compound 2 was isolated from this plant for the first time. Compounds 1–7 were determined by spectroscopic methods. Compounds 1–3, 6, and 7 showed significant inhibitory activities on ADP-induced platelet aggregation, and compounds 5–7 showed promising neuroprotective effects on H2O2-induced injury in PC12 cells.

Cytotoxic activity of dietary lignan and its derivatives: structure-cytotoxic activity relationship of dihydroguaiaretic acid.

Cytotoxic activities of synthesized lignan derivatives were estimated by WST-8 reduction assay against HL-60 and HeLa cells to show the structure-activity relationship. The activities of some effective compounds were examined against Colon 26 and Vero cells. Dietary secoisolariciresinol (SECO, 1) and its metabolite, 9,9'-anhydrosecoisolariciresinol (2), did not show the cytotoxic activity. On the other hand, all stereoisomers of dihydroguaiaretic acid (DGA, 9,9'-dehydroxysecoisolariciresinol, 3-5) exhibited the activity (IC50: around 30 μM). The IC50 value of (8R,8'R)-9-butyl DGA derivative 13 was around 6 μM. This fact means that the hydrophobic group was advantageous for higher activity at 9- and 9'-positions. By the evaluation of the effect of 7and 7'-aryl group on the activity, we discovered the highest activity of (8R,8'R)-7-(3-hydroxy-4-methoxyphenyl)-7'-(2-ethoxyphenyl) DGA derivative 47 showing around 1 μM of IC50 value, which is about 24-fold higher activity than that of natural (8R,8'R)-DGA. The derivative of dietary lignan showed the high cytotoxic activity.

New Schiartane-type Triterpene from Kadsura heteroclita and their Cytotoxic Activities

One new schiartane-type triterpene, heteroclitalactone N (1), and four known compounds (2-5), seco-coccinic acid F, dihydroguaiaretic acid, schizanrin F, and kadsuralignan B were isolated from the stems of Kadsura heteroclita. Their structures were determined by the combination of spectroscopic and chemical methods, including 1D-, 2D-NMR, and CD spectra as well as by comparing with the NMR data reported in the literature. The cytotoxic activities of all isolated compounds were evaluated on three human cancer cell lines. Compound 3 exhibited moderate to weak cytotoxic activities on three human cancer cell lines, OVCAR, HT-29, and A-549, with IC50 values ranging from 16.2 to 36.4 microM.

Quantitative Structure–Activity Relationship Analysis of Antifungal (+)-Dihydroguaiaretic Acid Using 7-Phenyl Derivatives

The relationship between antifungal activity against Alternaria alternata and structure on the 7-phenyl group of (+)-dihydroguaiaretic acid ((+)-DGA) was clarified by employing 38 synthesized (+)-DGA derivatives. The results were identified by quantitative structure-activity relationship (QSAR) analysis employing the Hansch-Fujita method. Some compounds showed higher activity than (+)-DGA. The compound showing highest activity was 3,5-difluorophenyl derivative 37. It was suggested that the small electron-withdrawing group at the meta-position of the 7-phenyl group is important for the higher activity by antifungal test and Hansch-Fujita analysis. The whitening activity of 3-hydroxy-4-methoxyphenyl derivative 28, 3-hydroxy-4-ethoxyphenyl derivative 29, and 3-hydroxy-4-isopropoxyphenyl derivative 30 against A. alternata Japanese pear pathotype was also discovered.

First Discovery of Insecticidal Activity of 9,9′-Epoxylignane and Dihydroguaiaretic Acid against Houseflies and the Structure–Activity Relationship

The insecticidal activity of (-)-(8R,8'R)-3,3'-dimethoxy-9,9'-epoxylignane-4,4'-diol (1) against houseflies was clarified for the first time. The activities of other stereoisomers were weaker than that of the (8R,8'R)-stereoisomer. In the course of research into structure-activity relationships involving 30 newly synthesized (8R,8'R)-derivatives, 5-fold higher activity (ED50 = 0.91 nmol/fly) was observed for (-)-(8R,8'R)-3,3',4-trimethoxy-9,9'-epoxylignan-4'-ol (21) than for the naturally occurring compound (1). The activity of 1 was weaker than that of (-)-(8R,8'R)-dihydroguaiaretic acid ((-)-DGA) (4); however, compound 21 showed almost the same level of activity as 4.

