Systematic Review of Chemical Constituents in the Genus Lycium (Solanaceae)

Home , Lycium, Lycium barbarum, Lycium chinense, Lycium ruthenicum

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Review Systematic Review of Chemical Constituents in the Genus Lycium (Solanaceae)

Dan Qian 1,2, Yaxing Zhao 3, Guang Yang 2 and Luqi Huang 2,*

1 Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; [email protected] 2 The State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; [email protected] 3 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; [email protected] * Correspondence: [email protected]; Tel.: +86-10-6401-1944

Academic Editor: Derek J. McPhee Received: 27 April 2017; Accepted: 5 June 2017; Published: 8 June 2017

Abstract: The Lycium genus is widely used as a traditional Chinese medicine and functional food. Many of the chemical constituents of the genus Lycium were reported previously. In this review, in addition to the polysaccharides, we have enumerated 355 chemical constituents and nutrients, including 22 glycerogalactolipids, 29 phenylpropanoids, 10 coumarins, 13 lignans, 32 ﬂavonoids, 37 amides, 72 alkaloids, four anthraquinones, 32 organic acids, 39 terpenoids, 57 sterols, steroids, and their derivatives, ﬁve peptides and three other constituents. This comprehensive study could lay the foundation for further research on the Lycium genus.

Keywords: Lycium genus; chemical constituents; goji berry; Lycii cortex

1. Introduction Lycium is one of the genera in the Solanaceae family, comprising 80 species, seven of which are found in China [1]. These species are all deciduous shrubbery, possessing a highly similar morphology and structure. The Lycium genus has been an important source of medicines and nutrient supplements for thousands of years in Southeast Asia, especially in China. Two species in particular, Lycium barbarum and Lycium chinense, have been widely used as traditional Chinese medicinal herbs for centuries and L. barbarum is currently widely cultivated in China. Goji berries (Chinese name Gouqizi), which are derived from the fruits of Lycium Linn, have been used as traditional herbs for a long time in China for their beneﬁts of replenishing vital essence to improve eyesight, nourish the liver and kidneys. Lycii cortex is a “heat cleansing” drug that is derived from the root bark of L. chinense and L. barbarum [2]. Goji berries and Cortex Lycii have demonstrated good therapeutic effects in some chronic diseases such as hectic fever, night sweats, cough, hemoptysis, and diabetes. Recently, medical research has indicated that these fruits and root bark have many pharmacological functions, such as antiglaucoma, immunoregulatory, antitumor, antioxidant, antiaging, neuroprotective, and blood sugar level reducing activities [3–10]. Traditionally, the berry and root bark available have been used as medicinal sources, as well as important components in some traditional Chinese patent medicines. They are not only famous medical herbs, but are also functional foods widely consumed in health-preserving cuisines, i.e., soups, congee, herbal tea, etc. People also eat the fresh leaves as vegetables. In particular, goji berries have become increasingly popular for improving overall well-being and as an anti-aging remedy. There are many goji derived-products on health food market, such as dried fruits, juice, goji wine and goji

Molecules 2017, 22, 911; doi:10.3390/molecules22060911 www.mdpi.com/journal/molecules Molecules 2017, 22, 911 2 of 33

Moleculesyoghurt. 2017 Many, 22, 911 research papers were published focused on the phytochemical fingerprinting2 of and 33 antioxidant activity of these products [11–14]. Two valuable medicinal herbs, namely L. barbarum and L. chinensechinense,, have received remarkable attention due due to to their their effective effective clinical clinical therapy, therapy, especi especiallyally in inthe the anti-aging anti-aging category. category. In addition, In addition, there there are increasingare increasing numbers numbers of publications of publications about about several several other other LyciumLycium plants,plants, i.e., i.e., LyciumLycium ruthenicum ruthenicum [15,16].[15,16]. Many researchersresearchers have have focused focused great great attention attention on theon Lyciumthe Lyciumgenus genus in recent in years,recent and years, many and chemical many chemicalcomponents components from this from genus this have genus been have isolated. beenTherefore, isolated. Theref a comprehensiveore, a comprehensive and systematic and systematic review on reviewthe chemical on the constituents chemical constituents of the Lycium of thegenus Lycium is much genus needed. is much needed. Most of of the the published published reviews reviews not not only only covered covered chemical chemical composition, composition, but but also also summarized summarized the pharmacology,the pharmacology, clinical clinical studies, studies,safety, toxicology safety, toxicologyand adverse and actions adverse of L. barbarum actions or of L. L.chinense barbarum [17–19].or TheL. chinense aim of [this17– 19review]. The was aim to of focus this reviewon chemical was tocons focustituents on chemical in different constituents parts of plants in different from different parts of speciesplants from in Lycium different genus, species especially in Lycium smallgenus, molecular especially compou smallnds molecular with updated compounds research with reports. updated This paperresearch comprehensively reports. This paper summarizes comprehensively the reports summarizes of constituents the reports from the of constituents genus Lycium from. Up the to genus2016, atLycium least. 355 Up constituents to 2016, at least were 355 repo constituentsrted from weredifferent reported species from in the different Lycium species genus inand the differentLycium genus parts (fruits,and different root bark, parts leaves, (fruits, seeds, root bark,and flowers) leaves, seeds,of the plant. and flowers) This review of the describes plant. This the review advances describes in the phytochemistrythe advances in theof the phytochemistry genus Lycium of from the genus 1975 Lyciumto 2016,from based 1975 on tothe 2016, 142based cited onreferences. the 142 citedThe reportedreferences. constituents The reported can constituents be classified can as be glycerogalactolipids, classified as glycerogalactolipids, phenylpropanoids, phenylpropanoids, coumarins, lignans,coumarins, flavonoids, lignans, flavonoids,amides, alkaloids, amides, anthraquinon alkaloids, anthraquinones,es, organic acids, organic terpenoids, acids, terpenoids, sterols, steroids, sterols, peptides,steroids, peptides,and other and constituents. other constituents. The aim Theof this aim revi of thisew is review to illustrate is to illustrate the recent the advances recent advances in the characterizationin the characterization of the Lycium of the genus.Lycium Thegenus. results, The based results, on these based phytochemical on these phytochemical studies, could studies, lay a solidcould foundation lay a solid foundationfor better understanding for better understanding of pharmacological of pharmacological activities activitiesof Lycium of andLycium qualityand assessment.quality assessment.

2. Constituents Until now, other than polysaccharides, more than 355 compounds have been isolated and identifiedidentiﬁed from from the the LyciumLycium genus.genus. The The small small molecules molecules can can be beassigned assigned to tovarious various classes classes of glycerogalactolipids,of glycerogalactolipids, phenylpropanoids, phenylpropanoids, coumar coumarins,ins, lignans, lignans, flavonoids, ﬂavonoids, amides, amides, alkaloids, anthraquinones, organicorganic acids, acids, terpenoids, terpenoids, sterols, sterols, steroids steroids and theirand derivatives,their derivatives, and peptides. and peptides. Beyond Beyondthat, other that, groups other of groups compounds of compounds have also beenhave reported.also been The reported. proportion The ofproportion different compoundsof different compoundsof the Lycium ofgenus the Lycium is show genus in Figure is show1. Theirin Figure structures 1. Their are structures shown below, are shown and theirbelow, names and their and namescorresponding and corresponding plant sources plant are sources included are in included this paper. in this paper.

FigureFigure 1. 1. DifferentDifferent subtype subtype comparison of the 355 constituents reported from Lycium genus.

Molecules 2017, 22, 911 3 of 33

2.1. Macromolecules in the Lycium Genus

Polysaccharides Polysaccharides are the most important group of substances in the goji berry, which are estimated to comprise 5–8% of the dried fruits [20], 1.02–2.48% of the raw material [21–23]. More than 40 polysaccharides, with a molecular weight range of 8–241 kDa, were isolated from the fruit of L. barbarum, L. chinense and L. ruthenicum. Two, LRLP4-A and LBLP5-A, were isolated from the leaves of L. ruthenicum. The polysaccharides share a glycan-O-Ser glycopeptide structure and contain galacturonic acid, 18 amino acids, and nine monosaccharides, namely, xylose (Xyl), glucose (Glc), arabinose (Ara), rhamnose (Rha), mannose (Man), galactose (Gal), fucose (Fuc), galacturonic acid (GalA), glucuronic acid (GlcA) [24]. The molar ratios of the polysaccharides are shown in Table1. The polysaccharides can be isolated and puriﬁed by water extract alcohol precipitation, DEAE ion-exchange cellulose, gel-permeation chromatography, high performance liquid chromatography (HPLC). Sevage method and organic reagents were used to remove proteins, pigments and other impurities. The structural composition of a LBP can be studied by SDS-PAGE gel electrophoresis, high perfomance size exclusion chromatography (HPSEC), gas-chromatographic–mass-spectrometry (GC-MS), nucleic magnetic resonance (NMR), and matrix-assisted laser desorption ionization-time of ﬂight-mass spectrometry (MALDI-Tof-MS) [18,21,25].

Table 1. The molar ratios and source of LBPs.

LBPs Molar Ratio Source Reference LbGp1 Ara:Gal:Glc = 2.5:1.0:1.0 L. barbarum [26] LbGp2 Ara:Gal = 4:5 L. barbarum [27] LbGp3 Ara:Gal = 1:1 L. barbarum [28,29] LbGp4 Ara:Gal:Rha:Glc = 1.5:2.5:0.43:0.23 L. barbarum [28,30] LbGp5 Rha:Ara:Xyl:Gal:Man:Glc = 0.33:0.52:0.42:0.94:0.85:1 L. barbarum [28] LbGp5B Rha:Ara:Glc:Gal = 0.1:1:1.2:0.3 L. barbarum [31] LBP3p Rha:Ara:Xyl:Gal:Man:Glc = 1.25:1.10:1.76:1:1.95:2.12 L. barbarum [32] LBPC2 Xyl:Rha:Man = 8.8:2.3:1 L. barbarum [33] LBPC4 Glc L. barbarum [33] LBPA1 heteroglycan L. barbarum [33] LBPA3 heteroglycan L. barbarum [33] LBP1a-1 Glc L. barbarum [34] LBP1a-2 Glc L. barbarum [34] LBP3a-1 GalA L. barbarum [34] LBP3a-2 GalA L. barbarum [34] LBPF1 - L. barbarum [35] LBPF2 - L. barbarum [35] LBPF3 - L. barbarum [35] LBPF4 - L. barbarum [35] LBPF5 Ara, Man, Xyl, Glu, Rha L. barbarum [35,36] LBPF6 - L. barbarum [36] LPBC4 Glc L. barbarum [37] LBP-1 Rha:Ara:Xyl:Gal:Man:GalA = 1:7.85:0.37:0.65:3.01:8.16 L. barbarum [22] WSP1 Rha:Fuc:Ara:Xyl:Man:Gal:Glc = 1.6:0.2:51.4:4.8:1.2:25.9:7.3 L. barbarum [23] AGP Rha:Ara:Xyl:Gal:Glc:GalA:GlcA = 3.3:42.9:0.3:44.3:2.4:7.0 L. barbarum [38] LBP-IV Rha:Ara:Xyl:Glc:Gal = 1.61:3.82:3.44:7.54:1.00 L. barbarum [39] LbGp1 Ara:Gal = 5.6:1 L. barbarum [40] Rha:Ara:Xyl:Man:Glu:Gal:Gal A = LBP-s-1 L. barbarum [41] 1.00:8.34:1.25:1.26:1.91:7.05:15.28 Fuc:Rha:Ara:Gal:Glc:Xyl:Gal A:Glc A = p-LBP L. barbarum [42] 1.00:6.44:54.84:22.98:4.05:2.95:136.98:3.35 Cp-2-A Ara:Gal:Man:Rha:Glu = 6.02:2.71:1.00:0.70:0.67 L. chinese [43,44] Cp-2-B Ara:Gal = 1:0.96 L. chinese [43,44] Hp-2-A Ara:Gal = 5.2:1 L. chinese [43,44] Hp-2-B Ara:Gal = 7.9:1 L. chinese [43,44] Molecules 2017, 22, 911 4 of 33

MoleculesMolecules 2017, 22 2017, 911, 22 , 911 4 of 33 4 of 33 Table 1. Cont. Hp-2-BHp-2-B Ara:Gal Ara:Gal = 7.9:1 = 7.9:1 L. chineseL. chinese [43,44][43,44] Hp-2-CHp-2-CLBPs Ara:Gal Molar Ara:Gal = 1.2:1 Ratio = 1.2:1 L. Source chineseL. chinese Reference[43,44][43,44] Hp-0-AHp-0-AHp-2-C Ara:Gal Ara:Gal Ara:Gal = 14:1 = 1.2:1 = 14:1 L. chinesechineseL. chinese [43,44][43,44[43,44] ] Cp-1-AHp-0-ACp-1-A Ara:Xyl Ara:Gal Ara:Xyl = 1:1 = 14:1 = 1:1 L. chinesechineseL. chinese [[45]43,44 ][45] Cp-1-BCp-1-ACp-1-B Ara:XylAra Ara = 1:1 L. chinesechineseL. chinese [45][45 ] [45] Cp-1-B Ara L. chinese [45] Cp-1-CCp-1-C Ara:Gal Ara:Gal = 3:1 = 3:1 L. chineseL. chinese [45] [45] Cp-1-C Ara:Gal = 3:1 L. chinese [45] Cp-1-D Ara:Gal = 1:1 L. chinese [45] Cp-1-DCp-1-D Ara:Gal Ara:Gal = 1:1 = 1:1 L. chinesechinese [45][45 ] LRGP1LRGP1 Rha:Ara:Xyl:Man:Glu:Gal Rha:Ara:Xyl:Man:Glu:GalRha:Ara:Xyl:Man:Glu:Gal = 0.65:10.71:0.33:0.67:1:10.41 = 0.65:10.71:0.33:0.67:1:10.41 = 0.65:10.71:0.33:0.67:1:10.41 L. ruthenicumL. ruthenicum [46][46 ] [46] LRGP2LRGP2 - - - L. ruthenicumL. ruthenicum [47][47 ] [47] LRGP3LRGP3 Rha:Ara:Gal Rha:Ara:GalRha:Ara:Gal = 1.0:14.9:10.4 = 1.0:14.9:10.4 = 1.0:14.9:10.4 L. ruthenicumL. ruthenicum [48][48 ] [48] LRGP4-ALRGP4-A Rha:Ara:Glu:Gal Rha:Ara:Glu:Gal Rha:Ara:Glu:Gal = 1:7.6:0.5:8.6 = 1:7.6:0.5:8.6 = 1:7.6:0.5:8.6 L. ruthenicumL. ruthenicum [49][49 ] [49] LRGP5LRGP5 Rha:Ara:Xyl:Gal:GalA Rha:Ara:Xyl:Gal:GalARha:Ara:Xyl:Gal:GalA = 1.0:2.2:0.5:1.2:4.7 = 1.0:2.2:0.5:1.2:4.7 = 1.0:2.2:0.5:1.2:4.7 L. ruthenicumL. ruthenicum [50][50 ] [50] L. ruthenicum LRLP4-ALRLP4-A Rha:Ara:Gal Rha:Ara:GalRha:Ara:Gal = 1:10.3:5.3 = 1:10.3:5.3 = 1:10.3:5.3 L. ruthenicumL. ruthenicum [47][47 ] [47] LBLP5-A - L. ruthenicum [51] LBLP5-ALBLP5-A - - L. ruthenicumL. ruthenicum [51] [51]

2.2.2.2. Small2.2. Small SmallMolecule Molecule Molecule Substances Substances Substances

2.2.1. Glycerogalactolipids 1–22 2.2.1. 2.2.1.Glycerogalactolipids Glycerogalactolipids 1–22 1–22 At present, 17 compounds of this type, a series of glycerogalactolipids 1–17, listed in Table2, have At present,At present, 17 compounds 17 compounds of this of ty thispe, tya pe,series a series of glycerogalactolipids of glycerogalactolipids 1–17, 1listed–17, listed in Table in Table 2, 2, been isolated and identiﬁed. Compounds 1–15 have been isolated and identiﬁed from the fruits of have havebeen isolatedbeen isolated and identified. and identified. Compounds Compounds 1–15 have1–15 havebeen isolatedbeen isolated and identified and identified from fromthe fruits the fruits L. barbarum [52], whereas 16 and 17 were isolated from the fruits of L. chinense [53]. Compounds 18–22, of L. barbarumof L. barbarum [52], whereas[52], whereas 16 and 16 17 and were 17 wereisolated isolated from fromthe fruits the fruits of L. chinenseof L. chinense [53]. Compounds[53]. Compounds illustrated in Figure2, were isolated from the root bark of L. chinense [54,55]. 18–2218, illustrated–22, illustrated in Figure in Figure 2, were 2, wereisolated isolated from fromthe root the bark root ofbark L. chinenseof L. chinense [54,55]. [54,55].

