Lignans of sesame: Purification methods,biological activities and biosynthesis – A review

Lignans are a group of compounds consisting of dimers of phenyl propane units. They are found in diverse forms distributed in a variety of plants. Sesame lignans in particular are obtained from Sesamum indicum, a highly prized oilseed crop cultivated widely in many countries in the east. The plant is the main source of clinically important antioxidant lignans such as sesamin, sesamolin, sesaminol and sesamol. These lignans exhibit antihypertensive, anticancerous and hypocholesterolemic activities as well especially in humans due to which they have become compounds of tremendous research interest in recent times. Sesamin is synthesized from shikimic acid through phenylpropanoid pathway and metabolised into enterolignans which play a pivotal role in protection against several hormone related diseases. In this paper we present an overview of current status of research on sesame lignans with respect to the analytical methods employed, the biological activities and biosynthesis of sesame lignans.     

Enterolignans

A review with 114 references about mammalian lignans (enterolignans). Several aspects have been reviewed: the precursors of mammalian lignans and their biosynthesis, biological activities and health effects, metabolism (in vivo and in vitro) in human and animals, some synthetic strategies to obtain enterolignan skeleton types, including the synthesis of haptens and deuterated lignans, and finally an overview of the analytical methods to detect and quantify lignans in biological matrices and foods.     

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.     

New Lignans and Their Biological Activities

Lignans, which are widely distributed in higher plants, represent a vast and rather diverse group of phenylpropane derivatives. They have attracted considerable attention due to their pharmacological activities. Some of the lignans have been developed approved therapeutics, and others are considered as lead structures for new drugs. This article is based on our previous review of lignans discovered in the period 2000–2004, and it provides a comprehensive compilation of the 354 new naturally occurring lignans obtained from 61 plant families between 2005 and 2011. We classified five main types according to their structural features, and provided the details of their sources, some typical structures, and diverse biological activities. A tabular compilation of the novel lignans by species is presented at the end. A total of 144 references were considered for this review.     

Structural determinants of plant lignans for growth of mammary tumors and hormonal responses in vivo

Low risk of breast cancer (BC) has been proposed to be associated with high intake of lignans. Some plant lignans are converted to mammalian lignans, e.g., enterolactone (ENL), suggested to be the biologically active lignan forms. Until now, little attention has been paid to the possible biological activities of plant lignans, even though some plant lignans are absorbed and present in serum and urine. In this study, we have investigated the antitumorigenic and endocrine-modulatory activities of different plant lignans in order to clarify the structure–activity relationships. 7-Hydroxymatairesinol (HMR) is converted to ENL, and both HMR and ENL inhibit the growth of 7,12-dimethylbenz[a]-anthracene (DMBA)-induced mammary cancer. Nortrachelogenin (NTG) resembles HMR, but has a hydroxyl group at C-8 instead of C-7 and is not converted to ENL. In DMBA-model, NTG showed no inhibition of tumor growth, but increased the uterine weight. Furthermore, life-long exposure to NTG increased uterine weight in immature females and ventral prostate weight in adult males. In contrast, life-long exposure to HMR had no effects on uterine or prostate weights at any age. Our results indicate that a difference in the position of one hydroxyl group results in distinct biological responses in vivo, as well as different lignan metabolite profiles.     

Lignans in treatment of cancer and other diseases†

Lignans are widely distributed in nature and display an impressive range of biological activities. The extensive pharmaceutical use of lignans is linked to their antitumor, antiviral, hepatoprotective, and platelet activating factor (PAF) antagonistic activities, among many others. This review article highlights selected pharmacologically active lignans, outlines their therapeutic relevance to the treatment of cancer and other diseases, and accentuates research on plant-derived lignans, particularly preclinical lead identification and optimization studies performed in the authors' Natural Products Laboratory (NPL). Antitumor and anti-HIV lignans have been discovered and developed in the NPL by using bioactivity-directed fractionation and isolation as well as rational drug design-based structural modification and analog synthesis approaches. Notably, a significant and ongoing project on podophyllotoxin and its semisynthetic analog etoposide has led to the development of a potent derivative designated GL-331. GL-331 has received investigational new drug (IND) approval from the FDA and is currently in clinical trials against various cancers, especially drug-resistant cancers. Further design, synthesis, and evaluation of GL-331-related analogs are discussed.     