Antibacterial and Antimycobacterial Lignans and Flavonoids from Larrea tridentata

Three lignans and four flavonoids were isolated and characterized from Larrea tridentata and compounds were tested against 16 bacterial species/strains. Results showed that: dihydroguaiaretic acid (1) had activity towards methicillin resistant (MR) Staphylococcus aureus (minimum inhibitory concentration (MIC) 50 µg/mL) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MIC 12.5-50 µg/mL); 4-epi-larreatricin (2) was active against Enterobacter cloacae (MIC 12.5 µg/mL), as well as sensitive (MIC 50 µg/mL) and MDR strains of M. tuberculosis (MIC 25 µg/mL). 3'-Demethoxy-6-O-demethylisoguaiacin (3) displayed activity against sensitive and resistant S. aureus (MIC 25 µg/mL), Enterococcus faecalis (MIC 12.5 µg/mL), Escherichia coli (MIC 50 µg/mL), E. cloacae (MIC 12.5 µg/mL) and MDR strains of M. tuberculosis (MIC 12.5 µg/mL). 5,4'-Dihydroxy-3,7,8,3'-tetramethoxyflavone (4) and 5,4'-dihydroxy-3,7,8-trimethoxyflavone (5) were active against M. tuberculosis MDR strains having MIC values of 25 and 25-50 µg/mL, respectively, while 5,4'-dihydroxy-7-methoxyflavone (6) was active against S. aureus (MIC 50 µg/mL) and E. faecalis (MIC 50 µg/mL). We concluded that lignan 3 is the main compound responsible for the antibacterial activity of L. tridentata. Lignans 1 and 2 as well as flavonoid 6 contribute with some degree of antibacterial activity. On the other hand, compounds 1, 2, 3, 4 and 5 contributed to the antimycobacterial activity found in L. tridentata.

Dibenzylbutane‐ and Butyrolactone‐type Lignans as Apoptosis Inducers in Human Hepatoma HuH‐7 Cells

Seven lignans, previously isolated from Pycnanthus angolensis or obtained by derivatization, namely the dibenzylbutane-type lignans threo-4,4'-dihydroxy-3-methoxylignan (1), 4'-hydroxy-3,3',4-trimethoxylignan (2), (-)-dihydroguaiaretic acid (3), 3,3',4,4'-tetramethoxylignan (4), 4,4'-diacetyl-3,3'-dimethoxylignan (5), heliobuphthalmin (6) and the butyrolactone lignan hinokinin (7), were evaluted for their ability as apoptosis inducers in human hepatoma HuH-7 cells. Cell viability assays, morphological evaluation of apoptosis and enzymatic analyses of caspase activity in HuH-7 cells were carried out. Using the lactate dehydrogenase lactate dehydrogenase (LDH) assay, it was demonstrated that the lignans (1-7) tested significantly reduced viability of HuH-7 cells. Morphologic evaluation of HuH-7 cells using Hoechst staining and fluorescence microscopy revealed that lignans 1-7 were strong inducers of apoptosis. In fact, HuH-7 cells developed morphological changes of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. However, lignans 2 and 7 were the most promising compounds in this study, inducing 2.4- and 2.5-fold increases in apoptotic cells as compared to controls. Caspase-3-like activity assays confirmed the morphologic data.