Table 2. Chemical structures of compounds 1–17. Table Table2. Chemical 2. Chemical structures structures of compounds of compounds 1–17. 1–17. HO HO

OH OH O O HO HO R O^ R O^ 2 2 OR OR OR OR1 1 3 3 O O O O OH OH O O OR2 OR2 OH OH OH OH OH OH O OO O OR1 OR1 OH OH OH OH 13–1713 –17 OH OH 1–12 1–12 No. No. CompoundsCompounds R1 R1 R2 R2 R3 R3 SourceSource No. Compounds R1 R2 R3 Source 1 1 GlycerogalactolipidsGlycerogalactolipids A A Palmitoyl Palmitoyl Linolenoyl Linolenoyl Linolenoyl Linolenoyl L. barbarumL. barbarum 1 Glycerogalactolipids A Palmitoyl Linolenoyl Linolenoyl L. barbarum 2 2 Glycerogalactolipids2 GlycerogalactolipidsGlycerogalactolipids B B B Palmitoyl Palmitoyl Palmitoyl Linolenoyl Linolenoyl Linolenoyl Linoleoyl Linoleoyl Linoleoyl L. barbarum L. barbarumL. barbarum 3 3 Glycerogalactolipids3 GlycerogalactolipidsGlycerogalactolipids C C C Palmitoyl Palmitoyl Palmitoyl Linolenoyl Linolenoyl Linolenoyl Palmitoyl Palmitoyl Palmitoyl L. barbarum L. barbarumL. barbarum 4 4 Glycerogalactolipids4 GlycerogalactolipidsGlycerogalactolipids D D D Palmitoyl Palmitoyl Palmitoyl Linoleoyl Linoleoyl Linoleoyl Palmitoyl Palmitoyl Palmitoyl L. barbarum L. barbarumL. barbarum 5 5 Glycerogalactolipids5 GlycerogalactolipidsGlycerogalactolipids E E E Palmitoyl Palmitoyl Palmitoyl Palmitoyl Palmitoyl Palmitoyl Palmitoyl Palmitoyl Palmitoyl L. barbarum L. barbarumL. barbarum 6 Glycerogalactolipids F Palmitoyl Palmitoyl H L. barbarum 6 6 7GlycerogalactolipidsGlycerogalactolipidsGlycerogalactolipids F G F Palmitoyl Linolenoyl Palmitoyl Palmitoyl Linolenoyl Palmitoyl H H H L. barbarumL. barbarumL. barbarum 7 7 Glycerogalactolipids8 GlycerogalactolipidsGlycerogalactolipids G H G Linolenoyl Linolenoyl Linolenoyl Linolenoyl Linoleoyl Linolenoyl H H H L. barbarumL. barbarumL. barbarum 8 8 Glycerogalactolipids9 GlycerogalactolipidsGlycerogalactolipids H IH Linolenoyl Palmitoyl Linolenoyl Linoleoyl Linolenoyl Linoleoyl H H H L. barbarumL. barbarumL. barbarum 9 9 10GlycerogalactolipidsGlycerogalactolipidsGlycerogalactolipids I J I Palmitoyl Palmitoyl Palmitoyl Linolenoyl Linoleoyl Linolenoyl H H H L. barbarumL. barbarumL. barbarum 11 Glycerogalactolipids K Palmitoyl Oleoyl H L. barbarum 10 10 GlycerogalactolipidsGlycerogalactolipids J J Palmitoyl Palmitoyl Linoleoyl Linoleoyl H H L. barbarumL. barbarum 12 Glycerogalactolipids L Stearoyl Linoleoyl H L. barbarum 11 1113 GlycerogalactolipidsGlycerogalactolipidsGlycerogalactolipids K M K Palmitoyl Palmitoyl Palmitoyl Oleoyl LinolenoylOleoyl – H H L. barbarumL. barbarumL. barbarum 12 1214 GlycerogalactolipidsGlycerogalactolipidsGlycerogalactolipids L N L Stearoyl Palmitoyl Stearoyl Linoleoyl LinoleoylLinoleoyl – H H L. barbarumL. barbarumL. barbarum 13 1315Glycerogalactolipids GlycerogalactolipidsGlycerogalactolipids M O M Palmitoyl Palmitoyl Palmitoyl Linolenoyl Oleoyl Linolenoyl – – – L. barbarumL. barbarumL. barbarum 14 1416 GlycerogalactolipidsGlycerogalactolipidsGlycerogalactolipids N P N Palmitoyl Linolenoyl Palmitoyl Linoleoyl Linolenoyl Linoleoyl – – – L. chinenseL. barbarumL. barbarum 17 Glycerogalactolipids Q Linoleoyl Linolenoyl – L. chinense 15 15 GlycerogalactolipidsGlycerogalactolipids O O Palmitoyl Palmitoyl Oleoyl Oleoyl – – L. barbarumL. barbarum 16 16 GlycerogalactolipidsGlycerogalactolipids P P Linolenoyl Linolenoyl Linolenoyl Linolenoyl – – L. chinenseL. chinense 17 17 GlycerogalactolipidsGlycerogalactolipids Q Q Linoleoyl Linoleoyl Linolenoyl Linolenoyl – – L. chinenseL. chinense

Molecules 2017, 22, 911 5 of 33 MoleculesMolecules 2017 2017, 22, ,22 911, 911 5 of5 33of 33

CH3 CH3 CH3 CH3 HO O OO O O OHOH O COOHCOOH O CH H3COH CO OO O CH33 OO OO 3 O O HO O HO O OCHOCH3 3 O OO O HOHO OHOH OHOH HO HO OHOH OHOH OHOH HO OH OCH HO OH OH OCH3 3 OHOH OH 19 33′′,4,4′′-Dimethoxy-benzylalcohol-l--Dimethoxy-benzylalcohol-l-O-Oβ-βD-D- 1818 LyciumosideLyciumoside A A xylopyranosyl-(1 → → 6)- 6)-OO-β--βD--glucopyranosideD-glucopyranoside HOHO O OO O HO O O HO O O HO O O O HO O O O HO O OCH3 HO O OCH3 HO OH HO OH OH OH OH HO OH OH OH OH OCH HO OH OH 3 OH H3CO OCH3 OH OH H3CO 20 3′,4′,5′-Trimethoxy-benzylalcohol-l-O-β-D- 21 4′-Hydroxystyrone-l-O-β-D-apiofuranosyl-(1 → 6)- 20 3′,4′,5′-Trimethoxy-benzylalcohol-l-O-β-D- 21 4′-Hydroxystyrone-l-O-β-D-apiofuranosyl-(1 → 6)- xylopyranosyl-(1 → 6)-O-β-D-glucopyranoside O-β-D-glucopyranoside xylopyranosyl-(1 → 6)-O-β-D-glucopyranoside O-β-D-glucopyranoside OHC OCH3 HO OHC OCH HO O 3 O O O HO O O O HO OH O OH HO OH HO OH OH 22 2-Hydroxy-4-methoxybenzaldehyde-2-O-βO-DH-glucopyraneosyl-l-6-O-β-D-xylopyranoside 22 2-Hydroxy-4-methoxybenzaldehyde-2-O-β-D-glucopyraneosyl-l-6-O-β-D-xylopyranoside Figure 2. Chemical structures of compounds 18–22. Figure 2. Chemical structures of compounds 18–22. Figure 2. Chemical structures of compounds 18–22. 2.2.2. Phenylpropanoids 23–51 2.2.2. Phenylpropanoids 23–51 2.2.2. PhenylpropanoidsFour phenylpropanoids 23–51 23 –26, namely E-cinnamic acid (23), E-ferulic acid (24), E-coniferol (25) Four phenylpropanoids 23–26, namely E-cinnamic acid (23), E-ferulic acid (24), E-coniferol (25) andFour isoscopoletin phenylpropanoids (26) are 23obtained–26, namely from Ewolfberries-cinnamic acid[56–58]. (23), FourE-ferulic phenylpropanoids, acid (24), E-coniferol namely (25 ) and isoscopoletin (26) are obtained from wolfberries [56–58]. Four phenylpropanoids, namely scopolin andscopolin isoscopoletin (27), fabiatrin (26) are (28 obtained), lyciumin from (29 wolfberries), and 9-O-( [56β-D–58].-glucopyranosyl)lyoniresinol Four phenylpropanoids, (30 )namely are (27obtained), fabiatrin from (28), lyciuminthe root (29bark), and of 9- OL.-( βchinense-D-glucopyranosyl)lyoniresinol [59–61]. 1-O-Methyl-4-O (30-p-)E are-coumaroyl- obtainedα from-L- scopolin (27), fabiatrin (28), lyciumin (29), and 9-O-(β-D-glucopyranosyl)lyoniresinol (30) are therhamnopyranoside root bark of L. chinense (31) is obtained[59–61]. 1-fromO-Methyl-4- the fruits Oof- pL.-E ruthenicum-coumaroyl- [62].α- LThe-rhamnopyranoside chemical structures (31 of) is obtained from the root bark of L. chinense [59–61]. 1-O-Methyl-4-O-p-E-coumaroyl-α-L- obtainedcompounds from 23 the–33 fruitsare listed of L.in Table ruthenicum 3 and Figure[62]. 3. The In 2016, chemical 11 phenylpropanoids structures of compounds 32–42 were isolated23–33 are rhamnopyranoside (31) is obtained from the fruits of L. ruthenicum [62]. The chemical structures of listedfor the in Table first time3 and by Figure Zhou 3et. Inal. 2016,from Lycium 11 phenylpropanoids [56], including 1-O32-–E42-feruloyl-6-were isolatedO-β-D-xylopyranosyl- for the ﬁrst timeβ- by compounds 23–33 are listed in Table 3 and Figure 3. In 2016, 11 phenylpropanoids 32–42 were isolated ZhouD-glucopyranoside et al. from Lycium (32[),56 6-],O including-E-feruloyl-2- 1-O-OE--feruloyl-6-β-D-glucopyranosyl-O-β-D-xylopyranosyl-α-D-glucopyranosideβ-D-glucopyranoside (33), 1-O-E- for the first time by Zhou et al. from Lycium [56], including 1-O-E-feruloyl-6-O-β-D-xylopyranosyl-β- (32feruloyl-), 6-Oβ-ED-glucopyranoside-feruloyl-2-O-β-D (-glucopyranosyl-34), ethyl-4-O-β-Dα-glucopyranosyl--D-glucopyranosideE-ferulate (33 (),35), ethyl 1-O- EE-feruloyl--ferulate β- D-glucopyranoside (32), 6-O-E-feruloyl-2-O-β-D-glucopyranosyl-α-D-glucopyranoside (33), 1-O-E- D-glucopyranoside(36), E-sinapinic acid (34 (37),), ethyl-4-syringeninO- β(38-D),-glucopyranosyl- Z-ferulic acid (39E), -ferulatephloretic acid (35), (40 ethyl), dihydroferulicE-ferulate acid (36 ), feruloyl-β-D-glucopyranoside (34), ethyl-4-O-β-D-glucopyranosyl-E-ferulate (35), ethyl E-ferulate E-sinapinic(41), and acidethyl ( 37dihydroferulate), syringenin ( 38(42),),Z -ferulicalong with acid the (39 ),nine phloretic new ly acidcibarbarphenylpropanoids (40), dihydroferulic acid A–I (41 ), (36), E-sinapinic acid (37), syringenin (38), Z-ferulic acid (39), phloretic acid (40), dihydroferulic acid and(compounds ethyl dihydroferulate 43–51) listed (42 in), Table along 4. with the nine new lycibarbarphenylpropanoids A–I (compounds (41), and ethyl dihydroferulate (42), along with the nine new lycibarbarphenylpropanoids A–I 43–51) listed in Table4. (compounds 43–51) listed in TableTable 3. 4. Chemical structures of compounds 26–28.

Table 3. ChemicalR2 structures of compounds 26–28. Table 3. Chemical structures of compounds 26–28. R R21 O O 26–28 No. Compounds R1 R1(R)O O R2 Source 26 Isoscopoletin 26OCH–28 3 OH L. barbarum

27 Scopolin O-β-1D-Glc OCH23 L. chinense No.No. CompoundsCompounds R1(R)R (R) R2 R Source 28 Fabiatrin O-β-D-Glc6-β-D-Xyl OCH3 L. chinense 2626 IsoscopoletinIsoscopoletin OCHOCH3 OHOH L.L. barbarum 3 D 3 2727 ScopolinScopolin O-βO-D-β-Glc- -Glc OCHOCH3 L. chinense 6 6 2828 FabiatrinFabiatrin O-Oβ--Dβ-Glc-D-Glc-β-D-β-Xyl-D-Xyl OCHOCH3 3 L. chinense

Molecules 2017, 22, 911 6 of 33 Molecules 2017, 22, 911 6 of 33

OH HO HO COOH

Molecules 2017, 22Molecules, 911 CO 2017O,H 22, 911 H CO 6 of 33 6 of 33 COOH 3 23 E-cinnamic acid OH 24 E-ferulicOH acid HO HO 25 Z-coniferol COOH COOH HO HO OH OH O O O O COOH COOH O OH H CO H CO COOH COOH 3 3 23 HE-cinnamic23H acid E -cinnamic 24acid E-ferulic acid24 E-ferulic acid 25 HOZ-coniferol25 ZO-coniferol OH OH OH OHOHO O O O O OH O O O O O OH O OH O HO OH H H H H HO OHO O 30 9-O-(β-D-glucopyranosyl)-OH OH 31 1-O-methyl-4-O-p-E-coumaroyl-α-L- 29 Lyciumin OH OH O O lyoniresinol rhamnopyranosideOH O O HO HO OH 30 9-O-(β-D-glucopyranosyl)-30 9-O-(β-D-glucopyranosyl)-31 1-O-methyl-4-31O 1--pO-E-methyl-4--coumaroyl-O-pα--EL-coumaroyl-- α-L- 29 Lyciumin 29 LyciuminFigure 3. Chemical structures of compounds 23–25, 29–31. Figurelyoniresinol 3. Chemicallyoniresinol structures rhamnopyranoside of compoundsrhamnopyranoside 23–25, 29–31 .

Figure 3. ChemicalTableFigure structures4. Chemical3. Chemical of compounds structuresstructures 23of – ofcompounds25 compounds, 29–31. 23–25 32, 29––5131.. Table 4. Chemical structures of compounds 32–51. TableR3 4. ChemicalTable structures 4. Chemical of compounds structures 32of– compounds51. 32–51. R3 R2R3 R3 R3 R2 R3 R2 R2 R2 R2