Separation procedures applicable to lignan analysis

Lignans are a class of secondary plant metabolites produced by oxidative dimerization of two phenylpropanoid units. They have been found in many plants of Oriental medicine. In consequence of recent knowledge it is held that lignans are responsible for the key pharmacological activities of these plants. This review surveys the chromatographic, electromigration and hyphenated methods so far applied for the separation of lignans in Oriental plants used in phytotherapy as well as for the analyses of these lignans and their metabolites in biological matrices and food samples. In addition, the sample clean-up procedures--solvent extractions and supercritical fluid extractions--are also included.     

Dibenzocyclooctadiene lignans: a class of novel inhibitors of multidrug resistance-associated protein 1

We recently reported that dibenzocyclooctadiene lignans were a novel class of P-glycoprotein (P-gp) inhibitors. In this study, we demonstrated that the lignans of this class were also effective inhibitors of multidrug resistance-associated protein 1 (MRP1). The activities of 5 dibenzocyclooctadiene lignans (schisandrin A, schisandrin B, schisantherin A, schisandrol A, and schisandrol B) to reverse MRP1-mediated drug resistance were tested using HL60/Adriamycin (ADR) and HL60/Multidrug resistance-associated protein (MRP), two human promyelocytic leukemia cell lines with overexpression of MRP1 but not P-gp. The five lignans could effectively reverse drug resistance of the two cell lines to vincristine, daunorubicin, and VP-16. This study, together with our previous reports, proves that dibenzocyclooctadiene lignans have multiple activities against cancer multidrug resistance, including inhibition of P-gp and MRP1, and enhancement of apoptosis. Considering that cancer multidrug resistance (MDR) is multifactorial, agents with broad activities are preferable to the use of combination of several specific modulators to prevent drug-drug interaction and cumulative toxicity.     

Lignan compounds and 4,4'-dihydroxybiphenyl protect C2C12 cells against damage from oxidative stress

Lignan compounds are known to have various biological activities, especially antioxidative effects. We investigated whether lignan compounds show antioxidative activity in myoblast C2C12 cells. Among 14 lignan compounds investigated, two lignans containing two phenolic functional groups, namely Gomisin J and GR-12, prevented hydrogen peroxide (H(2)O(2))-induced cell death. A simple compound, 4,4'-dihydroxybiphenyl, which was found to be a common component of Gomisin J and GR-12, also largely prevented H(2)O(2)-induced cell death and almost completely prevented H(2)O(2)-induced increases in p38 MAPK phosphorylation. Our present results provide a useful in vitro system for clarifying the molecular mechanisms of lignan-mediated antioxidative effects and evaluating lead molecules toward the development of therapeutic drugs.     