Larvicidal Activity of (−)-Dihydroguaiaretic Acid Derivatives againstCulex pipiens

The larvicidal activity against Culex pipiens of all stereoisomers of dihydroguaiaretic acid (DGA) and secoisolariciresinol was measured, and these DGAs were found to be potent. Sixteen (-)-DGA derivatives were then newly synthesized to analyze their structure-activity relationship. Two derivatives monohydroxylated at the 3- or 4-position of the 7-phenyl group of DGA induced acute paralytic activity in the mosquitoes. Derivatives with several hydroxyl groups had lower activity than the natural compound, suggesting that hydrophobicity was probably an important factor for their insecticidal activity.

Virtual screening to design drug molecules for human proto oncogene Fyn kinase

AbstractHuman Fyn tyrosine kinase, a Src-family enzyme plays a pivotal role in the integrin mediated cell signaling pathway and is known to interact with several molecular signals including FAK and paxillin that accounts for morphogenic transformation leading to cancer. The present study was aimed to design a persuasive inhibitor for Fyn kinase. The crystal structure was optimized and energy minimized applying OPLS2001 force field in Maestro v9.0. The inhibitor binding site residues such as LEU-17, GLY-18, ASN-19, VAL-25, ALA-37, LYS-39, GLU-54, THR-82, GLU-83, TYR-84, MET-85, GLY-88, ALA-134, ASN-135, LEU-137, and ASP-148 were located from the Fyn kinase co-crystal structure with staurosporine. Three published inhibitors (staurosporine, Rosmarinic acid and dasatinib) of Fyn kinase were searched through high throughput virtual screening in Ligand.Info Metadatabase and generated 1163 structural analogues. Glide 5.5 docking was performed to predict the binding orientation of prepared ligand molecule into a grid of 20 x 20 x 20 Å created around the centroid of optimized Fyn kinase. Isomers and tautomers were generated for 1163 chemical entities through LigPrep. Ligands having reactive functional groups and poor ADME properties were rejected from the prepared dataset and docked into the predicted active site of human Fyn kinase through a systematic application of virtual screening using Glide v5.5. Five lead molecules with good XP GScores were obtained with their binding orientations, further XP Gscores were interrelated with the existing three published inhibitors. Lead1 (nor dihydroguaiaretic acid) was observed to have the lowest XP Gscore (-11.39 Kcal/mol) compared to three published inhibitors and blocked the Fyn kinase active site by forming hydrogen bonds and good Van der Waals contacts. Thus, nor dihydroguaiaretic acid would be useful as drug molecule if synthesized and tested in animal models.

Simultaneous determination of eleven bioactive compounds in Saururus chinensis from different harvesting seasons by HPLC-DAD

A high performance liquid chromatography method coupled with diode array detection (HPLC-DAD) was developed for simultaneous determination of five major active flavonoids, two aristolactams and four main lignans in Saururus chinensis, namely rutin ( 1), isoquercitrin ( 2), quercetin-3-O-β- d-glucopyranosyl (1 → 4)-α- l-rhamnoside ( 3), quercitrin ( 4), quercetin ( 5), aristolactam A II ( 6), sauristolactam ( 7), dihydroguaiaretic acid ( 8), sauchinone ( 9), licarin A ( 10) and licarin B ( 11). The analysis was performed on an Agilent Eclipse XDB C 18 column (4.6 mm × 150 mm, 5 μm) with gradient elution of 0.4% aqueous phosphoric acid and acetonitrile. The detection wavelengths were 280 and 360 nm. All calibration curves showed good linearity ( r 2 > 0.9991) within test ranges. The method was reproducible with intra- and inter-day variation less than 3.2%. The recovery of the assay was in the range of 95.1–103.9%. The validated method was successfully applied for the analysis of the eleven bioactive compounds in seven samples from different harvesting seasons and significant variations were revealed. The results indicated that the developed method can be used as a suitable quality control method for S. chinensis and it should be harvested in August (fruiting period) for Jiangsu cultivation regions, taking the yield into consideration, with the highest amounts of lignans, relative higher amounts of flavonoids and lower amounts of aristolactams.