R1 R4 R1 R4 R1 R R4 R R R R R 32–391 , 43– 51 4 1 1 4 40–42 4 32–39, 43–51 32–39, 43–51 40–42 40–42

No.No. No. CompoundsCompounds Compounds R1 R 21 R1 R3 RR2 R4R 3R3 SourceR4 R4 Source Source No. Compounds R1 R2 R3 R4 Source 1-O1--EO-feruloyl-6--E-feruloyl-6-O1--Oβ-DE-xylopyranosyl--feruloyl-6-O-β-D-xylopyranosyl-O-β-βD--xylopyranosyl-β- β- COO-β-D-Glc6-β-COO-COO-β-D-Glcβ-6D-β-Glc- 6-β- 3232 32 OCH3 OCHOHOCH 3 3 H OHOH H H L. barbarum L. barbarumL. barbarum 1-DO-glucopyranoside-DE-feruloyl-6-DO-glucopyranoside -β- D-Xyl D-XylD 6 32 -glucopyranoside OCH3 OH H COO-β-D-Xyl-Glc -β-D-Xyl L. barbarum β 6 2 6 2 D6--xylopyranosyl-O-E-feruloyl-2-O6--Oβ-D-DE-glucopyranoside-glucopyranosyl--feruloyl-2-O-β-D-glucopyranosyl- COO -α-D-Glc -β-COO -α-D6-Glc -β- 2 33 6-O-E-feruloyl-2-33 O-β-D-glucopyranosyl-OCH3 OHOCH 3 H OH H COOL. barbarum-α-D -Glc6 L.-β barbarum- 33 6-αO-D--glucopyranosideE-feruloyl-2-αO-D-β-glucopyranoside -D-glucopyranosyl- OCH3 OH D-Glc H D-GlcCOO -α- L. barbarum 33 α-D-glucopyranoside OCH3 OH H D-Glc2 L. barbarum 34 α1--DO-glucopyranoside-E-feruloyl-34 β-D1--glucopyranosideO-E-feruloyl-β-D-glucopyranoside OCH3 OHOCH 3 H OH COO-β- HD-Glc COO-L. Dbarbarumβ-Glc-D-Glc-β -D-GlcL. barbarum 34 3534 1-Ethyl-4-O-1-E-feruloyl-O-OE--feruloyl-β35-D -glucopyranosyl-βEthyl-4--D-glucopyranosideβ-DO-glucopyranoside-β-DE-glucopyranosyl--ferulate OCH OCH E-ferulate3 3 O -OCHβ-DOCH-Glc3 3OH HO -βOH-D-Glc COOCH HH2CH H 3 COOCHL.COO- barbarum COO-2CHββ3- -DD-Glc-GlcL. barbarumL. L. barbarum barbarum 35 3635 Ethyl-4-EthylEthyl-4- E-ferulateO-β36-DO -glucopyranosyl-- βEthyl-D-glucopyranosyl- E-ferulate E-ferulateE-ferulateOCHOCH3 3 OCHOHOCH O3 -β3 -D-GlcO H- βOH-D-Glc COOCH H H2CH H 3 COOCHL. COOCHbarbarum COOCH2CH3 22CHCHL.33 barbarumL. L. barbarum barbarum 37 E-sinapinic 37acid E-sinapinic acid OCH3 OH OCH 3 OCH3 OH COOHOCH 3 L.COOH barbarum L. barbarum 36 36 EthylEthylE-ferulate E-ferulate OCH3 OCH3 OHOH H H COOCH COOCH22CHCH33 L. L.barbarum barbarum 37 38 ESyringenin-sinapinic 38 acid Syringenin OCH OCH3 3 OHOCH 3OH OCH3 OH CH OCHOCH2OH3 3 L.CH barbarum2OHCOOH L. barbarumL. barbarum 37 E-sinapinic acid OCH3 OH OCH3 COOH L. barbarum 38 39 SyringeninE-ferulic acid39 E-ferulic acid OCH OCH3 3 OH OCH 3OH H OH COOH OCH H 3 L. COOH barbarumCH 2 OH L. barbarumL. barbarum 38 Syringenin OCH3 OH OCH3 CH2OH L. barbarum 39 40 EPhloretic-ferulic acidacid40 Phloretic acid OCH H 3 OH H OH H OH COOH H H L. COOH barbarum COOH L. barbarumL. barbarum 40 4139 PhloreticDihydroferulicE-ferulic acid41 acid acidDihydroferulic acid OCH H3 OCHOH OCH 3 3 OH H OHOH COOH H H H L. COOH barbarum COOH COOH L. barbarumL. L. barbarum barbarum 42 Ethyl dihydroferulate OCH3 OH 3 H COOCH2CH3 L. barbarum2 3 41 40 DihydroferulicPhloretic42 acid acidEthyl dihydroferulate OCH3 H OCH OH OHOH H H H COOCH COOHCH COOH L. barbarumL. L. barbarum barbarum COO-β-D-Glc3-β-COO-β-D-Glc3-β- 42 4341 EthylLycibarbarphenylpropDihydroferulic dihydroferulate43 Lycibarbarphenylprop acidanoids A anoids OCHA H 3 OCH OH H3 OH H OH OH H H H L. barbarum COOCH COOH 2CH L.3 barbarumL. L. barbarum barbarum 43 Lycibarbarphenylpropanoids A H OHD-Glc H COO-D-Glcβ-D -Glc3-β-D-Glc L. barbarum 42 Ethyl dihydroferulate OCH3 OH H4 COOCH4 2CH3 L. barbarum 44 COO-β-D-Glc -β-COO-β-Dβ-GlcD -β- 4 β D L. barbarum 44 LycibarbarphenylpropanoidsLycibarbarphenylpropanoids44 Lycibarbarphenylpropanoids B B B H H OH H OH H OH H H COO-L. barbarum- -Glc - 3-L. -Glcbarbarum D-Glc COO-D-Glcβ -D-Glc3 -β- 45 43 LycibarbarphenylpropanoidsLycibarbarphenylpropanoids C A OCH3 H OH OH H H COO-β-D-Glc -β-D-Glc L. L.barbarum barbarum COO-β-D-Glc3-β-COO-β-D-GlcD-Glc3-β- 4 46 45 LycibarbarphenylpropanoidsLycibarbarphenylpr45 Lycibarbarphenylpropanoids C Dopanoids OCH OCHC 3 3 OH OCH 3OH H OH H H COO-L. barbarumβ-D-Glc -β-L.D -GlcbarbarumL. barbarum D-Glc D-Glc 4 47 Lycibarbarphenylpropanoids E OCH OH H CHCOO-O-ββ-D-D-Glc-Glc3-β--βD--Glc L. barbarum 3 4 2 4 44 Lycibarbarphenylpropanoids B H 3 OHCOO- β-D-Glc H -β-COO-β-D-Glc -β- L. barbarum 48 46 LycibarbarphenylpropanoidsLycibarbarphenylpr46 Lycibarbarphenylpropanoids D Fopanoids OCH D H3 OHO- OCHβ -D-Glc3 - Hβ -DOH-Glc H H L. barbarum COOCHD-Glc 2 CHL.3 barbarumL. barbarum 4 D-Glc D-Glc 49 Lycibarbarphenylpropanoids G H O-β-D-Glc -β-D-Glc H COOCH2CH3 3 L. barbarum CH2O-β-D-Glc3-β-CH2O-COO-β-D-Glcβ-D3--Glcβ- -β- 50 4745 LycibarbarphenylpropanoidsLycibarbarphenylprLycibarbarphenylpr47 Lycibarbarphenylpropanoidsopanoids E Hopanoids C OCH OCHE 3 OCHOHO- OCHβ -3D -Glc3 4- Hβ -DOHOH-Glc H H H L. barbarum COOCH CHL. barbarumL. L. barbarum barbarum 3 D-Glc D-GlcD -Glc2 3 51 Lycibarbarphenylpropanoids I O-β-D-Glc OH H COOCH CH L. barbarum O-β-D-Glc3- O-β-D-Glc3- COO-β-D-Glc2 4-3β- 48 Lycibarbarphenylpropanoids48 Lycibarbarphenylpropanoids F F H H H COOCHH2CH 3 COOCHL. barbarum2CH3 L. barbarum 46 Lycibarbarphenylpropanoids D β OCH-D-Glc3 β-OHD-Glc H L. barbarum D-Glc O-β-D-Glc4- O-β-D-Glc4- 49 Lycibarbarphenylpropanoids49 Lycibarbarphenylpropanoids G G H H H COOCHH2CH 3 COOCHCHL. barbarum2O-2CHβ-D3 -Glc3L.-β barbarum- 2.2.3.47 Coumarins Lycibarbarphenylpr52–61 opanoids E β OCH-D-Glc3 β-OHD-Glc H L. barbarum O-β-D-Glc4- O-β-D-Glc4- D-Glc 50 Lycibarbarphenylpr50 Lycibarbarphenylpropanoids H opanoids OCH H 3 OCH3 H COOCHH2CH 3 COOCHL. barbarum2CH3 L. barbarum β-D-Glc O-ββ-D-Glc-Glc 3- Nine coumarins, namely E-p-coumaric acid (52), Z-p-coumaric acid (253),3 esculetin (54), 48 Lycibarbarphenylpropanoids F O-β-D- HO -β-D- H COOCH CH L. barbarum 51 Lycibarbarphenylpropanoids51 Lycibarbarphenylpropanoids I I OH Hβ -DOH-Glc COOCH H2CH 3 COOCHL. barbarum2CH3 L. barbarum fabiatrin (55), scopolin (56), and scopoletinGlc (57Glc), have been reported, and three new coumarins, O-β-D-Glc4- 49 Lycibarbarphenylpropanoids G H H COOCH2CH3 L. barbarum 6-O-E-p-coumaroyl-2-O-β-D-glucopyranosyl-α-D-glucopyranosideβ-D-Glc (58), ethyl-4-O-β-d-glucopyranosyl- 2.2.3. Coumarins2.2.3. 52 Coumarins–61 52–61 E-p-coumarate (59), ethyl E-p-coumarate (60) and lycibarbarcoumarinO-β-D-Glc4- A (61), have been obtained from 50 Lycibarbarphenylpropanoids H OCH3 H COOCH2CH3 L. barbarum the fruitsNine of coumarins,L. barbarumNine namely coumarins,in 2016E-p-coumaric namely [56]. Compounds acidE-p-coumaric (52), Z-p-coumaric acid55 and(52),β Zacid56-D-p-Glc-coumaricwere (53 ), esculetin isolated acid ((5354 from),), esculetinfabiatrin the root(54), fabiatrin bark and fruits (55), scopolin (55(56),), scopolinand scopoletin (56), and (57 scopoletin), have been (57 ),reported,O have-β-D- been and reported, three new and coumarins, three new 6- coumarins,O-E-p- 6-O-E-p- 51 Lycibarbarphenylpropanoids− I OH H COOCH2CH3 L. barbarum of L.coumaroyl-2- chinense [Ocoumaroyl-2-61-β],-D-glucopyranosyl- while O52-β-D54-glucopyranosyl-andα-D-glucopyranoside57 wereα-D isolated-glucopyranosideGlc (58), fromethyl-4- the O(58- fruitsβ),-d-glucopyranosyl- ethyl-4- of L.O- barbarumβ-d-glucopyranosyl-E-p- [63]. TheE-p- chemical structurescoumarate of (59 thesecoumarate), ethyl coumarins E-p (-coumarate59), ethyl are E -(p60 listed-coumarate) and lycibarbarcoumarin in Figure (60) and4 lycibarbarcoumarinand TableA (61),5 .have been A (61 obtained), have been from obtained from the2.2.3. fruits Coumarins of L.the barbarum fruits 52 of in– 61L. 2016 barbarum [56]. Compoundsin 2016 [56]. 55Compounds and 56 were 55 isolatedand 56 werefrom isolatedthe root frombark theand root bark and

Nine coumarins, namely E-p-coumaric acid (52), Z-p-coumaric acid (53), esculetin (54), fabiatrin (55), scopolin (56), and scopoletin (57), have been reported, and three new coumarins, 6-O-E-p- coumaroyl-2-O-β-D-glucopyranosyl-α-D-glucopyranoside (58), ethyl-4-O-β-d-glucopyranosyl-E-p- coumarate (59), ethyl E-p-coumarate (60) and lycibarbarcoumarin A (61), have been obtained from the fruits of L. barbarum in 2016 [56]. Compounds 55 and 56 were isolated from the root bark and

Molecules 2017, 22, 911 7 of 33 Molecules 2017, 22, 911 7 of 33 Moleculesfruits2017 of, L.22 ,chinense 911 [61], while 52−54 and 57 were isolated from the fruits of L. barbarum [63]. The7 of 33 fruitschemical of L. structures chinense [61],of these while coumarins 52−54 and are 57listed were in Figureisolated 4 andfrom Table the fruits5. of L. barbarum [63]. The chemical structures of these coumarins are listed in Figure 4 and Table 5. HO HO HO HO HO COOH HO COOH Molecules 2017, 22, 911 COOH HO O O7 of 33 52 E-p-coumaricCOOH acid 53 Z-p-coumaric acid HO54 esculetinO O fruits of52 L.E chinense-p-coumaric [61], acid while 52−54 andO 5357 O wereZ-p-coumaric isolatedR acidfrom the fruits of L.54 barbarum esculetin [63]. The O O R chemical structures of these coumarins are listed in Figure 4 and Table 5. O HO 55 Fabiatrin HO R=O-β-D-GlcO6-β-D-Xyl HO COOH 5556 FabiatrinScopolin R=R=OO-β-β-D-D-Glc-Glc 6-β-D-Xyl 5657 ScopolinCOOHScopoletin R= R=OHO-β-D -Glc HO O O 52 E-p-coumaric5761 Scopoletin acidLycibarbarcoumarin 53 A Z - pR=R=OH-coumaricO-β- D-Glc acid6-β -D-Xyl4-β-D-Glc 54 esculetin 61 LycibarbarcoumarinO AO R=O-β-D-GlcR 6-β-D-Xyl4-β-D-Glc Figure 4. Chemical structures of compounds 52–57, 61. Figure 4. Chemical structures of compounds 52–57, 61. Figure 4. Chemical structures of compoundsO 52–57, 61. Table 5. Chemical structures of compounds6 58–60. 55 TableFabiatrin 5. Chemical structures R=O-β-D of-Glc compounds-β-D-Xyl 58–60. 56 TableScopolin 5. Chemical structures RR=3O-β-D -Glcof compounds 58–60. 57 Scopoletin R=OH R2 R3 61 Lycibarbarcoumarin A R=O-β-D-Glc6-β-D-Xyl4-β-D-Glc R2 Figure 4. Chemical structures of compounds 52–57, 61. R1 R4 59–61 Table 5. ChemicalR1 structures of compoundsR4 58–60. No. Compounds R1 R2 R3 R4 Source 59–61 6-O-E-p-coumaroyl-2-O-β-D-glucopyranosyl-R3 COO6-α-D- No.58 Compounds HR1 OHR2 HR 3 R4 L. barbarumSource No. Compounds R R R 2R Source α-D-glucopyranoside R2 1 2 3 Glc -β4-D-Glc 6-O-E-p-coumaroyl-2-O-β-D-glucopyranosyl- COO6-α-D- 59 Ethyl-4-O-β-D-glucopyranosyl-E-p-coumarate H O-β-D-Glc H COOCH6 2CH3 L. barbarum 58 6-O-E-p-coumaroyl-2-O-β- H OH H COO2 -α-D- L. barbarum 58 α-D-glucopyranoside H OH H Glc2 -β-D-Glc L. barbarum 60 EthylD-glucopyranosyl- E-p-coumarateα- D-glucopyranosideR H R OH H GlcCOOCH-β-D-Glc2CH3 L. barbarum 59 Ethyl-4-O-β-D-glucopyranosyl-E-p-coumarate1 H O-4β -D-Glc H COOCH2CH3 L. barbarum Ethyl-4-O-β-D-glucopyranosyl- 59 H 59–61 O-β-D-Glc H COOCH CH L. barbarum 60 EthylE-p-coumarate E-p-coumarate H OH H COOCH2 2CH3 3 L. barbarum 2.2.4.No. Lignans 62–74 Compounds R1 R2 R3 R4 Source 60 Ethyl E-p-coumarate H OH H COOCH2CH3 L. barbarum 6-O-E-p-coumaroyl-2-O-β-D-glucopyranosyl- COO6-α-D- 2.2.4.58 LignansEight lignans, 62–74 including pinoresinol (62), arctigeninH OH ( 63), Harctiin (64), medioresinolL. barbarum (65 ), α-D-glucopyranoside Glc2-β-D-Glc syringaresinol (66), 4-O-(β-D-glucopyranosyl)syringaresinol (67), threo-1,2-bis(4-hydroxy-3-methoxy- 2.2.4. LignansEight59 Ethyl-4- lignans,62–74O-β -Dincluding-glucopyranosyl- pinoresinolE-p-coumarate (62), arctigeninH O-β-D -Glc(63 ), Harctiin COOCH (64),2CH medioresinol3 L. barbarum (65), phenyl)-1,3-propanediol60 Ethyl E-p-coumarate (68 ), and erythro-1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediolH OH H COOCH2CH3 L. barbarum (69 ), syringaresinol (66), 4-O-(β-D-glucopyranosyl)syringaresinol (67), threo-1,2-bis(4-hydroxy-3-methoxy- haveEight been lignans, isolated includingfrom the fruits pinoresinol of L. barbarum (62 ),[56]. arctigenin (β)-Lyoniresinol (63), arctiin3-O-β-D-glucopyranoside (64), medioresinol (70), (65), phenyl)-1,3-propanediol (68), and erythro-1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol (69), syringaresinollyciumlignan2.2.4. Lignans (66 A ),62 ( 4-71–74O), -( lyciumlignanβ-D-glucopyranosyl)syringaresinol B (72), lyciumlignan C ( (7367),), andthreo (7-1,2-bis(4-hydroxy-3-methoxy-R,8S)-4,9,9′-trihydroxy-3,3′- D havedimethoxy-7 been isolated′-en-8,4 from′-oxyneolignan-7- the fruits of L.O barbarum-β-D-glucopyranoside [56]. (β)-Lyoniresinol (74) were 3- obtainedO-β- -glucopyranoside from the root bark (70 ), phenyl)-1,3-propanediolEight lignans, including (68), andpinoresinolerythro -1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol(62), arctigenin (63), arctiin (64), medioresinol (65), lyciumlignanof L. chinense [54,60,64].A (71), lyciumlignan Among them, B65 (–7270), were lyciumlignan first isolated C from (73), the and fruits (7R of,8 SL.)-4,9,9 barbarum′-trihydroxy-3,3 in 2016 [56]. ′- (69),syringaresinol have been (66 isolated), 4-O-(β-D from-glucopyranosyl)syringaresinol the fruits of L. barbarum (67), threo[-1,2-bis(4-hydroxy-3-methoxy-56]. (β)-Lyoniresinol 3-O-β- dimethoxy-7The chemical′-en-8,4 structures′-oxyneolignan-7- of these lignansO-β are-D-glucopyranoside listed in Figure 5 and (74 )Table were 6. obtained from the root bark D-glucopyranosidephenyl)-1,3-propanediol (70), lyciumlignan (68), and erythro A-1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol (71), lyciumlignan B (72), lyciumlignan C ( (6973),), and of L. chinense0 [54,60,64]. Among0 them, 65–700 were first0 isolated from the fruits of L. barbarum in 2016 [56]. (7R,8Shave)-4,9,9 been-trihydroxy-3,3 isolated from the-dimethoxy-7 fruits of L. barbarum-en-8,4 [56].-oxyneolignan-7- (β)-LyoniresinolO 3--Oβ-βD--glucopyranosideD-glucopyranoside ( (7074),) were The chemical structures ofTable these 6. Chemicallignans arestructures listed ofin compoundsFigure 5 and 62 andTable 65 –6.67 . obtainedlyciumlignan from the A root (71 bark), lyciumlignan of L. chinense B (72[54), lyciumlignan,60,64]. Among C (73 them,), and65 (7–R70,8Swere)-4,9,9 ﬁrst′-trihydroxy-3,3 isolated from′- the H dimethoxy-7′-en-8,4′-oxyneolignan-7-O-β-D-glucopyranoside (74) were obtained from the root bark fruits of L. barbarum in 2016Table [56 6.]. Chemical The chemical structures structures of compounds ofOH these 62 and lignans 65–67. are listed in Figure5 and of L. chinense [54,60,64]. Among them, 65–70 were first isolated from the fruits of L. barbarum in 2016 [56]. Table6. H The chemical structures of these lignans are listedO in Figure 5 and Table 6. OOH Table 6. Chemical structures of compoundsH 62 and 65–67. Table 6. Chemical structuresH of compounds 62 and 65–67. O O O O H H H OH HO O O H O 62, 65–67 O HO H H No. Compounds R1 R2 R3 Source O H 62 Pinoresinol 62, 65O–67 H OH H L. barbarum 65 Medioresinol H OH OCH3 L. barbarum No. Compounds HO R1 R2 R3 Source 66 Syringaresinol OCH3 OH OCH3 L. barbarum 62 Pinoresinol H H OH H L. barbarum 67 4-O-(β-D-glucopyranosyl)syringaresinol62, 65–67OCH 3 O-β-D-Glc OCH3 L. barbarum 65 Medioresinol H OH OCH3 L. barbarum No. Compounds R1 R2 R3 Source 66No. Syringaresinol Compounds ROCH1 3 ROH2 OCHR3 3 L. Sourcebarbarum 62 Pinoresinol H OH H L. barbarum 6762 4-O-(β-D-glucopyranosyl)syringaresinolPinoresinol HOCH3 O OH-β-D-Glc OCH H 3 L. barbarum 65 Medioresinol H OH OCH3 L. barbarum 65 Medioresinol H OH OCH L. barbarum 66 Syringaresinol OCH3 OH OCH3 3 L. barbarum 66 Syringaresinol OCH OH OCH L. barbarum 67 4-O-(β-D-glucopyranosyl)syringaresinol OCH3 3 O-β-D-Glc OCH3 3 L. barbarum 67 4-O-(β-D-glucopyranosyl)syringaresinol OCH3 O-β-D-Glc OCH3 L. barbarum