Flax seed lignan in disease prevention and health promotion

Lignans have been part of both diet and herbal medicines for centuries. It is only in the last half century that phytochemists have described the structures of the lignans. Pharmacologists have only become interested in the biological activity of lignans in the last few decades. Much of the early interest focused on podophyllotoxin type lignans and their derivatives. Recent literature has recorded very many new lignans or lignan derivatives with a diverse range of biological activities. In 1955, the isolation from flax seed and the structure of the lignan derivative secoisolariciresinol diglucoside (SDG) was reported. Possible biological activity of SDG, and the mammalian lignan metabolites, enterolactone and enterodiol, was initially reported about 20 years later. During the next 30 years, there has been extensive research on the biological effects of both flax seed and rye lignans since both are metabolized into the mammalian lignans. Research on the activity of lignans on breast, colon, prostate and thyroid cancer has generally shown beneficial effects although there are some studies with either no conclusive or negative effect. Lignans have been shown to have positive effects in lowering relative risk factors for heart disease. Use of flax seed or SDG has been shown to have positive effects in both lupus and polycystic kidney disease models. Studies of both type I and II diabetes models have reported positive results when using SDG. Flax seed has also been reported to be hepatoprotective. Reproductive effects have been observed with flax seed or SDG and have been found to be dose and time related. There are many possible mechanistic explanations for the observed bioactivities including involvement in hormonal metabolism or availability, angiogenesis, anti-oxidation and gene suppression. Abbreviations: ALA – alpha linolenic acid; ApcMin – adenomatous polyposis coli multiple intestinal neoplasia; BBdp – BioBreeding diabetic prone; CCl₄– carbon tetrachloride; CDC – Crop Development Centre; CHD – cardiovascular heart disease; DMBA – dimethylbenzanthracene; DNA – deoxyribonucleic acid; ER – estrogen receptor; λGT –γ-glutamyltranspeptidase; HDL – high-density lipoprotein; HMGA – hydroxymethyl glutaric acid; IDDM – insulin dependent diabetes mellitus; LDL – low-density lipoprotein; MRL/lpr, Murine Lupus/lymphoproliferative; MDA – malondiadehyde; NIDDM – non-insulin dependent diabetes mellitus; ORF – oxygen free radical; PAF – platelet activating factor; PKD – Polycystic kidney disease; PEPCK – phosphoenolpyruvate carboxykinase; PMNL – polymorphonuclear monocytes; STZ – streptozoticin; TC – total cholesterol; TG – triglycerides; SDG – secoisolariciresinol diglucoside; ZDF – Zucker diabetic fatty. This revised version was published online in June 2006 with corrections to the Cover Date.     

Isolation of lignans as seed germination and plant growth inhibitors from Mediterranean plants and chemical synthesis of some analogues

Lignans and lignins are among the main metabolic products of phenylpropanoid metabolism in vascular plants. They are compounds representing the building blocks of plant cell walls. Moreover they have a broad range of biological activities such as antitumoral, antimitotic, antiviral and cytotoxic and are thought to be involved in the plant defense against pathogens and pests. In this paper we report a survey of the past and current literature about lignans and neolignans and their germination inhibitory activity on cultivated and wild species from plants of the Mediterranean area. Some examples of synthetic methodologies of these molecules have also been reported.     

Development of antibodies against secoisolariciresinol--application to the immunolocalization of lignans in Linum usitatissimum seeds

Lignans are widely distributed plant metabolites associated with a large range of biological activities. In order to gain insight into their biosynthesis and their spatio-temporal accumulation an immunological probe was developed. Secondary metabolites generally have too small molecular weight to be antigenic and have to be associated with a carrier protein. Secoisolariciresinol was chosen as the hapten and was linked to bovine serum albumin via a spacer arm, the p-aminohippuric acid. The artificial antigen was injected to New Zealand rabbits. The successful production of polyclonal antibodies against secoisolariciresinol was assessed with indirect enzyme immunosorbent assay (ELISA) by comparison with pre-immune serum and by competitive assays using dilutions of secoisolariciresinol standards. The antibodies had an IC(50) value of 94 μg/ml and showed moderate cross-reactivities with structurally related compounds. They were thus used to immunolocalize lignans in flaxseed (Linum usitatissimum), one of the richest sources of lignans. The immunohistochemical labeling allowed us to localize for the first time lignans in planta. They are mainly localized in the secondary wall of the sclerite cells of the outer integument of the seed. A very light labeling is also observed in cytoplasmic inclusions of the endosperm. The results were correlated with HPLC analytical results which enabled to evaluate the relative lignan quantities: in flaxseed about 90% of the metabolites are localized in the outer integument.     

