molecules Review Lignans and Their Derivatives from Plants as Antivirals Qinghua Cui 1,2,3,*, Ruikun Du 1,2,3 , Miaomiao Liu 1 and Lijun Rong 4,* 1 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; [email protected] (R.D.); [email protected] (M.L.) 2 Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China 3 Research Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China 4 Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA * Correspondence: [email protected] (Q.C.); [email protected] (L.R.); Tel.: +86-186-6017-1818 (Q.C.); +1-312-996-0110 (L.R.) Academic Editor: David Barker Received: 8 November 2019; Accepted: 23 December 2019; Published: 1 January 2020 Abstract: Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans—podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals—are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed. Keywords: lignans; antivirals; mechanism; drug development 1. Introduction Lignans are a large group of naturally occurring compounds that are derived from the shikimic acid biosynthetic pathway [1]. Structurally, Lignans contain a basic scaffold of two or more phenylpropanoid units [2], and the monomers forming lignans are cinnamic acid, cinnamyl alcohol, propenyl benzene, and allyl benzene. When the molecular linkage of monomers occurs between positions β-β0 (also referred to as an 8-80), these compounds are designated as “classical lignans”. In contrast, the compounds are grouped into “neolignans” if the main structural units are coupled in any other way (non β-β0 linkage). Figure1 shows the monomers and the classification. Neolignans have more varied structures than classical lignans. Lignans are widely distributed in the plant kingdom, and they exist in plant roots, rhizomes, stems, leaves, flowers, fruits, seeds, xylem, and resins. Plants, such as the Lauraceae family, especially the genera of Machilus, Ocotea, and Nectandra are rich sources of lignans. Additionally, Annonaceae, Orchidaceae, Berberidaceae, and Schisandraceae family contain a large number of constituents of lignans and neolignans [3–5]. Up to date, lignans are found in over 70 families in plant kingdom, and more than 200 classical lignans and 100 neolignans have been characterized [6]. They are usually present as dimers, but some of them are trimers or tetramers. Most of the lignans in plants are in a free state, while some of them can combine with glycon and form glycosides and other derivatives. Molecules 2020, 25, 183; doi:10.3390/molecules25010183 www.mdpi.com/journal/molecules Molecules 2020, 25, 183 2 of 17 Molecules 2019, 24, x 2 of 19 FigureFigure 1. The 1. The monomers monomers and and thisthis classification classification of lignans. of lignans. With such structural diversity of lignans being discovered, it is not surprising that many attractive Withpharmacological such structural activities diversity of the lignan of lignans family, such being as antitumor discovered, [7], antioxidant it is not [5], surprising antibacterial [that8], many attractiveimmunosuppressive pharmacological [9 ],activities and antiasthmatic of the propertieslignan family, [10] were such reported. as antitumor Pertinent to[7], this antioxidant review, [5], antibacterialmany [8], lignans immunosuppressive have been identified with [9], antiviral and antias activitiesthmatic [11]. Tubulinproperties binding, [10] reverse were transcriptasereported. Pertinent to this review,inhibition, many integrase lignans inhibition, have and been topoisomerase identified inhibition with areantiviral included activities as the reported [11]. mechanisms Tubulin binding, of antiviral activities [12]. Here, we will highlight the antiviral activities and mechanisms of action reverse transcriptase inhibition, integrase inhibition, and topoisomerase inhibition are included as (MOA) of different lignans and their derivatives. the reported mechanisms of antiviral activities [12]. Here, we will highlight the antiviral activities and mechanisms2. Antiviral of E ffactionect and (MOA) MOA of different lignans and their derivatives. Lignans display a vast structural diversity due to the numerous potential coupling modes of the 2. Antiviralphenoxy Effect radicals and [ 13MOA]. As mentioned above, they can be grouped into two subclasses: classical lignans and neolignans. Next, we will discuss the antiviral lignans and possible MOA, according