Molecules Molecules2017, 22 ,2017 911, 22, 911 8 of 33 8 of 33

R O MeO OH O HO HO O-β-D-Glc O HO O Molecules 2017Molecules, 22, 911 2017Molecules , 22, 911 2017 , 22, 911 OMe 8 of 33 8 of 33 8 of 33 O OH OH MeO OMe

O 68 threo-1,2-bis(4-Hydroxy-3- OH R OR R O O O MeO MeO MeO 63 Arctigenin R=OH methoxyphenyl)-1,3-propanediol 70 (β)-LyoniresinolOH 3-OHO-β-D- OH O O O HO 69HO erythroHO -1,2-bis(4-Hydroxy-3-HOHO HO 64 Arctiin R=O-β-D-Glc glucopyranosideO-β-D-Glc O-β-D-GlcO-β-D-Glc O O O HO HO HO methoxyphenyl)-1,3-propanediolO O O HO OH OMeHO OMe OH HO OOMe O O O OH OH OH OH O OCH O O OCH 3 OH OH MeOOH MeO OMeMeOOMe OMe 3 O O OCHO3 68 Othreo-1,2-bis(4-Hydroxy-3-68 threo-1,2-bis(4-Hydroxy-3-68 threo-1,2-bis(4-Hydroxy-3-O O OCH3 O O O O OHOH OH OH OH methoxyphenyl)-1,3-propanediolmethoxyphenyl)-1,3-propanediol OH 63 Arctigenin63 Arctigenin R=OH63 Arctigenin R=OH R=OHO methoxyphenyl)-1,3-propanediol 70 (β)-LyoniresinolOH70 (β)-Lyoniresinol70 3- O(β-)-Lyoniresinolβ-OD- 3-O-β-D- 3-O-β-D- 69 erythro69-1,2-bis(4-Hydroxy-3- erythro69-1,2-bis(4-Hydroxy-3- erythro-1,2-bis(4-Hydroxy-3-OH 64 Arctiin64 R= ArctiinO-β-D64 -GlcR= ArctiinO -βO-D-Glc R=OO -β-D-Glc HO OH glucopyranosideglucopyranosideO Oglucopyranoside methoxyphenyl)-1,3-propanediolOH methoxyphenyl)-1,3-propanediolmethoxyphenyl)-1,3-propanediol OH HO HO OHOHHO OH OH HO HO OHOHHO OH OH HO HO HO HO OH O O HO O OH OH OH OH OH OH 71O LyciumlignanO OCH AO3 OCH3 OCH3 O O 72 LyciumlignanO O B OCH3O OCH3 OCH3 OCH OCHO 3 OCHO 3 O O O O O O OOCH HO OCHO 3 OOCH3 OHO 3 OH OH3 OH OHHO OH OHOH HO OH OH OH O O O O OH OH OHO O O OH OH OH O O O O O O HO HO OH HO OHO O O O O O OH OH OH OH OH O OH OHOCH3OH O O OCH3 OH OH OH OCH3 OH O OH OH HOHO HOOH HOOHOCH OH O HO HOOH HOOH OH OH OH OH OH3 OH OH OHOH 71 Lyciumlignan71 Lyciumlignan A71 Lyciumlignan A OH A 72 Lyciumlignan72 Lyciumlignan B72 LyciumlignanO B B OH O HO HO HOOH OH OH HO HO HO HO HOHO OHHO OHHO OH O O O OH OH OH OH OH OH O O OOOCHH 3 OCH3 OCH3 O O 73O LyciumlignanO O C OCHO 3 OCH3 74OCH (7R3,8S)-4,9,9′-Trihydroxy-3,3′-dimethoxy-7′-en- OCH3 OCHO3 OCHO 3 O HO HO HO OCH3 OCHO 3 OCHO 3 O 8,4′-oxyneolignan-7-O-β-D-glucopyranoside OH OH OH OH OH OH OH OH OH O O O OH OH OHFigureO 5. OChemicalO structures of compounds 63–64 and 68–74. HOFigureHO 5. ChemicalHO structures of compoundsHO 63–HO64 and 68HO–74. OH OH OH OH OH OH 2.2.5. Flavonoids 75–106 OH OH OH OH OH O H 73 Lyciumlignan73 Lyciumlignan C73 Lyciumlignan C C74 (7R,8S74)-4,9,9 (7R′,8-Trihydroxy-3,3S74)-4,9,9 (7R′-Trihydroxy-3,3,8S)-4,9,9′-dimethoxy-7′-Trihydroxy-3,3′-dimethoxy-7′-en- ′-dimethoxy-7′-en- ′-en- 2.2.5. FlavonoidsTwenty-seven75–106 flavonoids 75–101 have been reported from the genus Lycium, are listed in Tables 7 8,4′-oxyneolignan-7-8,4′-oxyneolignan-7-8,4O′--oxyneolignan-7-β-D-glucopyranosideO-β-D-glucopyranosideO-β-D -glucopyranoside Twenty-sevenand 8 and Figures flavonoids 6 and 7. Compound75–101 have 75 was been isolated reported from fromthe flowers the genus of L. barbarumLycium [58],, are while listed 76 in–83 Tables 7 were identifiedFigure from the5. FigureChemical fruits 5. ofChemicalFigure structures L. barbarum 5. Chemicalstructures of compounds [62,65–69]. structures of compounds 63 Compound– 64of andcompounds 63 68–64–74 and84. 63was 68––6474 isolated and. 68–74 from. the fruits of and8 and Figures6 and7. Compound 75 was isolated from the flowers of L. barbarum [58], while L. chinense [70], whereas 85–91 were isolated from the leaves of L. chinense [62,66,68,71]. Compound 92 2.2.5. Flavonoids2.2.5. Flavonoids 2.2.5.75–106 Flavonoids 75–106 75–106 76–83 wereand 93 identified were isolated from from the the fruits leaves ofof L.L. halimifolium barbarum [72].[62, 65Compounds–69]. Compound 94–98 were 84isolatedwas from isolated the from the fruitsTwenty-sevenfruits of L.ofTwenty-seven L. chinense ruthenicum flavonoidsTwenty-seven[ 70flavonoids [16,62]. ],75 whereas–101 Compoundsflavonoids have 75–101 been85 have– 7591 reported 99– 101werebeen–101 have werereported from isolated been isolated the reportedfrom genus from from the Lycium fromgenus the root ,the leaves areLycium genusbark listed, ofare Lyciumin L.L. listed Tableschinense chinense, are in 7 Tableslisted[54,73,74].[62 in 7, 66Tables ,68, 717 ]. Compoundand 8 andAdditionally,and Figures 928 andandand 6Figures and 8Zhou93 and 7.were Compound6 Figures etand al. isolated7. isolated Compound 6 and 75 was7. fromfi Compoundve isolated 75isoflavonoids, was the fromisolated leaves 75 was the from namely ofisolatedflowersL. the halimifolium ofderronefromflowers L. barbarum the of (flowers102 L. barbarum),[ [58],72 alpinumisoflavone of]. while L. Compounds barbarum[58], 76 while–83 [58], 76 – (while9410383 –),98 76were–83 isolatedwere identifiedauriculasin fromwere identified the fromwere ( fruits104 the identified), from fruitsmaackianin of L.the of ruthenicum fromfruitsL. barbarum ( the105 of L.)fruits and barbarum [62,65–69].[ 16maackiainof ,L.62 barbarum[62,65–69].]. CompoundsCompound (106 [62,65–69].) fromCompound 84 the was99 Compoundfruits– isolated 10184 wasofwere L. isolatedfrom barbarum84 isolatedwas the from isolatedfruits [56,75,76]. the from of fromfruits the the of root fruits bark of L. chinenseL. chinense[70], whereasL. [70],chinense whereas85– [70],91 were whereas85– 91isolated were 85– isolatedfrom91 were the from isolatedleaves the of fromleaves L. chinense the of leavesL. chinense[62,66,68,71]. of L. [62,66,68,71].chinense Compound [62,66,68,71]. Compound 92 Compound 92 92 of L. chinense [54,73,74]. Additionally, Zhou et al. isolated five isoflavonoids, namely derrone (102), and 93 wereand 93isolated wereand isolatedfrom93 Tablewere the from isolated7.leaves Chemical the of fromleaves L. structureshalimifolium the of leavesL. halimifolium of compoundsof[72]. L. Compoundshalimifolium [72]. 75 Compounds–80 ,[72]. 8294–8398 Compounds, were85 94–87– 98 isolatedand were 89 94–– 93isolatedfrom98. were the from isolated the from the alpinumisoflavonefruits of L.fruits ruthenicum of L.fruits ruthenicum [16,62]. ( 103of L.), ruthenicum Compounds auriculasin[16,62]. Compounds [16,62].R 99– (101104 Compounds were ),99– maackianin101 isolated were 99– from101isolated were the (105 fromroot isolated) and bark the rootfrom maackiainof L. bark thechinense rootof L. bark [54,73,74].chinense (106 of) L. from[54,73,74]. chinense the [54,73,74]. fruits of 2 OH R3 L.Additionally, barbarumAdditionally,[56 Zhou,75Additionally,, 76et Zhou].al. isolated et al.Zhou isolatedfive et isoflavonoids, al. fiisolatedve isoflavonoids, fi venamely isoflavonoids, derronenamely derrone(namely102), alpinumisoflavone (derrone102), alpinumisoflavone (102), alpinumisoflavone (103), (103), (103), R1 O R1 O R1 O auriculasinauriculasin (104), auriculasinmaackianin (104), maackianin ( 104(105),) maackianinand (105 maackiainOH) and ( 105maackiain (106) and) from maackiain (106 the) from fruits (106 the of) fromfruitsL. barbarum the of L.fruits barbarum [56,75,76]. of L. barbarum[56,75,76]. [56,75,76]. R2 Table 7. Chemical structures of compounds 75R–80, 82–83, 85–87 and 89–93. R3 2 Table 7. ChemicalTable 7. Chemical structuresTable 7. Chemicalstructures of compounds structures of compounds 75– 80of, compounds82 –7583–,80 85, –8287– 75 83and–, 8085 89,– 8287–93– and83. , 85 89––8793 and. 89–93. OH O OH O OH O 75,77–80,87R,90,92 R R 7,82–83,93 85–86,89,91 2 2 2 OH OH OH R3 R3 R3 No. Compounds R1 R2 R3 Source R1 R1O R1O O R1 R1O RO1 O R1 RO1 RO1 O 75 Quercitrin OH OH OH OH OH O-α-L-Rha R2 L. barbarumR2 R2 76 Kaempferol OH OH – L. barbarum R R R R2 R2 R2 77 Quercetin 3 3 3 OH OH OH L. barbarum OH O OH O OH O OH O OH O OH O OH O OH O OH O 78 Rutin OH OH O-β-D-Glc6-α-L-Rha L. barbarum 75,77–80,8775,90,77,92–80 ,8775,90,77,92– 80,87,90,92 7,82–83,93 7,82–83,93 7,82–83,93 85–86,89,9185 –86,89,9185 –86,89,91 79 Narcissoside OH OCH3 O-β-D-Glc6-α-L-Rha L. barbarum No. No. No.Compounds Compounds Compounds R1 R1 R2 R1 R2 R3R2 R3 SourceR3 Source Source No. Compounds R1 R2 R3 Source 75 Quercitrin75 Quercitrin 75 Quercitrin OH OH OH OH OH O-α-LOH-Rha O- α-L-RhaL. O- barbarumα-L-RhaL. barbarumL. barbarum 75 76 QuercitrinKaempferol76 Kaempferol 76 Kaempferol OH OHOH OH OH OH OH –OH – L. O- barbarumα-L–-Rha L. barbarumL. L. barbarum barbarum 76 77 KaempferolQuercetin77 Quercetin77 Quercetin OH OHOH OH OH OH OH OHOH OH L. barbarumOH – L. barbarumL. L. barbarum barbarum 77 78 QuercetinRutin78 Rutin78 Rutin OH OHOH OH OH OHO- OHβ -D-Glc6OOH-α-β-L -D-Rha-Glc 6-Oα--βLL.--RhaD barbarum-Glc OH 6-α-L.L -Rha barbarum L. L. barbarum barbarum 6 66 78 79 RutinNarcissoside79 Narcissoside 79 Narcissoside OH OHOH OCH3 OHOCH O- OHβ3- D-GlcOCH6O-α-β-L-3D-Rha -GlcO --Oβα--βLL.D--RhaD-Glc barbarum-Glc --α-L.L -Rha -Rhabarbarum L. L. barbarum barbarum 6 79 Narcissoside OH OCH3 O-β-D-Glc -α-L-Rha L. barbarum 80 7-O-(β-D-Glucopyranosyl)-rutin O-β-D-Glc OH O-β-D-Glc6-α-L-Rha L. barbarum 82 7-O-(β-D-Glucopyranosyl)-nicotiflorin O-β-D-Glc O-β-D-Glc6-α-L-Rha – L. barbarum Molecules 2017, 22, 911 9 of 33

Molecules 2017, 22, 911 9 of 33

80 7-O-(β-D-Glucopyranosyl)-rutin TableO-β- 7.D-GlcCont. OH O-β-D-Glc6-α-L-Rha L. barbarum O-β-D-Glc6- 82 7-O-(β-D-Glucopyranosyl)-nicotiflorin O-β-D-Glc – L. barbarum α-L-Rha No. Compounds R1 R2 R3 Source 7-O-(β-D-Glucopyranosyl)-3-O-[β-D- O-β-D-Glc6- 7-O-(β83-D -Glucopyranosyl)-3-O-[β- O-β-D-Glc – L. barbarum 83 glucopyranosyl]-(1 → 2)-β-D-galactop O-β-D-Glc O βαD-L-Glc6 α L – L. barbarum β - - -Glc - - -Glc D-glucopyranosyl]-(185 Luteolin → 2)- -D-galactop OH OH OH L. chinense 85 Luteolin OH OH OH L. chinense 86 Acacetin OH H OCH3 L. chinense 86 Acacetin7-O-(β-D-Glucopyranosyl)-3-O-[β-D- OH H OCH3 L. chinense β D β 7-O-( 87- -Glucopyranosyl)-3-glucopyranosyl-(1 →O -[2)-β--D- O-β-D-Glc OH O-β-D-Glc2-β-D-Glc L. chinense 2 87 D-glucopyranosyl-(1galactopyranosyl]-quercetin→ O-β-D-Glc OH O-β-D-Glc -β-D-Glc L. chinense β D 2)- - -galactopyranosyl]-quercetin7-O-[α-L-Rhamno-pyranosyl-(1 → 6)-β- O-β-D-Glc6- α89L → β D H OCH3 L. chinense 7-O-[ - -Rhamno-pyranosyl-(1D-glucopyranosyl]-acacetin O- -α-L--Rha 89 H OCH3 L. chinense β D 6 α L 6)- - 90-glucopyranosyl]-acacetin 3-O-Sophoroside-quercetin Glc - - -RhaOH OH O-β-D-Glc2-β-D-Glc L. chinense 2 90 3-O-Sophoroside-quercetin91 Apigenin OHOH H OH OOH-β -D-Glc -β-DL.-Glc chinense L. chinense 91 Apigenin92 Isoquercitrin OHOH OH H O-β-D-Glc OH L. halimifoliumL. chinense 92 Isoquercitrin OHO-β-D-Glc OH6- O-β-D-Glc L. halimifolium 93 Nicotiflorin OH 6 – L. halimifolium 93 Nicotiﬂorin OH O-βα-D-L-Glc-Rha -α-L-Rha – L. halimifolium

OH HO OH OH HO O HO O OH

OH OH OH O OH O 81 Myricetin 84 Morin OMe O OMe OH

HO O HO O OH O

MeO OH OH OH O OH 88 3,5,7,3′-Tetrahydroxy-6,4′,5′trimethoxyflavone 94 Malvidin Molecules 2017, 22, x 10 of 33 Figure 6. Chemical structures of compounds 81, 84, 88 and 94. Figure 6.FigureChemical 6. Chemical structures structures of compounds compounds 81, 8481, 88, and84, 9488. and 94. Table 8. Chemical structures of compounds 95–98. Table 8.TableChemical 8. Chemical structures structures of of compounds compounds 95–98. 95–98. O

OH O HO O OH R1 HO O O R1 O O O OH O HO O O OH HO O HO OH OH HO OHOH OH OH OH O OH HOOH O OH HO O OO O

R2R2 No. Compounds R1 R2 Source No. Compounds R1 R2 Source No.5-O -(β-D-Glucopyranosyl)-3-CompoundsO-[4-O-p- E-coumaroyl-α-L- R1 R2 Source 95 H OH L. ruthenicum 5-O5-O-(-β(β-D-D-Glucopyranosyl)-3--Glucopyranosyl)-3-O-[4O--[4-O-p-OE-coumaroylp-E-coumaroyl--α-L- α- 95rhamnopyranosyl-(1 → 6)-β-D-glucopyranosyl]-peonidin H OH L. ruthenicum L rhamnopyranosyl-(1 → 6)→-β-D-glucopyranosyl]-peonidin 95 5-O-(-rhamnopyranosyl-(1β-D-Glucopyranosyl)-3-O-[4-O-p-E-coumaroyl-α-L- H OH L. ruthenicum 96 6)-5β-O-D-(β-glucopyranosyl]-peonidin-D-Glucopyranosyl)-3-O-[4-O-p-E-coumaroyl-α-L- OH OH L. ruthenicum 96rhamnopyranosyl-(1 → 6)-β-D-glucopyranosyl]-petunidin OH OH L. ruthenicum rhamnopyranosyl-(1 → 6)-β-D-glucopyranosyl]-petunidin 5-O-(β-D-Glucopyranosyl)-3-O-[4-O-p-E-coumaroyl-α- 5-O-(β-D-Glucopyranosyl)-3-O-[4-O-p-Z-coumaroyl-α-L- 97 L → OCH3 OH L. ruthenicum 96 -rhamnopyranosyl-(1rhamnopyranosyl-(1 → 6)-β-D-glucopyranosyl]-malvidin OH OH L. ruthenicum

6)-5β-O-D-(β-glucopyranosyl]-petunidin-D-Glucopyranosyl)-3-O-[4-O-p-E-(β-D- 98 5-Oglucopyranoside)-(β-D-Glucopyranosyl)-3--coumaroyl-α-OL--[4-rhamnopyranosylO-p-Z-coumaroyl--(1 → 6)α- - OH O-β-D-Glc L. ruthenicum β-D-glucopyranosyl]-petunidin 97 L-rhamnopyranosyl-(1 → OCH3 OH L. ruthenicum 6)-β-D-glucopyranosyl]-malvidin

5-O-(β-D-Glucopyranosyl)-3-O-[4-O-p-E-(β- O-β- 98 D-glucopyranoside)-coumaroyl-O α-L-rhamnopyranosyl-(1 OH OL.H ruthenicum D-Glc → 6)-β-D-glucopyranosyl]-petunidin OH HO O HO O OH HO O OH 101 ,4′-Dihydroxy-5′-isopentene flavane 99 Lyciumflavane A 100 Kcazinol A

O O O O O O

OH OH O OH OH O OH O OH 103 Alpinumisoflavone OH 102 Derrone 104 Auriculasin HO O HO O H

H O O O O O O 105 Maackianin 106 Maackiain

Figure 7. Chemical structures of compounds 99–106.

