Nor-Lignans: Occurrence in Plants and Biological Activities—A Review

In this review article, the occurrence of nor-lignans and their biological activities are explored and described. Nor-lignans have proven to be present in several different families also belonging to chemosystematically distant orders as well as to have many different beneficial pharmacological activities. This review article represents the first one on this argument and is thought to give a first overview on these compounds with the hope that their study may continue and increase, after this.


Introduction
A large part of secondary plant phenolic natural products derives from the aromatic amino acids couple tyrosine/phenylalanine. The de-amination of these compounds gives raise, through the shikimic acid pathway, to the intermediate metabolites C(6)-C(3), i.e., propenyl-phenols and allyl-phenols, generally named as phenylpropanoids. These are the starting points of the biosynthesis of several classes of active constituents related to the stability of the cell wall and to the defense of plants against herbivorous animals and pathogens. The first line of defense in terrestrial plants is a mechanical one, related to a polymerization process which leads to the formation of lignin, the main component of wood. Lignin is a very strong and stable macromolecule. Its introduction inside the plant cell wall instead of the carbohydrate polymer cellulose, confers force and resistance, allowing the formation of giant tree's structure and making the digestions of the adult parts of the plant from herbivorous animals very difficult. Yet, the lignin defense line has resulted to be quite insufficient in many cases and the incoming predominance of herbal species determined the shift towards another form of defense, i.e., the chemical one. Actually, the phenylpropanoids pathway has never been dismissed, but rather it has turned towards the synthesis of smaller products having more precise targets. Among these molecules, the dimerization process of C(6)-C(3) precursors gives rise to three important classes of natural secondary metabolites: lignans, neo-lignans and nor-lignans. These classes present similar features due to their common biosynthetic origin. Their general structure is characterized by the presence of two terminal phenyl groups, which are more or less functionalized with hydroxyl groups and connected by a central chain of six carbon atoms, differently arranged and oxidized. The main oxidized. The main difference among lignans, neo-lignans and nor-lignans is due to the different type of junction between the two C(6)C(3) (=PhC3) units. In particular, in lignans, this junction is through a β-β (8-8′) bond and in neo-lignans the junction is not a β-β type. Therefore, lignans and neo-lignans, and their several different derived subclasses, can be identified depending upon the carbon skeletons which they possess. For what concerns nor-lignans, the structure is more complicated. In fact, norlignans own a peculiar characteristic, with respect to lignans and neo-lignans, which is the cut of one carbon from the central chain. This loss forces this chain to be differently arranged from lignans and neo-lignans, such as in a linear sequence or in a C(3)C(2) arrangement meaning 8,9′-coupling and 7′, 8coupling or alternatively in the bis-nor-lignan and cyclo-nor-lignan skeletons (8,8′) where chirality plays a central role. From this description, it is quite easy to understand the other definition of the structure of nor-lignans: natural compounds based on diphenyl-pentanes, derived by the union of two phenylpropanoid units in the positions α, β′ or β, γ′ and characterized with the loss of the terminal carbon of the chain [1][2][3]. Figure 1 shows the possible different arrangements for nor-lignans.

Occurrence of Nor-Lignans in the Plant Kingdom
From the environmental and taxonomical points of view, lignans are mainly biosynthesized in woody plants, since main occurrences are related to Gymnospermae and Angiospermae. In particular, they can be found in the trees' members of ancient forests like the Amazonian one, but, probably because of their simple biosynthetic pathway, they can be present also in herbal plants like those of monocotyledons.
In this review article, the attention is focused on nor-lignans, their occurrence in the plant kingdom and their importance as bioactive molecules.