台湾扁柏化学成分研究进展

从植物台湾扁柏（Chamaecyparis obtusa var．formosana）中提取分离得到一百多种化合物,这些化合物大多结构新颖、具有较强生理活性,主要有倍半萜类、双萜类、木酚素类、固醇类以及其它化合物。本文综述了从该植物中得到的各类化学成分的结构和^13C NMR谱图数据。     

Phytochemical and biological studies of Abies species

In the present review, the literature data on the phytochemical and biological investigations on the genus of Abies are summarized with 110 references. Up to now, 277 compounds were isolated from 19 plants of Abies species. The chemical constituents are mostly terpenoids, flavonoids, and lignans, together with minor constituents of phenols, steroids, and others. The crude extracts and metabolites have been found to possess various bioactivities including insect juvenile hormone, antitumor, antimicrobial, anti-ulcerogenic, anti-inflammatory, antihypertensive, antitussive, and CNS (central nervous system) activities.     

白木香的化学成分与生物活性研究进展

白木香(Aquilaria sinensis)的化学成分主要包括黄酮、苯甲酮、木脂素、苯丙素、萜类、生物碱、甾体以及其他酚性化合物,一些化学成分具有抗肿瘤、抗菌、抗炎、镇痛、利泄、降糖等生物活性。对近年来从白木香中分离鉴定出的化学成分,以及部分化学成分的生物活性进行了综述,为白木香资源的合理开发利用提供科学依据。     

五味子科植物的木脂素成分

五味子科植物分为五味子属 ( Schisandra)和南五味子属 ( Kadsura) 2个属 ,其中五味子 ( S.chinensis)为著名中药 ,其应用已有 2 0 0 0多年的历史 ,一直为我国药典所收载 ,该科其它许多种也在民间广泛应用 [1 ]。 2 0世纪 70年代初 ,我国临床研究中发现五味子能明显降低肝炎患者血清谷丙转氨酶水平 ,引起广泛研究的热潮 ,并由此开发出治疗肝炎药物联苯双酯 [2 ] 。迄今 ,国内外已对二十余种五味子科植物进行了研究 ,分离鉴定出大约 2 0 0个成分 ,其中 1 50多个为木脂素。五味子科木脂素结构类型多 ,立体化学复杂 ,而且生物活性广泛。除了…     

鬼臼毒素及其衍生物

鬼臼毒素作为鬼臼属植物的主要活性成分,已经有广泛的研究报道。其同系物及衍生物具有很强的抗肿瘤活性。依托泊甙、替尼泊甙已经成功地用于临床抗肿瘤治疗。优化结构、寻找新的鬼臼毒素类化合物资源替代品,已成为当前进一步研究的主要方向。     

Lignans in flower buds of Magnolia fargesii

Four lignans were isolated from the flower buds of Magnolia fargesii Cheng, two of which were known lignans, pinoresinol dimethyl ether and lirioresinol-B dimethyl ether; the other two were new lignans, magnolin and fargesin, and their structures have been determined by spectroscopic studies.     

Naphthoquinone derivatives and lignans from the Paraguayan crude drug "tayï pytá" (Tabebuia heptaphylla,Bignoniaceae)

The Paraguayan crude drug "tay? pytá" is used to treat cancer, wounds and inflammation. It consist of the bark and trunkwood of Tabebuia heptaphylla (Bignoniaceae). A phytochemical study of the crude drug gave, in addition to previously described naphthoquinones and the known lignans cycloolivil and secoisolariciresinol, three new lapachenol (lapachonone)-, two naphthofuran-, a chromone and a naphthalene derivative. The structures were elucidated by means of high field NMR spectroscopy. The biological activity of the main compound lapachol and the related alpha-lapachone as well as the lignans cycloolivil and secoisolariciresinol can explain, at least in part, the effect atributed to the crude drug in Paraguayan folk medicine.     

Immunosuppressive flavones and lignans from Bupleurum scorzonerifolium

Two lignans, isochaihulactone and chaihunaphthone, together with eleven known compounds were isolated from the root of Bupleurum scorzonerifolium. Their structures were established on the basis of spectral evidence. In biological testing, eugenin and saikochromone potently inhibited CD28-costimulated activation of human peripheral blood T cells.