Molecules 2017, 22, 911 10 of 33 Molecules 2017, 22, 911 10 of 33 5-O-(β-D-Glucopyranosyl)-3-O-[4-O-p-Z-coumaroyl-α-L- 97 OCH3 OH L. ruthenicum rhamnopyranosyl-(15-O-(β-D-Glucopyranosyl)-3- → 6)-β-DO-glucopyranosyl]-malvidin-[4-O-p-Z-coumaroyl-α-L- 97 OCH3 OH L. ruthenicum 5-rhamnopyranosyl-(1O-(β-D-Glucopyranosyl)-3- → 6)-β-OD-glucopyranosyl]-malvidin-[4-O-p-E-(β-D- 98 glucopyranoside)-coumaroyl-5-O-(β-D-Glucopyranosyl)-3-Oα-[4--L-rhamnopyranosyl-(1O-p-E-(β-D- → 6)- OH O-β-D-Glc L. ruthenicum Molecules98 2017βglucopyranoside)-coumaroyl--,D22-glucopyranosyl]-petunidin, 911 α -L-rhamnopyranosyl-(1 → 6)- OH O-β-D-Glc L. ruthenicum10 of 33 β-D-glucopyranosyl]-petunidin

O OH O OH OH HO O HO O OH OH HO O HO O HO O OH OH HO O OH 101 ,4′-Dihydroxy-5′-isopentene 101 ,4′-Dihydroxy-5flavane ′-isopentene 99 Lyciumflavane A flavane 99 Lyciumflavane A 100 Kcazinol A 100 Kcazinol A O O O O O O OO O O OO OH OH O OH OH OH O OH O OH O OH 103 Alpinumisoflavone OH OH OH O OH O 102 Derrone OH 103 Alpinumisoflavone 104 Auriculasin OH 102 HODerrone O HO O 104 Auriculasin HO O HO O H H H O O O O H O O O O O O 105 Maackianin O 106 Maackiain O 105 Maackianin 106 Maackiain FigureFigure 7.7. ChemicalChemical structures of compounds compounds 9999––106106. . Figure 7. Chemical structures of compounds 99–106. 2.2.6. Amides 107–143 2.2.6. Amides 107–143 2.2.6. Amides 107–143 Sixteen amides 107–122 have been isolated from the root bark of L. chinense [9,54,60,77–80], 19 Sixteen amides 107–122 have been isolated from the root bark of L. chinense [9,54,60,77–80], amidesSixteen (123 –amides141) have 107 –been122 have isolated been fromisolated the from fruits the of root L. barkbarbarum of L. [81–88].chinense [9,54,60,77–80],Meanwhile, two 19 123 141 L. barbarum 19cerebrosidesamides amides (123 ( –142–141 and) )have have 143 beenhave been beenisolated isolated obtained from from fromthe the fruits fruits ofof of L. L. chinense barbarum [89]. [[81–88].81 The–88 chemical]. Meanwhile, Meanwhile, structures two two cerebrosidesofcerebrosides these amides142 142and are and shown143 143have have in beenFigure been obtained 8.obtained from from fruits fruits of ofL. L. chinense chinense[89 [89].]. The The chemical chemical structures structures of theseof these amides amides are shownare shown in Figure in Figure8. 8. OH OH O O OH OH O O N N H H N N HO H HO H HO OH HO OH 107 N-(α,β-Dihydrocaffeoyl)tyramine 108 N-[(E)-Caffeoyl]tyramine OHOH OH 107 N-(α,β-Dihydrocaffeoyl)tyramine 108 N-[(E)-Caffeoyl]tyramine OH HO O OH OH O HO OH N H O OH OH N O H O N OH H O OH 109 N-[(Z)-Caffeoyl]tyramineN 110 N-[(E)-Feruloyl]octopamine H OH 109 N-[(Z)-Caffeoyl]tyramine 110 N-[(E)-Feruloyl]octopamine

Figure 8. Cont.

Molecules 2017, 22, 911 11 of 33 Molecules 2017, 22, 911 11 of 33

OH O O O N OH H O HN HO N O H O HO O OH

O 112 (E)-2-[4,5-Dihydroxy-2-[3-[2-(4-hydroxyphenyl) 111 Aurantiamide acetate ethylamino]-3-oxopropyl]phenyl]-3-(4-hydroxy- 3,5-dimethoxyphenyl)-N-[2-(4-hydroxyphenyl) ethyl]prop-2-enamide O O O NH OH OH N O H O O HO N N R H H HO HO N OH O H 113 (E)-N-(4-Acetamidobutyl)-2-[4,5-dihydroxy- O 2-[3-[2-(4-hydroxyphenyl)ethylamino]-3- HO OH oxopropyl]-phenyl]-3-(4-hydroxy-3- OH methoxyphenyl)prop-2-enamide R=H 115 (1R,2S)-1-(3,4-Dihydroxyphenyl)-7-hydroxy- 114 (E)-N-(4-Acetamidobutyl)-2-[4,5-dihydroxy- N2,N3-bis(4-hydroxyphenethyl)-6,8-dimethoxy- 2-[3-[2-(4-hydroxyphenyl)ethylamino]-3- 1,2-dihydro-naphthalene-2,3-dicarboxamide oxopropyl]-phenyl]-3-(4-hydroxy-3,5- dimethoxyphenyl)prop-2-enamide R=OCH3 O OH H O N N H OH O HN O HO O N O N O O H H O O

HO OH HO OH 117 (2,3-E)-3-(3-Hydroxy-5-methoxyphenyl)-N-(4- 116 (1S,2R)-N3-(4-Acetamidobutyl)-1-(3,4- hydroxyphenethyl)-7-{(E)-3-[(4- dihydroxy-phenyl)-7-hydroxy-N2-(4- hydroxyphenethyl)-=amino]-3-oxoprop-1-en-1- hydroxyphenethyl)-6,8-dimethoxy-1,2- yl}-2,3-dihydrobenzo-[b][1,4]dioxine-2- dihydro-naphthalene-2,3-dicarboxamide carboxamide OH

O OH HN OH HO

O O O O N O H O O O N HO H 119 (Z)-3-{(2,3-E)-2-(4-hydroxy-3-methoxyphenyl)-3- HO hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxin-6- 118 (2,3-E)-3-(3-hydroxy-5-methoxyphenyl)-N- yl}-N-(4-hydroxyphenethyl)acrylamide (4-hydroxyphenethyl)-7-{(Z)-3-[(4-hydroxyphenethyl)amino]-3-oxoprop-1-en-1-yl}-2,3- dihydrobenzo[b][1,4]dioxine-2-carboxamide OH O O HO N H OGlc6-Xyl O O

HO 120 (E)-3-{(2,3-E)-2-(4-hydroxy-3-methoxyphenyl)- N H 3-hydroxymethyl-2,3-dihydrobenzo[b][1,4] 121 Indole glycoside dioxin-6-yl}-N-(4-hydroxyphenethyl)- acrylamide

Figure 8. Cont. Molecules 2017, 22, 911 12 of 33 Molecules 2017, 22, 911 12 of 33

OH O HO O H3CO N H H HO N HO N H OCH O 3 O OH 123 Lyciumide A 122 Lyciumamide D O O O O O O N N NH H H HO OH O HO HO OH H N O O 124 Lyciumamide A O 125 Lyciumamide B OH O OH O N O H HO HO O N O H HO 126 Lyciumamide C 127 N-Z-p-coumaroyl-tyramine OH O OH O

N HO O N H H HO 128 N-Z-feruloyl-tyramine 129 N-E-p-coumaroyl-tyramine OH O OH O O O N O H N HO O H HO 130 N-E-feruloyl-tyramine OH OH 131 (±)-(7′′S*,8′′R*)-Canabisine H OH O OH O O O O N N H H HO O O O O NH NH O HO

HO OH 132 Cannabisin F 133 (±)-Grossamide OH O O OH N O O OH H O O HO O N OH OH H O OH 134 N-Z-feruloyl-4-O-(β-D-glucopyranosyl) OH tyramine OH OH 135 N-(4-O-(β-D-Glucopyranosyl)-E-feruloyl)- tyramine

Figure 8. Cont.

Molecules 2017, 22, 911 13 of 33 Molecules 2017, 22, 911 13 of 33

OH OH O O O OH O O N O H Molecules 2017, 22, 911 N O HO 13 of 33 H OH O

HO OH OH OH O 136 N-E-feruloyl-4-O-(β-D- O O OH OHO OH glucopyranosyl)tyramine O N O 137 (±)-(7′′R*,8′′R*)-CanabisineH H N O HO H OHOH O OH O O HO O OH 136 NO-E-feruloyl-4-O-(β-D- N H H CO OH OH N glucopyranosyl)tyramine 3 HO O 137 (±)-(7′′R*,8′′R*)-CanabisineH H OH H OH O O HO O N O O OH N NH H H3CO ON HO O H OH H O HO O N HO OH OH NH O 138 (±)-Cannabisin E 139 (±)-Cannabisin D OH OH O O O OH H CO N OHO 3 H OH HO H O O N 138 (±)-CannabisinN E 139 (±)-Cannabisin D O OH H O O O O OH OH OH O H CO N O 3 NH H HO O H O O N O N OH H O OH OH O OH HO OH OHO NH 140 (±)-Melongenamide D 141 N-(4-O-(β-D-Glucopyranosyl)-Z-eruloyl)-tyramine H O OH OH OH O OH O HO OH HO HO 140 NH(±)-Melongenamide D 141 N-(4-O-(β-D-Glucopyranosyl)-NH Z-eruloyl)-tyramine O O H O O OH O O OH OH OH OH OH HO OHHO OH NH OH NH O 142O Cerebrosides A O O 143 Cerebrosides B OH OH OH OH OH OH OH Figure 8. Chemical structures of compoundsOH 107–143. 142 CerebrosidesFigure 8. AChemical structures of compounds143 Cerebrosides107–143. B

2.2.7. Alkaloids 144–215 Figure 8. Chemical structures of compounds 107–143. 2.2.7. Alkaloids 144–215 To date, 72 alkaloids have been identified, which can be classified into five categories: 2.2.7. Alkaloids 144–215 nortropane,To date, 72 alkaloidsimidazole, havepiperidine, been identified,pyrrole, spermine, which cantropane, be classified and other into alkaloids. five categories: nortropane, imidazole, piperidine,To date, 72 pyrrole,alkaloids spermine,have been tropane,identified, and which other can alkaloids. be classified into five categories: Nortropanenortropane, Alkaloids imidazole, piperidine, pyrrole, spermine, tropane, and other alkaloids. NortropaneFourteen Alkaloids nortropane alkaloids 144–157, shiwn in Figure 9, have been isolated from the root bark Nortropane Alkaloids ofFourteen L. chinense nortropane [90]. alkaloids 144–157, shiwn in Figure9, have been isolated from the root bark Fourteen nortropane alkaloids 144–157, shiwn in Figure 9, have been isolated from the root bark of L. chinenseof L. chinense[90]. [90]. HO HN OH OH HN HO HN OH HO HN HN HO OH HN HO HO HO HO OH HN HO HO OH HO HN HO 144 Calystegine A3 145HO Calystegine A5 146 CalystegineHO A6 147HO Calystegine A7 HO HO OH HO OH HN144 CalystegineOH A3 HN145 CalystegineOH A5 146HN Calystegine A6OH 147 Calystegine A7 OH OH HN HO HO HO OH OH OH HOHN OH HN OH OH HO HO HO OH HN HN HO HO OH OHOH 148 HOCalystegine B1 149 Calystegine B2 HO150 Calystegine B3 HO HO HO 151 Calystegine B4 148 CalystegineOH B1 149 Calystegine B2 OH OH HN 150 CalystegineOH B3 151 HNCalystegine B4 HN OH HN OH OH HO OH HO OH HN OH HO OH OH HHN2N OH HN HO OH OH HN OH HO OH HO OH H N OHOH HOHO 153HO Calystegine C1 HO OH 2155 Calystegine N1 152 Calystegine B5 OH 154HO Calystegine C2 OH HO 153 Calystegine C1 155 Calystegine N1 152 Calystegine B5 154 Calystegine C2

Figure 9. Cont. Molecules 2017, 22, 911 14 of 33 Molecules 2017, 22, 911 14 of 33 Molecules 2017, 22, 911 14 of 33 Molecules 2017, 22, 911 14 of 33 N OH N OH HO N OH HO N OH N OH OH HO OH OH HO OHOH HON OHOH 156 HON-MethylcalystegineOHOH B2 157 HON-MethylcalystegineHO OHOH C1 156 N-MethylcalystegineOH B2 157 NHO-MethylcalystegineOH C1 Figure 9. Chemical structures of compounds 144–157. 156 N-MethylcalystegineFigure 9. Chemical B2 structures of compounds157 N144-Methylcalystegine–157. C1 Figure 9. Chemical structures of compounds 144–157. Imidazole Alkaloids Figure 9. Chemical structures of compounds 144–157. ImidazoleImidazole AlkaloidsAlkaloids ImidazoleSix imidazole Alkaloids alkaloids 158–162 were detected in the leaves of L. cestroides [91]: Meanwhile, one Six imidazole alkaloids 158–162 were detected in the leaves of L. cestroides [91]: Meanwhile, one imidazole,Six imidazole Na-[(E)-cinnamoyl]histamine alkaloids 158–162 were (163 detected), was obtained in the leaves from ofthe L. leaves cestroides of L. [91]: barbarum Meanwhile, [66], listed one imidazole,Six imidazole Na-[(E)-cinnamoyl]histamine alkaloids 158–162 were (163 detected), was obtained in the leaves from of the L. leavescestroides of L. [91]: barbarum Meanwhile,[66], listed one inimidazole, Figure 10. Na-[( E)-cinnamoyl]histamine (163), was obtained from the leaves of L. barbarum [66], listed inimidazole,in FigureFigure 10 10. Na-[(. E)-cinnamoyl]histamine (163), was obtained from the leaves of L. barbarum [66], listed in Figure 10. N O N N O NN O N O N H N O N N NH NNH NH N O N N NH NH H N HN H O NH NH 159 Na-[(E)-Cinnamoyl]-N1- N N 158 Na-[(Z)-Cinnamoyl]histamineNH 160 N(Z)-QuasibicyclicH O H 159 methylhistamineNa-[(E)-Cinnamoyl]- N1- 158 Na-[(Z)-Cinnamoyl]histamine 160 (ZH)-QuasibicyclicO 159 Na-[(E)-Cinnamoyl]-N1- N 158 Na-[(Z)-Cinnamoyl]histamine methylhistamine 160 (Z)-Quasibicyclic methylhistamine O NH N N O NNH N NH O N N O N NH N NH O H N NH O NN N NH N O N NH H O H N H O N N H 162 Na-[(Z)-Cinnamoyl]-H N1- N 163 Na-[(E)-Cinnamoyl]- 161 (E)-Quasibicyclic 162 methylhistamineNa-[(Z)-Cinnamoyl]-H N1- 163 Na-[(E)-Cinnamoyl]- 161 (E)-Quasibicyclic 162 Na-[(methylhistamineZ)-Cinnamoyl]- N1- histamine 163 Na-[(E)-Cinnamoyl]- 161 (E)-Quasibicyclic methylhistamine histamine Figure 10. Chemical structures of compounds 158–163histamine. FigureFigure 10.10. ChemicalChemical structuresstructures ofof compoundscompounds158 158––163163.. Piperidine Alkaloids Figure 10. Chemical structures of compounds 158–163. Piperidine Alkaloids Piperidine5-hydroxy-2-pyridy Alkaloids lmethyl ketone (164), methyl 5-hydroxy-2-pyridinecarboxylate (165), fagomine5-hydroxy-2-pyridy (166), and 6-deoxyfagominelmethyl ketone (167 (),164 listed), methyl in Figure 5-hydroxy-2-pyridinecarboxylate 11, have been isolated and identified (165), 5-hydroxy-2-pyridylmethyl5-hydroxy-2-pyridylmethyl ketone (164), methyl 5-hydroxy-2-pyridinecarboxylate ( (165),), fromfagomine the genus (166), Lycium and 6-deoxyfagomine; among them. Compounds (167), listed 164 in and Figure 165 11,are fromhave thebeen fruits isolated of L. andbarbarum identified [92], fagomine ((166166),), andand 6-deoxyfagomine 6-deoxyfagomine (167 (167), listed), listed in Figurein Figure 11, have11, have been been isolated isolated and identiﬁedand identified from andfrom 166 the and genus 167 Lycium are from; among the root them. bark Compounds of L. chinense 164 [90]. and 165 are from the fruits of L. barbarum [92], thefrom genus the genusLycium Lycium; among; among them. them. Compounds Compounds164 and 164 165andare 165 from are from the fruits the fruits of L. of barbarum L. barbarum[92], [92], and and 166 and 167 are from the root barkL. chinenseof L. chinense [90]. 166andand HO166 167andare 167 from are from the root the barkrootHO bark of of L. chinense[90]. [90]. HO HO HO HO NH HO HO HO NH HO N COCH3 N COOCH3 HO HO NH HOHO NH HO 164 5-Hydroxy-2-pyridyl-N COCH3 165 MethylN 5-hydroxy-2-COOCH3 NH 167 HO6-DeoxyfagomineHO NH N COCH N COOCH HO166H OFagomine 164 methyl5-Hydroxy-2-pyridyl- ketone 3 165 pyridinecarboxylateMethyl 5-hydroxy-2- 3 HO 167 H6-DeoxyfagomineO 164 5-Hydroxy-2-pyridyl- 165 Methyl 5-hydroxy-2- 166 Fagomine methyl ketone pyridinecarboxylate 166 Fagomine 167 6-Deoxyfagomine methyl ketone Figure 11.pyridinecarboxylate Chemical structures of compounds 164–167. Figure 11. Chemical structures of compounds 164–167. Figure 11. Chemical structures of compounds 164–167. Pyrrole Alkaloids Figure 11. Chemical structures of compounds 164–167. Pyrrole Alkaloids PyrroleThirteen Alkaloids pyrrole alkaloids 168–180 have been isolated from the fruits of L. chinense [93–95]. PyrroleLikewise,Thirteen Alkaloids 2-formyl-5-hydroxymethylpyrrole pyrrole alkaloids 168–180 have (181 been) and isolated 2-formyl-5-methoxymethylpyrrole from the fruits of L. chinense (182 [93–95].) were Thirteen pyrrole alkaloids 168–180 have been isolated from the fruits of L. chinense [93–95]. isolatedLikewise, from 2-formyl-5-hydroxymethylpyrrole the fruits of L. barbarum [92]. Two (181 pyrrolidine) and 2-formyl-5-methoxymethylpyrrole alkaloids, alkaloid I (183) and alkaloid(182) were II Likewise,Thirteen 2-formyl-5-hydroxymethylpyrrole pyrrole alkaloids 168–180 have (181 been) and isolated 2-formyl-5-methoxymethylpyrrole from the fruits of L. chinense (182[93) were–95]. (isolated184), are from obtained the fruits from of the L. barbarumroot bark [92]. of L. Two chinense pyrrolidine [96]. The alkaloids, chemical alkaloid structures I (183 of) andthese alkaloid pyrrole II Likewise,isolated from 2-formyl-5-hydroxymethylpyrrole the fruits of L. barbarum [92]. Two (181 pyrrolidine) and 2-formyl-5-methoxymethylpyrrole alkaloids, alkaloid I (183) and (alkaloid182) were II isolatedalkaloids(184), are from are obtained listed the fruits in from Figure of L.the barbarum12. root bark[92 of]. TwoL. chinense pyrrolidine [96]. The alkaloids, chemical alkaloid structures I (183 )of and these alkaloid pyrrole II (alkaloids184), are areobtained listed fromin Figure the root12. bark of L. chinense [96]. The chemical structures of these pyrrole (alkaloids184), are are obtained listed in from Figure the 12. root bark of L. chinense [96]. The chemical structures of these pyrrole alkaloids are listed in Figure 12.