Occurrence of Nor-Lignans in the Plant Kingdom
From the environmental and taxonomical points of view, lignans are mainly biosynthesized in woody plants, since main occurrences are related to Gymnospermae and Angiospermae. In particular, they can be found in the trees' members of ancient forests like the Amazonian one, but, probably because of their simple biosynthetic pathway, they can be present also in herbal plants like those of monocotyledons.
In this review article, the attention is focused on nor-lignans, their occurrence in the plant kingdom and their importance as bioactive molecules. Table 1 reports on the nor-lignans identified in the plant kingdom differentiating them according to the species, genus and family. In addition, the organs from which these compounds have been isolated, and the techniques used for their isolation and identification were completely added.
Aerial parts Vitex rotundifolia L.f.  Whole plant Solanaceae

Chemotaxonomy
As Table 1 clearly shows, nor-lignans have been recognized as phytochemical constituents of several families, even chemosystematically far away from each other. This is in accordance with the easy phytochemical pathway connected with very common PhC3 intermediate metabolites. However, the rearrangements following the junction of the two originating moieties are another matter.
Therefore, some specific compounds can be evidenced as chemotaxonomic makers at every classification level.
Pachypostaudins A-B and pachypophyllin (Figures 16 and 17) may be chemotaxonomic markers for the entire Annonaceae family given their specific occurrence here [7,8].
Asparenydiol ( Figure 17) and its derivatives are considered as some of the chemotaxonomic markers for the genus Asparagus L. [17].
Within the Lamiaceae family, surely negundins A-B ( Figure 20) are chemotaxonomic markers for the species Vitex negundo L given their occurrence in several exemplars of this species [69][70][71].

Chemotaxonomy
As Table 1 clearly shows, nor-lignans have been recognized as phytochemical constituents of several families, even chemosystematically far away from each other. This is in accordance with the easy phytochemical pathway connected with very common PhC3 intermediate metabolites. However, the rearrangements following the junction of the two originating moieties are another matter.
Therefore, some specific compounds can be evidenced as chemotaxonomic makers at every classification level.
Pachypostaudins A-B and pachypophyllin (Figures 16 and 17) may be chemotaxonomic markers for the entire Annonaceae family given their specific occurrence here [7,8].
Asparenydiol ( Figure 17) and its derivatives are considered as some of the chemotaxonomic markers for the genus Asparagus L. [17].
Within the Lamiaceae family, surely negundins A-B ( Figure 20) are chemotaxonomic markers for the species Vitex negundo L given their occurrence in several exemplars of this species [69][70][71].

Antioxidant
Egonol (Figure 3) highly inhibits the production of NO and highly reduces the release of ROS in a dose dependent manner. The same is valid for homoegonol but in a minor way [111].

Antifungal and Antibacterial
Homoegonol and egonol ( Figure 3) exhibit strong effects against Candida albicans, Cladosporium sphaerospermum and Staphylococcus aureus with MIC values equal to 10, 5 and 10 µg/mL, respectively for the former compound, and 12, 10 and 10 µg/mL respectively for the latter compound. Indeed, egonol ( Figure 3) and homoegonol ( Figure 3) exhibit lower effects only against Candida albicans and Staphylococcus aureus with MIC values equal to 15 and 15 µg/mL, respectively for the former compound and 20 and 20 µg/mL, respectively for the latter compound [106].
Iso-agatharesinol and gobicusin A (Figure 7) are also able to exert these effects. In particular, gobicusin A is a better antibacterial compound against Escherichia coli and Staphylococcus aureus than iso-agatharesinol given its MIC values (0.12 and 0.05 mg/mL vs. 0.25 and 0.12 mg/mL, respectively) and its efficacy is extremely comparable to streptomycin especially against Staphylococcus aureus (MIC = 0.01 mg/mL) [19].
Nyasol (Figure 7) is able to inhibit the mycelial growth of Colletotrichum orbiculare, Phytophthora capsici, Pythium ultimum, Rhizoctonia solani and Cladosporium cucumerinum in a MIC range comprised between 1 and 50mg/mL [13]. Moreover, it potently inhibits the growth of Leishmania major with an IC 50 value equal to 12 µM and moderately inhibits Plasmodium falciparum with an IC 50 value equal to 49 µM [14].