to different Lignanssubclasses, display and thena vast summarize structural them diversity in Table1 dueat the to end the of numerous this section. potential coupling modes of the phenoxy radicals [13]. As mentioned above, they can be grouped into two subclasses: classical lignans 2.1. Classical Lignans and neolignans. Next, we will discuss the antiviral lignans and possible MOA, according to different subclasses, andThe then classical summarize lignans contain them dimeric in Table structures 1 at the that end are of formedthis section. by a β -β0-linkage between two phenyl propane units, some of them with a different degree of oxidation in the side-chain and a different substitution pattern in the aromatic moieties. They can be classified into six 2.1. Classical Lignans major subtypes—dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalenes/aryltetralins, substituted Thetetrahydro-furans, classical lignans 2,6-diarylfurofurans, contain dimeric andstructures dibenzocyclooctadienes that are formed [6,14 by]. Figurea β-β′2-linkage illustrates between the two phenyl propanestructures andunits, relationships some of amongthem them.with a different degree of oxidation in the side-chain and a different substitution pattern in the aromatic moieties. They can be classified into six major subtypes—dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalenes/aryltetralins, substituted tetrahydro-furans, 2,6-diarylfurofurans, and dibenzocyclooctadienes [6,14]. Figure 2 illustrates the structures and relationships among them. Molecules 2020, 25, 183 3 of 17 Molecules 2019, 24, x 3 of 19 Molecules 2019, 24, x 4 of 19 TMP is the shorter title of tetra-O-methyl nordihydroguaiaretic acid. It is a methylated derivative of NDGAFigure and 2.2. Relationships Relationshipswas also initially between between founded di ffdifferenterent classicalin theclassical resin lignans. lignans.of the It depicts creosote It depicts the basicbush the mother [26].basic As nucleusmother the derivative structurenucleus of NDGA,ofstructure di itff erentwas of subtypestested different the of subtypes antiviral classical of lignans, effectsclassical the agains lignans, maint structuralWNV the main and feature structural ZIKV of simultaneously this feature subclass of this is the subclass withβ-β0 NDGA;linkage. is the the resultsDibenzylbutaneβ- β′showed linkage. both Dibenzylbutane (central compounds position) (central inhibited is theposition) basic the structure isinfe thection basic of ofstructure classical WNV lignan,ofand classical ZIKA, other lignan, with subtypes othergood of subtypes and lignans similar derive from this structure with different chemical reactions. IC50 values,of lignans and derive MOA from was this likely structur by impairinge with different viral chemical replication reactions. [24]. Meanwhile, Pollara showed that TMP2.1.1. inhibits Dibenzylbutanes poxvirus growth in vitro by preventing the efficient spread of virus particles from cell to2.1.1. cell Dibenzylbutanes [27]. Additionally, there were some reports regarding the antiviral activity of TMP against herpesDibenzylbutanes, simplex virus (HSV)which andare alsohuman known immunodeficiency as simple lignans, virus are (HIV) the simplest [28,29]. Moreover,classical lignans, it was whichmade intoare are the thevaginal only only lignanointment lignan subtype subtype for women without without with being being HPV-linked cyclized. cyclized. They cervical They are phenylpropane areintraepithelial phenylpropane dimersneoplasia dimers that and have that it β β showedhavea β-β′ alinkage. an- excellent0 linkage. Dibenzylbutane safety Dibenzylbutane profile lignans in Phase lignansalso I/II show trials also an [30]. show increased an increased diversity diversity due to multiple due to multiplepossible possibleoxidationBesides, oxidation states Xu isolatedalong states the alongfour butane new the butanelignanschain [15]. chainfrom Niranthin, [the15]. aerial Niranthin, partsnordihydroguaiaretic of nordihydroguaiaretic Justicia procumbens acid (Acanthaceae)(NDGA), acid (NDGA), and andterameprocol terameprocoltested their (TMP), activity (TMP), are againstthe are representative the HIV-1. representative One compound of compoundsthe news with secoisolariciresinol withantiviral antiviral activity activity dimethylether in this in subclass, this subclass, acetate and and Figure3