Molecules 2017, 22, 911 15 of 33 Molecules 2017, 22, 911 15 of 33

O O O OCH OH OH 3

N N N OHC OHC OHC OCH OH OCH 3 3 170 Methyl 4-[2-formyl-5-(methoxy- 168 4-[2-Formyl-5-(hydroxymethyl)- 169 4-[2-Formyl-5-(methoxymethyl) methyl)1H-pyrrol-1-yl]- 1H-pyrrol-1-yl]butanoic acid -1H-pyrrol-1-yl]butanoic acid butanoate COOCH 3 H COOC HOOC 3 COOH N N OHC OHC N OHC OH OH OH 173 (2R)-[2-Formyl-5-(hydroxy- (2S)-[2-Formyl-5- 171 Methyl 4-[2-formyl-5-(hydroxy- 172 methyl)-1H-pyrrol-1-yl]-1- (hydroxymethyl)-1H-pyrrol-1- methyl)-1H-pyrrol-1-yl]- methoxy-1-oxo-butanoic acid yl]-3-methyl-butanoic acid butanoate

H COOC HOOC 3 COOH H3COOC N N OHC OHC O N OH OHC O 175 Methyl 2-[2-formyl-5- 174 3-[2-Formyl-5-(hydroxymethyl)- (methoxymethyl)-1H-pyrrol- 176 Methyl (2R)-[2-formyl-5- 1H-pyrrol-1-yl]-pentanedioic acid 1-yl]propanoate (methoxymethyl)-1H-pyrrol- 1-yl]-4-methyl-pentanoate

H3COOC H3COOC COOCH3 COOCH3 H COOC OHC N OHC N 3 O O OHC N O 177 Dimethyl 2-[2-formyl-5-(methoxy- 178 Dimethyl 2-[2-formyl-5-

methyl)-1H-pyrrol-1-yl]-butane- (methoxy-methyl)-1H-pyrrol-1- 179 Methyl (2R)-[2-formyl-5- dioate yl]-pentanedioate (methoxymethyl)-1H-pyrrol- 1-yl]-3-(phenyl)-propanoate OH H H OHC N OHC N OH O

181 2-Formyl-5- 182 2-Formyl-5-methoxymethyl- H3COOC hydroxymethylpyrrole pyrrole HO OH OH OH OHC N O HO OH OH 180 Methyl 2-[2-formyl-5-(methoxy- N N HO H methyl)-1H-pyrrol-1-yl]-3-(4- HO H hydroxyphenyl)-propanoate 183 Alkaloid I 184 Alkaloid II

Figure 12. Chemical structures of compounds 168–184. Figure 12. Chemical structures of compounds 168–184. Spermine Alkaloids Spermine Alkaloids Nineteen spermine alkaloids have been found in the genus Lycium. Kukoamines A (185) and kukoaminesNineteen B spermine (186) are alkaloidsfrom the root have bark been of L. found chinense in the[97,98], genus whileLycium N1-caffeoyl-. KukoaminesN3-dihydrocaffeoyl A (185) and kukoaminesspermidine B (187 (186) )and are lyrium from the spermidine root bark A of (188L. chinense) are from[97 the,98 ],fruits while of NL.1-caffeoyl- ruthenicumN [62,99],3-dihydrocaffeoyl listed in spermidineFigure 13. Another (187) and 15 lyriumspermine spermidine alkaloids, lycibarbarspermidine A (188) are from the A–O fruits (189 of–203L.), ruthenicum listed in Tables[62 ,999 and], listed 10 in Figureand Figures 13. Another 13–15, are 15 from spermine L. barbarum alkaloids, [100]. lycibarbarspermidine A–O (189–203), listed in Tables9 and 10 and Figures 13–15, are from L. barbarum [100].

Molecules 2017, 22, x 16 of 33

OH H H OHC N OHC N OH O

Figure 12. Chemical structures of compounds 168–184.

Spermine Alkaloids Nineteen spermine alkaloids have been found in the genus Lycium. Kukoamines A (185) and kukoamines B (186) are from the root bark of L. chinense [97,98], while N1-caffeoyl-N3- dihydrocaffeoyl spermidine (187) and lyrium spermidine A (188) are from the fruits of L. ruthenicum [62,99], listed in Figure 13. Another 15 spermine alkaloids, lycibarbarspermidine A–O (189–203), Molecules 2017, 22, 911 16 of 33 listed in Tables 9 and 10 and Figures 13–15, are from L. barbarum [100]. Molecules 2017, 22, 911 16 of 33 OH Molecules 2017, 22, 911 OH 16 of 33 HO OH HO O OH O H H OH O HO NH NH O HO N N N N OH HO O HN HN OHOH O O H H O HO N NH2 HO H H O HO N N NNH2 HOHO N N HN HN O N 185 NKukoamines A OH O H H H 185 HKukoamines A HO O HOHO NNH2 HO N KukoaminesN B 186H H 185 Kukoamines A OH 186 KukoaminesCOOH B OH O OH HO O COOH OH O H H O H NH NH 186 KukoaminesN BNH N N N OH N N N OH HN OHOH HN COOH OHOH O H O O H O HO H H O HO H O HO N N HO N N OH N OH OH N OH H H OH O OH O HO187 N11-Caffeoyl--Caffeoyl-N33-dihydrocaffeoyl-dihydrocaffeoyl spermidine HO 188 Lyrium spermidine A OH OH 187 N1-Caffeoyl-N3-dihydrocaffeoylFigure 1313.. Chemical spermidine structures of compounds188 185Lyrium–188 ..spermidine A Figure 13. Chemical structures of compounds 185–188. Figure 13. Chemical structures of compounds 185–188. Table 99.. Chemical structures of compounds 189–193.. Table 9. Chemical structures of compounds 189–193. O Table 9. Chemical structures of compounds 189–193. R2 - O O H CF3COO R O N O RR21 H - 2 O H CF3NCOO- N O O R N CF3COO R1 O N H2 H 1 O N N OR4 O N N O O O H2 H R3 O H2 H R4 189–193 O R R4 O R3 No. Compounds R1 189–193 R2 R3 R4 3 Source 189–193 189 Lycibarbarspermidine A H β-D-Glc H H L. barbarum No. Compounds R1 R2 R3 R4 Source No.No. CompoundsCompounds R R1 R R2 RR3 R4 R SourceSource 190 Lycibarbarspermidine B 1 H 2 H β-D-Glc3 H 4 L. barbarum 189 LycibarbarspermidineLycibarbarspermidine A A H β-D-Glc-Glc H H L.L. barbarum 189191 LycibarbarspermidineLycibarbarspermidine A C Hβ-D-Glc β-D-Glc H H H H H L. L.barbarum barbarum 190 LycibarbarspermidineLycibarbarspermidine B B H H β-D-Glc-Glc H L.L. barbarum 190192 LycibarbarspermidineLycibarbarspermidine B D H H H H β-D H-Glc β-D-Glc H L. L.barbarum barbarum 191 LycibarbarspermidineLycibarbarspermidine C C β-D-Glc-Glc H H H L.L. barbarum 191193 LycibarbarspermidineLycibarbarspermidine C E β-D-Glc H β H-D-Glc β-D H-Glc H H L. L.barbarum barbarum 192 Lycibarbarspermidine D H H H β-D-Glc L. barbarum 192192 LycibarbarspermidineLycibarbarspermidine D D HH HH H H β-Dβ-Glc-D-Glc L. barbarumL. barbarum 193 Lycibarbarspermidine E H β-D-Glc β-D-Glc H L. barbarum 193193 LycibarbarspermidineLycibarbarspermidine E E H H β-βD--GlcD-Glc ββ--DD--GlcGlc H H L. barbarumL. barbarum O H H O Glc-D-βO N H OO H N N O O H O H H O Glc-D-β HN H O O Glc-D-β N N N βO-D-Glc O H H O 194 LycibarbarspermidineN N F HO O H H O β-D-Glc H β-D-GlHc 194 Lycibarbarspermidine F O O β-D-Glc O H β-D-Glc 194 Lycibarbarspermidine F O O O Glc-D-β - O H CF3COO HO N Glc-D-β - O H CF COON N O 3 H H O N 2 H O 195 LycibarbarspermidineN GN O H2 H Figure 14. Chemical195 Lycibarbarspermidine structures of compounds G 194 and 195.

Figure 14. Chemical structures of compounds 194 and 195. FigureTable 14. 10.Chemical Chemical structures structures of of compounds compounds194 196and–200195. .

O Table 10. Chemical structures of compounds 196–200. R2 O H CF COO- R O N 3 R 1 O 2 O H N - N O O N CF3COOH H R1 2 R O N N O O 4 R3 O H2 H 196–200 R4 O R No. Compounds R1 R2 R3 R4 3 Source 196–200 196 Lycibarbarspermidine H H H H β-D-Glc L. barbarum No. Compounds R1 R2 R3 R4 Source 197 Lycibarbarspermidine I H β-D-Glc H H L. barbarum 196 Lycibarbarspermidine H H H H β-D-Glc L. barbarum 198 Lycibarbarspermidine J H H β-D-Glc H L. barbarum 197 Lycibarbarspermidine I H β-D-Glc H H L. barbarum 199 Lycibarbarspermidine K β-D-Glc H β-D-Glc H L. barbarum 198 D 200 Lycibarbarspermidine JL H H β-DH-Glc β- H-Glc β-DH-Glc L.L. barbarumbarbarum 199 Lycibarbarspermidine K β-D-Glc H β-D-Glc H L. barbarum 200 Lycibarbarspermidine L H β-D-Glc H β-D-Glc L. barbarum

Molecules 2017, 22, x 17 of 33

H β-D-Glc O O

O Glc-D-β - O H CF3COO H N O N N O H2 H 195 Lycibarbarspermidine G

Molecules 2017, 22, 911 Figure 14. Chemical structures of compounds 194 and 195. 17 of 33

Table 10. Chemical structures of compounds 196–200. Table 10. Chemical structures of compounds 196–200.

O R O 2 H - N CF3COO R1 O N N O O H H 2 R O 4 R3 196–200 No. Compounds R1 R2 R3 R4 Source No. Compounds R1 R2 R3 R4 Source 196 Lycibarbarspermidine H H H H β-D-Glc L. barbarum 196 Lycibarbarspermidine H H H H β-D-Glc L. barbarum 197 Lycibarbarspermidine I H β-D-Glc H H L. barbarum 197 Lycibarbarspermidine I H β-D-Glc H H L. barbarum 198 Lycibarbarspermidine J H H β-D-Glc H L. barbarum 198 Lycibarbarspermidine J H H β-D-Glc H L. barbarum 199 Lycibarbarspermidine K β-D-Glc H β-D-Glc H L. barbarum 199 Lycibarbarspermidine K β-D-Glc H β-D-Glc H L. barbarum 200 Lycibarbarspermidine L H β-D-Glc H β-D-Glc L. barbarum 200 Lycibarbarspermidine L H β-D-Glc H β-D-Glc L. barbarum Molecules 2017, 22, 911 17 of 33

O H O O H H O HN Glc-D-β N Glc-D-β O N N O O O NH NH O O H H β-D-Glc O H β-D-Glc O H 201 Lycibarbarspermidine M 201 LycibarbarspermidineO M O N NH HO H HO +H2NCF COO- O +H2NCF3COO- O O 3 R O R H HN HO N HO O O 202 Lycibarbarspermidine N R = β-D-Glc 202 Lycibarbarspermidine N R = β-D-Glc 203 Lycibarbarspermidine O R = β-D-Glc3β-D-Glc 203 Lycibarbarspermidine O R = β-D-Glc3β-D-Glc Figure 15. Chemical structures of compounds 201–203. FigureFigure 15. 15.Chemical Chemical structures of of compounds compounds 201201–203–203. . Tropane Alkaloids TropaneTropane Alkaloids Alkaloids As we know, the genus Lycium has been used as both a medicine and a food for a long time in As we know, the genus Lycium has been used as both a medicine and a food for a long time in Asia,As weparticularly know, the in genus China.Lycium However,has been the usedsafety as of both Lycium a medicine has been and questioned a food for a for long some time time, in Asia, Asia, particularly in China. However, the safety of Lycium has been questioned for some time, particularlyespecially inafter China. the detection However, of thethe safetythree tropane of Lycium alkaloidshas been atropine questioned (204), hyoscyamine for some time, (205 especially), and especially after the detection of the three tropane alkaloids atropine (204), hyoscyamine (205), and afterscopolamine the detection (206 of) [101]. the three Atropine tropane and alkaloids hyoscyamine atropine were (204 identified), hyoscyamine from the ( 205fruits), andof L. scopolamine barbarum scopolamine (206) [101]. Atropine and hyoscyamine were identified from the fruits of L. barbarum (206gathered)[101]. in Atropine India, while and scop hyoscyamineolamine was were identified identified from fromL. halimifolium the fruits at of concentrationsL. barbarum gathered higher than in the India, gathered in India, while scopolamine was identified from L. halimifolium at concentrations higher whiletoxic scopolamine dose. However, was another identified scholar, from seekingL. halimifolium to verify theseat concentrations reports, demonstrated higher than that thethe toxicatropine dose. than the toxic dose. However, another scholar, seeking to verify these reports, demonstrated that the However,content of another L. barbarum scholar, from different seeking sources to verify was these just 3.0 reports, ppb—far demonstrated below the poisoning that the dose atropine [102]. It content was atropine content of L. barbarum from different sources was just 3.0 ppb—far below the poisoning dose of demonstratedL. barbarum from that none different of the sources toxic compounds was just 3.0were ppb—far detected belowin fruits, the leaves, poisoning stems and dose roots [102 of]. three It was [102]. It was demonstrated that none of the toxic compounds were detected in fruits, leaves, stems L. barbarum varieties (‘No. 1’, ‘New Big’ and ‘Amber Sweet Goji’) by densitometric TLC analysis [103]. demonstratedand roots of thatthree none L. barbarum of the toxic varieties compounds (‘No. 1’, were‘New detected Big’ and in‘Amber fruits, Sweet leaves, Goji’) stems by and densitometric roots of three L. barbarumThrough fieldvarieties investigation (‘No. 1’, and ‘New model Big’ andspecimen ‘Amber insp Sweetections, Goji’) the above by densitometric three tropane TLC alkaloids analysis were [103 ]. Through determined field to investigation be from Lycium and europaeum model specimen rather than inspections, the L. barbarum the above. Thus, three the genus tropane Lycium alkaloids is likely were determinednon-toxic, toand be consumers from Lycium can europaeum rest assuredrather that thanits use the is safeL. barbarum [104]. . Thus, the genus Lycium is likely Other than the alkaloids that have been already mentioned, there are nine others that have been non-toxic, and consumers can rest assured that its use is safe [104]. obtained from this genus, including 9-formylharman (207), 1-(methoxycarbonyl)-β-carboline (208), Other than the alkaloids that have been already mentioned, there are nine others that have perlolyrine (209), choline (210), 1β-amino-3β,4β,5α-trihydroxycycloheptane (211), betaine been obtained from this genus, including 9-formylharman (207), 1-(methoxycarbonyl)-β-carboline hydrochloride (212), nicotianamine (213), betaine (214), and melatonin (215). Compounds 207–209 (208), perlolyrine (209), choline (210), 1β-amino-3β,4β,5α-trihydroxycycloheptane (211), betaine were isolated from the fruits of L. chinense [105], while 210–212 were isolated from the root bark of hydrochlorideL. chinense [90]. (212 Compound), nicotianamine 213 was (isolated213), betaine from the (214 leaves), and and melatonin flowers of (215 L. chinense). Compounds [106], and207 214–209 wereand isolated 215 were from isolated the from fruits the of fruitsL. chinense of L. barbarum[105], while [107,108].210– The212 chemicalwere isolated structures from ofthe these root tropane bark of L. chinensealkaloids[ 90are]. listed Compound in Figure213 16.was isolated from the leaves and flowers of L. chinense [106], and 214

OH OH OH N N N O O O O

O O O 204 Atropine 205 Hyoscyamine 206 Scopolamine

N N N N N N H COOMe H O CHO 208 1-(Methoxycarbonyl)-β- OH 207 9-Formylharman carboline 209 Perlolyrine HO HO O N HO NH N+ OH 2 O- HCl 211 1β-Amino-3β,4β,5α- 210 Choline 212 Betaine hydrochloride trihydroxycycloheptane

Molecules 2017, 22, 911 17 of 33

O H H O Glc-D-β N O N N O O H H β-D-Glc O H 201 Lycibarbarspermidine M O

N H HO +H2NCF COO- O 3 O R H N HO O 202 Lycibarbarspermidine N R = β-D-Glc 203 Lycibarbarspermidine O R = β-D-Glc3β-D-Glc

Figure 15. Chemical structures of compounds 201–203.