Antiasthma
Homoegonol (Figure 3) is the only compound able to exert antiasthma effects by a complex mechanism of action composed by several paths [116]. The most important of these is that this compound is able to reduce the expression of the protease MMP-9 in the lung tissue and the presence of this protease greatly increases the asthmatic effect [117].

Analgesic
Hypoxoside ( Figure 12) does not display any effect on the locomotor activity in mice but exerts a high analgesic effect even at low doses (5 mg/kg) probably via an anti-inflammatory mechanism [59].

Anticomplement
Styraxlignolide A, egonol and masutakeside I ( Figure 3) show a strong effect with IC 50 values equal to 123, 33 and 166 µM, respectively. This activity, in the case of egonol (Figure 3), is much higher than the control, i.e., rosmarinic acid, which shows an IC 50 value equal to 182 µM [107].

Vascular
Pilosidine, nyasicoside and curculigine (Figure 4), in low doses ranging from 1 to 30 mM, are able to induce a reversible facilitating effect on adrenaline evoked contractions [47]. Moreover, they all have a dose dependent vasoconstricting effect on rabbit aorta strips [48]. Their mechanism of action involves an interaction with the peripheral adrenergic system, in particular with α1 and β1 adrenoceptors [48].
(2S)-1-O-butyl-nyasicoside and nyasicoside ( Figure 4) possess high effects against the ouabain-induced arrhythmia in the heart preparations of guinea pig at the doses of 3 µM, especially at the left atrium level.

Antistress
Negundin A ( Figure 20) shows a very good effect in mice by greatly decreasing the number of writhes at the dose of 25 mg/kg. Moreover, it is able to reduce the blood glucose level and serum cholesterol level but at higher doses (50 and 100 mg/kg) [119].
Egonol and homoegonol ( Figure 3) exhibit medium effects against B16F10 (murine melanoma), MCF-7 (human breast adenocarcinoma), HepG2 (human hepatocellular liver carcinoma), HeLa (human cervical adenocarcinoma) and MO59J (human glioblastoma) cell lines. These effects were observed to be higher with the passing of time reaching their peaks after 72 h. Anyway, they were not better than the controls doxorubicin, camptotechin and etoposide [105]. For what concerns egonol (Figure 3), the results for MCF-7 and HeLa were confirmed in another study and it was also observed that it is active against theHL-60 (human leukemia) cell line with an IC 50 value equal to 47.8 µM [108].
Sequirin C (Figure 7) exerts good effects against the HL-60 cell line with an IC 50 value of 5.5 µM, which is comparable to that of cisplatin (2.0 µM) [33].
Noralashinol B ( Figure 15) exhibits a weak activity against the HepG2 cancer cell line with an IC 50 value equal to 31.7 µM, which is higher than the positive control, methotrexate showing an IC 50 value equal to 15.8 µM [90]. Its mechanism of action is via apoptosis [90].
Metasequirin G, metasequirin H and metasequirin I ( Figure 9) possess low cytotoxic effects against the A549 cell line with IC 50 values close to 100 µM [34].
Yateresinol ( Figure 17) is a decent cytotoxic compound against the human HL60 and Hepa G2 cancer cell lines with IC 50 values higher than 20 µM [27].
Cestrumoside ( Figure 14) is a strong protein kinase C inhibitor in an animal food additive [120]. Lastly, (S)-(+)-imperanene ( Figure 18) strongly inhibits tyronase isolated from HMV-II cells with an IC 50 value equal to 1.85 mM [121]. Its mechanism of action is essentially identical to that of arbutin [121]. Moreover it shows a high effect in rabbits giving a complete inhibition at the concentration of 6 × 10 −4 M when the platelet aggregation is induced by thrombin [96].

Conclusions
Nor-lignans have proven to be quite present in the plant kingdom. Nevertheless, some of them can be even considered to be chemotaxonomic markers. In addition, they are endowed with a vast number of biological activities with a myriad of possible application in several medicinal and pharmacological fields. Yet, not all the nor-lignans have been studied and discovered at the present. This review article means to be a first step towards the understanding of how important nor-lignans are as well as to be an incentive to continue their research and study.