Tropane Alkaloids As we know, the genus Lycium has been used as both a medicine and a food for a long time in Asia, particularly in China. However, the safety of Lycium has been questioned for some time, especially after the detection of the three tropane alkaloids atropine (204), hyoscyamine (205), and scopolamine (206) [101]. Atropine and hyoscyamine were identified from the fruits of L. barbarum gathered in India, while scopolamine was identified from L. halimifolium at concentrations higher than the toxic dose. However, another scholar, seeking to verify these reports, demonstrated that the atropine content of L. barbarum from different sources was just 3.0 ppb—far below the poisoning dose [102]. It was demonstrated that none of the toxic compounds were detected in fruits, leaves, stems and roots of three L. barbarum varieties (‘No. 1’, ‘New Big’ and ‘Amber Sweet Goji’) by densitometric TLC analysis [103]. Through field investigation and model specimen inspections, the above three tropane alkaloids were determined to be from Lycium europaeum rather than the L. barbarum. Thus, the genus Lycium is likely non-toxic, and consumers can rest assured that its use is safe [104]. Other than the alkaloids that have been already mentioned, there are nine others that have been obtained from this genus, including 9-formylharman (207), 1-(methoxycarbonyl)-β-carboline (208), perlolyrine (209), choline (210), 1β-amino-3β,4β,5α-trihydroxycycloheptane (211), betaine Moleculeshydrochloride2017, 22, 911(212), nicotianamine (213), betaine (214), and melatonin (215). Compounds 207–20918 of 33 were isolated from the fruits of L. chinense [105], while 210–212 were isolated from the root bark of L. chinense [90]. Compound 213 was isolated from the leaves and flowers of L. chinense [106], and 214 andand215 215were were isolatedisolated from the fruits fruits of of L.L. barbarum barbarum [107,108].[107,108 The]. The chemical chemical structures structures of these of these tropane tropane alkaloidsalkaloidsare are listedlisted inin FigureFigure 16.16.

OH OH OH N N N O O O O

O O O 204 Atropine 205 Hyoscyamine 206 Scopolamine

N N N N N N H COOMe H O CHO 208 1-(Methoxycarbonyl)-β- OH 207 9-Formylharman carboline 209 Perlolyrine HO HO O N HO NH N+ OH 2 O- HCl 211 1β-Amino-3β,4β,5α- Molecules 2017210, 22Choline, 911 212 Betaine hydrochloride 18 of 33 trihydroxycycloheptane Molecules 2017, 22, 911 18 of 33 NH2 H N OH O O NH2 H HN N OH + O HOO HN OH O N N - N + O HO OOH O N O H O N 214 Betaine - N 213 Nicotianamine O 215 Melatonin O O H O

213 Nicotianamine 214 Betaine 215 Melatonin FigureFigure 16. 16.Chemical Chemical structures structures ofof compoundscompounds 204–215215.. Figure 16. Chemical structures of compounds 204–215. 2.2.8. Anthraquinones 216–219 2.2.8. Anthraquinones 216–219 2.2.8. AnthraquinonesFour anthraquinones: 216–219 emodin (216), physcion (217), 6-hydroxyrubiadin (218), and 3-O-(2-O-α-L- Four anthraquinones: emodin (216), physcion (217), 6-hydroxyrubiadin (218), and 3-O-(2-O-α- rhamnopyranosyl-6-Four anthraquinones:O-acetyl- emodinβ-D -glucopyranosyl)-6-hydroxy-rubiadin(216), physcion (217), 6-hydroxyrubiadin (219 (218), ),listed and 3-inO -(2-FigureO-α -L17,- L-rhamnopyranosyl-6-O-acetyl-β-D-glucopyranosyl)-6-hydroxy-rubiadin (219), listed in Figure 17, rhamnopyranosyl-6-have been obtainedO from-acetyl- theβ root-D-glucopyranosyl)-6-hydroxy-rubiadin bark of L. chinense [61,109]. (219), listed in Figure 17, L. chinense havehave been been obtained obtained from from thethe rootroot barkbark of L. chinense [61,109].[61,109]. OHO OH OHO OH O OH OHO OH OHO OH O OH

OH O HO OH O OH O O HO O OH 216 Emodin 217 Physcion 218 6-Hydroxyrubiadin O O OHO O 216 Emodin 217 Physcion 218 6-Hydroxyrubiadin O OH

HO O O O O HO OO OH O O O O OH OH OH OH O O OH OH OH OH O O OH

219 3-O-(2-O-α-L-Rhamnopyranosyl-6-O-acetyl-β-D-glucopyranosyl)-6-hydroxyrubiadin 219 3-O-(2-O-α-L-Rhamnopyranosyl-6-Figure 17. Chemical structuresO-acetyl-β of-D -glucopyranosyl)-6-hydroxyrubiadincompounds 216–219. Figure 17. Chemical structures of compounds 216–219. 2.2.9. Organic Acids 220Figure–251 17. Chemical structures of compounds 216–219. 2.2.9. Organic Acids 220–251 2.2.9. OrganicTo this Acidspoint, 22032 organic–251 acids, listed in Figure 18, have been identified from the genus Lycium, whichTo thiscan point,be classified 32 organic into acids, two listedgroups: in Figurealiphatic 18, haveacids been220– identified238 and aromatic from the acidsgenus and Lycium their, whichderivativesTo thiscan be point, 239 classified–251 32. Compounds organic into two acids, groups:220– listed225 aliphaticand in 240 Figure– 244acids were18 ,220 have isolated–238 beenand from aromatic identiﬁed the fruits acids from of L.and thebarbarum their genus Lyciumderivatives[56,63,65,107,110–112];, which 239 can–251 be. Compounds classiﬁed 239 and 245 into 220 were– two225 isolated groups:and 240 from–244 aliphatic thewere leaves isolated acids of 220L. from barbarum–238 theand fruits [66]; aromatic 226of L. was barbarumacids isolated and their[56,63,65,107,110–112];from derivatives the root of 239L. chinense–251 239. and [113]; Compounds 245 227 were, 248 isolated and220 –249225 from wereand the isolated 240leaves–244 offrom L.were barbarum the isolatedfruits [66]; of L. from226 chinense was the isolated [70,114]; fruits of L.from barbarum228– the233 root and[56 of 248,63 L., 65 werechinense,107 isolated,110 [113];–112 from 227]; 239, the248and leavesand 245249 of wereL. chinense isolated isolated [115]; fr fromom 234 the, 235 the fruits, leavesand of 249 L. of–chinense251L. were barbarum [70,114]; isolated[66 ]; 228from–233 the and root 248 barkwere ofisolated L. chinense from the[53,78,93,116,117], leaves of L. chinense and [115];236–238 234 ,were 235, andisolated 249– 251from were the isolated fruits of fromL. urcomanicum the root bark [118,119] of L. .chinense [53,78,93,116,117], and 236–238 were isolated from the fruits of L. urcomanicum [118,119]. O O O O O OH OH O OH OH OH OH

220 Linoleic acid 221 Oleic acid 222 Linolenic acid O O O O 220 Linoleic acid 221 Oleic acid 222 Linolenic acid O O O O Me(H2C)28 OH Me(H2C)12 OH Me(H2C)14 OH Me(H2C)16 OH Me(H223 C)Melissic OHacid Me(H224 C)Myristic OHacid Me(H225 C)Palmitic OHacid Me(H226 C)Stearic acidOH 2 28 2 12O 2 14 O 2 16 223 MelissicO acid 224 Myristic acid 225 Palmitic acid 226 StearicO O acid O HO O O OH OH O O OH HO HO OH 227 Pentanoic acid OH OH O OH 230 Malonic acid OH 228 Lactic acid 229 Oxalic acid HO OH 227 Pentanoic acid OH O 230 Malonic acid 228 Lactic acid 229 Oxalic acid

Molecules 2017, 22, 911 18 of 33

NH2 H N OH O O HN + HO OH O N N - N O O O H O

213 Nicotianamine 214 Betaine 215 Melatonin

Figure 16. Chemical structures of compounds 204–215.

2.2.8. Anthraquinones 216–219

Four anthraquinones: emodin (216), physcion (217), 6-hydroxyrubiadin (218), and 3-O-(2-O-α-L- rhamnopyranosyl-6-O-acetyl-β-D-glucopyranosyl)-6-hydroxy-rubiadin (219), listed in Figure 17, have been obtained from the root bark of L. chinense [61,109].

OHO OH OHO OH O OH

OH O HO OH O O O 216 Emodin 217 Physcion 218 6-Hydroxyrubiadin O OH

HO O O O O O OH

OH OH OH O O OH

219 3-O-(2-O-α-L-Rhamnopyranosyl-6-O-acetyl-β-D-glucopyranosyl)-6-hydroxyrubiadin

Figure 17. Chemical structures of compounds 216–219.

2.2.9. Organic Acids 220–251

Molecules 2017, To22, this 911 point, 32 organic acids, listed in Figure 18, have been identified from the genus Lycium, 19 of 33 which can be classified into two groups: aliphatic acids 220–238 and aromatic acids and their derivatives 239–251. Compounds 220–225 and 240–244 were isolated from the fruits of L. barbarum 226 was[56,63,65,107,110–112]; isolated from the root 239 and of L.245 chinense were isolated[113 from]; 227 the, 248 leavesand of 249L. barbarumwere isolated[66]; 226 was from isolated thefruits of L. chinensefrom[70 the,114 root]; of228 L. –chinense233 and [113];248 227were, 248 isolatedand 249 were from isolated the leaves from the of fruitsL. chinense of L. chinense[115 ];[70,114];234, 235 , and 249–251228were–233 isolated and 248 were from isolated the root from bark the leaves of L. chinenseof L. chinense[53 [115];,78,93 234,116, 235,117, and], and249–251236 were–238 isolatedwere isolated from the root bark of L. chinense [53,78,93,116,117], and 236–238 were isolated from the fruits of from theL. fruits urcomanicum of L. urcomanicum [118,119]. [118,119].

O O O

OH OH OH

220 Linoleic acid 221 Oleic acid 222 Linolenic acid O O O O

Me(H2C)28 OH Me(H2C)12 OH Me(H2C)14 OH Me(H2C)16 OH 223 Melissic acid 224 Myristic acid 225 Palmitic acid 226 Stearic acid O O O O O HO OH OH OH HO OH Molecules227 2017 Pentanoic, 22, 911 acid OH O 230 Malonic acid19 of 33 228 Lactic acid 229 Oxalic acid O OH O O OH OH OH HO HO HO O O O 231 Malic acid 232 Succinic acid 233 Fumaric acid OH O OH O OH OH O

Me(H2C)10 OH 236 Dodecanoic acid 235 (9S,10E,12Z,15Z)-9- 234 Dimorphecolic acid Hydroxyoctadeca-10,12,15- trienoic acid OH O O O OH Me(H2C)18 OH Me(H2C)13 OH 237 Arachidic acid 238 Pentadecanoic acid 239 Salicylic acid COOCH3 O HO HO O OH OH HO O H COOH 240 p-Hydroxybenzoic acid HO OH 241 p-Coumaric acid OH 242 Methyl chlorogenate O O O HO MeO MeO OH OH OH HO HO HO 243 Caffeic acid 244 Ferulic acid 245 Vanillic acid COOH HO O O OH O HO O O OH OH HO O HO OH OH OH HO OH 247 Protocatechuic acid 248 Citric acid 246 Chlorogenic acid O MeO O O O-β-D-Glc MeO OH O(CH2)17Me HO OMe HO 249 Cinnamic acid 251 Stearyl ferulate 250 β-D-Glucopyranosyl syringate

Figure 18. Chemical structures of compounds 220–251. Figure 18. Chemical structures of compounds 220–251. 2.2.10. Terpenoids 252–290 Thirty-seven terpenoids, listed in Figures 19−21 and Tables 11 and 12, have been found in the genus Lycium, mainly including monoterpenes 252–256, sesquiterpenes 257–263, diterpenoids 264–274, and carotenoids 275–290. Among them, carotenoids are one of the more important constituents of the Lycium fruits. Thus compounds 256 and 275–286 were isolated from the fruits of L. barbarum [120–123]; 253, 254, 258, 259 and 287–290 were isolated from the fruits of L. chinense [120,121,124–126]; 252 and 264–272 were isolated from the leaves of L. chinense [127,128]; 255, 258 and 273–274 were isolated from the root bark of L. chinense [80,116]; 260 and 261 were isolated from the leaves of L. halimifolium [23]; and 262 and 265 were isolated from the leaves of L. barbarum [129].

Molecules 2017, 22, 911 20 of 33

2.2.10. Terpenoids 252–290 Thirty-seven terpenoids, listed in Figures 19–21 and Tables 11 and 12, have been found in the genus Lycium, mainly including monoterpenes 252–256, sesquiterpenes 257–263, diterpenoids 264–274, and carotenoids 275–290. Among them, carotenoids are one of the more important constituents of the Lycium fruits. Thus compounds 256 and 275–286 were isolated from the fruits of L. barbarum [120–123]; 253, 254, 258, 259 and 287–290 were isolated from the fruits of L. chinense [120,121,124–126]; 252 and 264–272 were isolated from the leaves of L. chinense [127,128]; 255, 258 and 273–274 were isolated from the root bark of L. chinense [80,116]; 260 and 261 were isolated from the leaves of L. halimifolium [23]; andMolecules262 and 2017265, 22, 911were isolated from the leaves of L. barbarum [129]. 20 of 33

O O O O

O OH O O HO 252 7,8-Dihydro-3-hydroxy-β- 253 L-Monomethyl glutarate 254 L-Dimethyl glutarate ionone O OH O O-Glc-6Api OH O O O OH OH O OH O HO 255 Monoterpene glycoside 256 L-Monomethyl succinate 257 10-O-(β-D-Apiofuranosyl)-(1 → 6)-(β-D-glucopyranosyl)- pinanediol O O O

258 (-)-1,2-Didehydro-α- 260 Damascenone cyperone 259 Solavetivone C O O-β-D-Glc O HO HO OH OH 261 3-(2,4-Dihydroxy-2,6,6- OH trimethylcyclohexylidene)-1-methylprop-2- OH enyl-β-D-glucopyranoside 262 Lyciumionoside A O

OH OGlc HO O O HO HO O HO O OGlc OH 266 Lyciumosides III HOHO 263 Lyciumionoside B

Figure 19. Chemical structures of compounds 252–263, 266. Figure 19. Chemical structures of compounds 252–263, 266.

Table 11. Chemical structures of compounds 264–265, 267–270 and 272–273.

OR1 OR2

264–265, 267–270, 272–273 No. Compounds R1 R2 Source 264 Lyciumosides I Glc Glc L. chinense 265 Lyciumosides II Glc2-Glc Glc L. chinense 267 Lyciumosides IV Glc Glc4-Rha L. chinense 268 Lyciumosides V Glc6-Rha Glc L. chinense 269 Lyciumosides VI Glc6-Rha Glc4-Rha L. chinense 270 Lyciumosides VII Glc2-Rha(6-Glc) Glc L. chinense 272 Lyciumosides IX Glc 6-O-malonyl-Glc L. chinense 273 Capsianoside II Rha3-Glc6-Rha Glc2-Glc L. chinense

Molecules 2017, 22, x 21 of 33 Molecules 2017, 22, x 21 of 33 O O OH OGlc OH HO OGlc O O HO HO O O HOHO O HO O O OGlc HO O OH OGlc266 Lyciumosides III OH 266 Lyciumosides III HOHO 263HO HLyciumionosideO B 263 Lyciumionoside B Figure 19. Chemical structures of compounds 252–263, 266. Molecules 2017, 22, 911 Figure 19. Chemical structures of compounds 252–263, 266. 21 of 33 Table 11. Chemical structures of compounds 264–265, 267–270 and 272–273. Table 11. Chemical structures of compounds 264–265, 267–270 and 272–273. Table 11. Chemical structures of compounds 264–265, 267–270 and 272–273.

OR1 OR1 OR2 OR2

264–265, 267– 270,272–273 264–265, 267–270,272–273 No. Compounds R1 R2 Source No. Compounds R1 R2 Source 264No. Lyciumosides Compounds I Glc R1 GlcR2 L. Sourcechinense 264265 LyciuLyciumosidesmosides III GlcGlc2-Glc Glc L. chinense 264 Lyciumosides I Glc2 Glc L. chinense 265 Lyciumosides II Glc -Glc Glc4 L. chinense 267265 Lyciumosides IV Glc2 Glc -Rha L.L. chinense chinense Lyciumosides II Glc -Glc 4Glc 267 Lyciumosides IV Glc6 Glc -Rha L. chinense 268267 LyciumosidesLyciumosides V IV Glc Glc-Rha GlcGlc4-Rha L.L. chinense chinense 6 268 Lyciumosides V Glc6-Rha Glc4 L. chinense 269268 LyciumosidesLyciumosides VI V GlcGlc6--RhaRha GlcGlc-Rha L.L. chinense chinense 6 4 269270269 LyciumosidesLyciumosides VIIVI VI GlcGlc2Glc-Rha(6-Rha-Rha6-Glc) Glc GlcGlc4-Rha-Rha L.L. chinense chinense 2 6 270272270 LyciumosidesLyciumosidesLyciumosides VII IX VII GlcGlc2--Rha(Rha(Glc 6-Glc)-Glc) 6-O-malonylGlcGlc -Glc L.L. chinense chinense 272273272 LyciumosidesCapsianosideLyciumosides IXII IX Rha3-Glc Glc 6-Rha 6 6--OO-malonylGlc-malonyl-Glc2-Glc- Glc L.L. chinense chinense 273273 CapsianosideCapsianoside II II RhaRha33--GlcGlc66-Rha-Rha Glc Glc22-Glc-Glc L.L. chinense chinense Molecules 2017, 22, 911 21 of 33

OH OH OGOGlclc OH OGlc OGOGlclc OGlc

O OHOH H O H O 271OH Lyciumosides VIII H 271 Lyciumosides VIII 274274 Diterpene Diterpene sugiol sugiol 271 Lyciumosides VIII 274 Diterpene sugiol FigureFigure 20. 20.Chemical Chemical structures structures of compounds of compounds 271 271 and and 274 274. . Figure 20 20.. Chemical structures of compounds 271 and 274. TableTable 12. 12.Chemical Chemical structures structures of compounds of compounds 275 275–282–282. . Table 12.12. Chemical structures of compounds 275–282.. R2 R2 R2

R1 R1 275–282 R No. 1 Compounds 275– R2821 R2 Source 275–282 No.No.275 Compounds Compoundsβ-Carotene R R11 H RR22 H SourceL. barbarum No. Compounds R1 R2 Source 275276 ββ--CryptoxanthinCarotene H OH H H L. barbarumL. barbarum 275275 β-Carotene-Carotene H H H L.L. barbarum 276276277 β-βCryptoxanthin-CryptoxanthinZeaxanthin OH OHOH H OH L. barbarumL. barbarum 276 β-Cryptoxanthin OH H L. barbarum 277277278 ZeaxanthinZeaxanthinZeaxanthin monopalmitate OCO(CHOH OH 2)14CH3 OHOH L. barbarumL. barbarum 277278 ZeaxanthinZeaxanthin monopalmitate OCO(CHOH ) CH OH L.L. barbarum 278279 ZeaxanthinZeaxanthin monopalmitate dipalmitate OCO(CH OCO(CH2)14CH2)14CH3 3 OCO(CHOH 2)14CH3 L. barbarumL. barbarum 278279 ZeaxanthinZeaxanthin monopalmitate dipalmitate OCO(CH OCO(CH2))14CHCH3 OCO(CHOH2) 14CH3 L.L. barbarum 279280 ZeaxanthinZeaxanthin dipalmitate monomyristate OCO(CH OH2)14CH 3 OCO(CH OCO(CH2)14CH2)12CH3 3 L. barbarumL. barbarum 280 Zeaxanthin monomyristate OH OCO(CH ) CH L. barbarum 279 Zeaxanthin dipalmitate OCO(CH2)14CH3 OCO(CH22)1214CH33 L. barbarum 281 Zeaxanthin dimyristate OCO(CH2)12CH3 OCO(CH2 122)12CH3 3 L. barbarum 280281 ZeaxanthinZeaxanthin monomyristate dimyristate OCO(CHOH2 )12CH3 OCO(CH2))12CHCH3 L. barbarum 280 Zeaxanthin monomyristate OH OCO(CH2)12CH3 L. barbarum 281282282 Zeaxanthinββ-Cryptoxanthin-Cryptoxanthin dimyristate palmitate palmitate OCO(CH OCO(CH OCO(CH2)1214CH2CH)14CH3 3 OCO(CHH 2)H12 CH3 L. barbarumL. barbarum 281 Zeaxanthin dimyristate OCO(CH2)12CH3 OCO(CH2)12CH3 L. barbarum 282 β-Cryptoxanthin palmitate OCO(CH2)14CH3 H L. barbarum 282 β-Cryptoxanthin palmitate OCO(CH2)14CH3 H L. OHbarbarum

HO 283 Lutin OCO(CH2)14CH3 O

O H3C(H2C)14OCO 284 Violaxanthin dipalmitate OCO(CH2)14CH3

H3C(H2C)14OCO 285 Mutatoxanthin dipalmitate OCO(CH2)14CH3

O H3C(H2C)14OCO 286 Antheraxanthin dipalmitate

Molecules 2017, 22, 911 21 of 33

OGlc OH OGlc

O OH H 271 Lyciumosides VIII 274 Diterpene sugiol

Figure 20. Chemical structures of compounds 271 and 274.

Table 12. Chemical structures of compounds 275–282.

R1 275–282 No. Compounds R1 R2 Source 275 β-Carotene H H L. barbarum 276 β-Cryptoxanthin OH H L. barbarum 277 Zeaxanthin OH OH L. barbarum 278 Zeaxanthin monopalmitate OCO(CH2)14CH3 OH L. barbarum 279 Zeaxanthin dipalmitate OCO(CH2)14CH3 OCO(CH2)14CH3 L. barbarum 280 Zeaxanthin monomyristate OH OCO(CH2)12CH3 L. barbarum Molecules 2017, 22, 911 22 of 33 281 Zeaxanthin dimyristate OCO(CH2)12CH3 OCO(CH2)12CH3 L. barbarum 282 β-Cryptoxanthin palmitate OCO(CH2)14CH3 H L. barbarum

HO 283 Lutin OCO(CH2)14CH3 O

O H3C(H2C)14OCO 284 Violaxanthin dipalmitate OCO(CH2)14CH3

H3C(H2C)14OCO 285 Mutatoxanthin dipalmitate OCO(CH2)14CH3

O H3C(H2C)14OCO Molecules 2017, 22, 911 22 of 33 286 Antheraxanthin dipalmitate OH HO OH

O O O OOH O O O O OH OH O OH OH HO O OH OH O O OH OH OH 287 Lyciumtetraterpenic hexaarabinoside OH HO OH

O O O O O

O OH OOH HO O O OH O OH O OH OH O OH OH OH OH 288 Tetraterpenyl hexaarabinoside OH

HO 289 Lutein OH

290 Mutatoxanthin Figure 21. Chemical structures of compounds 283–290. Figure 21. Chemical structures of compounds 283–290. 2.2.11. Sterols, Steroids, and Their Derivatives 291–347 2.2.11. Sterols,Fifty-seven Steroids, andsterols, Their steroids, Derivatives and their 291derivatives–347 291–347, listed in Figure 22, have been identified from the genus Lycium, mainly from the seeds and the fruits. Compounds 293 and 343 were Fifty-sevenidentified sterols, from steroids,the flowers and of L. their barbarum derivatives [130], 291291–292–347; 295,, listed 298, 319 in– Figure324 and 22337, have–339 were been identiﬁed from the genusidentifiedLycium from, the mainly fruits of from L. chinense the seeds [23,35,52,63,107,131]; and the fruits. 341 342 Compounds, 346 and 347 were293 andidentified343 fromwere identiﬁed the leaves of L. chinense [132,133]; 336 and 340 were identified from the root bark of L. chinense [80,121]; 294 was identified from the seed of L. ciliatum [66]; all others were identified from the seed of L. chinense [134–137] 344 and 345 were identified from the seeds of L. barbarum [138].

H H H H H

H H H H HO HO HO H 291 β-Sitosterol 292 Campesterol 293 Lanosterol

Molecules 2017, 22, 911 22 of 33

OH HO OH

O O O OOH O O O O OH OH O OH OH HO O OH OH O O OH OH OH 287 Lyciumtetraterpenic hexaarabinoside OH HO OH

O O O O O

O OH OOH HO O O OH O OH O OH OH O OH OH OH OH 288 Tetraterpenyl hexaarabinoside OH

HO 289 Lutein OH

290 Mutatoxanthin Molecules 2017, 22, 911 Figure 21. Chemical structures of compounds 283–290. 23 of 33

2.2.11. Sterols, Steroids, and Their Derivatives 291–347 from the flowersFifty-seven of L. barbarum sterols, steroids,[130], 291and –their292 ;derivatives295, 298 291, 319–347–,324 listedand in Figure337– 33922, havewere been identified from the fruits of L.identified chinense from [the23 genus,35,52 Lycium,63,107, mainly,131 from]; 341 the seeds 342, and346 theand fruits.347 Compoundswereidentified 293 and 343 were from the leaves identified from the flowers of L. barbarum [130], 291–292; 295, 298, 319–324 and 337–339 were of L. chinenseidentified[132,133 from]; the336 fruitsand of L. 340chinensewere [23,35,52,63,107,131]; identified from341 342,the 346 and root 347 were bark identified of L. from chinense [80,121]; 294 was identifiedthe leaves from of L. chinense the seed[132,133]; of 336L. and ciliatum 340 were [identified66]; all from others the root were bark of identified L. chinense [80,121]; from the seed of L. chinense [134294– 137was] identified344 and from345 thewere seedidentified of L. ciliatum from [66]; all the others seeds were of idenL. barbarumtified from the[138 seed]. of L. chinense [134–137] 344 and 345 were identified from the seeds of L. barbarum [138].

H H H H H

H H H H HO HO HO H Molecules 2017291, 22β, 911-Sitosterol 23 of 33 292 Campesterol 293 Lanosterol

H H H H H H

H H H H H H HO HO HO

294 24-Ethylidenecholesterol 295 Cholesterol 296 24-Methylcholesterol

H H H H H H H H H H H H HO HO HO 299 24-Methylcholesta-5,24- 297 24-Ethylcholesterol 298 Stigmasterol dien-3β-ol

H H H H H H H H H H H H HO HO HO 302 24-Ethylcholesta-5,24-dien- 300 28-Isofucosterol 301 24-Methylidenecholesterol 3β-ol

H H H H H H

H H H H H H HO HO HO H H H 303 Cholestan-3β-ol 304 24-Methylcholestan-3β-ol 305 24-Ethylcholestan-3β-ol

H H H H H

H H HO HO HO H H H 306 Cholest-7-en-3β-ol 307 Cycloartanol 308 Cycloartenol

H H H H H

HO HO HO H H H 309 24-Methylidenecycloartanol 310 31-Norcycloartenol 311 31-Norlanosterol

H H H H

HO HO HO H H H 312 31-Norcycloartanol 313 31-Norlanost-8-enol 314 31-Norlanost-9(11)-enol

H H H H

H H HO HO H HO H H 315 24-Methyl-31-norlanost- 317 4α-24-Dimethylcholesta- 316 4α-Methylcholest-8-en-3β-ol 9(11)-enol 7,24-dien-3β-ol

Figure 22. Cont.

Molecules 2017, 22, 911 24 of 33 Molecules 2017, 22, 911 24 of 33

H H H H H H H HO H H H H H HO HO

318 24-Ethyl-4α-methylcholesta- 319 Cholest-5-en-3β-ol 320 24-Methylcholest-5-en-3β-ol 7,24-dien-3β-ol

H H H H H H H H H H H H HO HO 321 24-Ethylcholesta-5,22-dien- HO 323 24-Ethylidenecholest-5-en- 322 24-Ethylcholest-5-en-3β-ol 3β-ol 3β-ol

H H H

H H H H H H HO HO HO 324 24-Ethylidenecholest-7-en- H H 3β-ol 325 Lophenol 326 24-Ethyllophenol

H H H

H H H H H H HO HO HO H H H 327 24-Methyllophenol 328 Gramisterol 329 Citrostadienol

H H H H

HO HO HO H H H 330 Cycloeucalenol 331 Obtusifoliol 332 Lanost-8-enol

H H

H H HO H H H HO 334 24-Methylenelanost-8-enol(24- HO H H methylenelanost-8-en-3β-ol) 333 β-Amyrin 335 Lupeol

H H H H H H H H O H Glc-D-β-O O 337 β-Sitosterol β-D-glucopyranoside 336 5α-Stigmastane-3,6-dione

Figure 22. Cont.

Molecules 2017, 22, 911 25 of 33 Molecules 2017, 22, 911 25 of 33

H H OR HO O-β-D-Glc O H H H HO O H O HO OH H 338 β-Sitosterol 3-O-(6-palmitoyl-β-D- H H O Glc-D-β-Gal2-D-β-O 340 Furostanol glycoside R1 = β-D-Gal2-β-D- glucopyranoside) R = (CH2)14Me Glc,R2 = β-D-Glc 339 β-Sitosterol 3-O-(6-stearoyl-β-D-glucopyranoside) O

R = (CH2)16Me

H H O HO H O O O O H H O O H H H H H H H H H H HO OH O 343 Diosgenin OH O 342 Lyciumsubstanz B 341 Lyciumsubstanz A H H N O N O

OMe O O Glc' Glc H H Glc' Glc H H HO HO HO HO O O H H O O H H HO HO HO O O HO O O OH HO O H OH HO O H Me Me O HO O HO HO HO OH OH Rha Rha 344 Lycioside A 345 Lycioside B

R H

H O O O H

H H

OH O 346 Withanolide A R=OH 347 Withanolide B R=H

Figure 22. Chemical structures of compounds 291–347. Figure 22. Chemical structures of compounds 291–347.

2.2.12. Peptides 348–352 2.2.12. Peptides 348–352 Five peptides have been isolated from the root bark of L. chinense [80,139], including one dipeptide,Five peptides lyciumamide have been (348 isolated), and four from octapeptides, the root bark called of L. chinense lyciumins[80 ,A–D139], (compounds including one 349 dipeptide,–350), lyciumamideillustrated in ( 348Figure), and 23. four octapeptides, called lyciumins A–D (compounds 349–350), illustrated in Figure 23.

Molecules 2017, 22, 911 26 of 33 Molecules 2017, 22, 911 26 of 33 Molecules 2017, 22, 911 26 of 33 O O OH O HO O OH OHO O NH O H N NH O N N O O O H H H NH N N N N N O H O O HO N H H O NH N N HN H O N N O O H N O H HO N O N HN H O O O O O 349 HLyciumins A 348 LyciumamideO 349 Lyciumins A 348 Lyciumamide OH HO O OH O HN OHO O HO H N O O HN O N N O O HO H H H N H N NH O N N O N N N O H O N O N H H O N N H H H NH N HO O N NH N N N N H O H N O O O H N H O N H O N HO H N O NH N N HO H O N O H O N O O O H O O N H H HO N O N H O O O O 350H Lyciumins B 351 Lyciumins C

350 Lyciumins B 351OH Lyciumins C HO O OH OHO O H O N N N O O H H H NH N N N N N O H O N H H O NH N N H O N N O O H N O H O N H O N O O H O 352 Lyciumins D 352 Lyciumins D Figure 23. Chemical structures of compounds 348–352. Figure 23. Chemical structures of compounds 348–352. Figure 23. Chemical structures of compounds 348–352. 2.2.13. Other Compounds 353–355 2.2.13. Other Compounds 353–355 2.2.13. Other Compounds 353–355 Other than what has already been mentioned, a few other chemical constituents, listed in Figure 24, Other than what has already been mentioned, a few other chemical constituents, listed in Figure 24, wereOther also isolatedthan what from has thealready genus been Lycium mentioned,. Digupigan a few A other (353 ),chemical 2-O-(β- Dco-glucopyranosyl)ascorbicnstituents, listed in Figure acid 24, were also isolated from the genus Lycium. Digupigan A (353), 2-O-(β-D-glucopyranosyl)ascorbic acid were(354) also and isolated p-hydroxybenzaldehyde from the genus Lycium (355) .also Digupigan have been A (obtained353), 2-O -(fromβ-D-glucopyranosyl)ascorbic the root bark of L. chinense acid, the (354) and p-hydroxybenzaldehyde (355) also have been obtained from the root bark of L. chinense, (354fruits) and of L. p-hydroxybenzaldehyde chinense, and the fruits of(355 L. )barbarum also have [75,76,121,137,140,141], been obtained from the respectively. root bark of ManyL. chinense minerals,, the the fruits of L. chinense, and the fruits of L. barbarum [75,76,121,137,140,141], respectively. Many fruitsamino of acids,L. chinense, and andproteins the fruits have of also L. barbarum been found [75,76,121,137,140,141], in the genus Lycium, respectively. such as Ca,Many Mg, minerals, Zn, Fe, minerals, amino acids, and proteins have also been found in the genus Lycium, such as Ca, Mg, Zn, Fe, aminoaminoethanesulfonic acids, and proteins acid, γhave-aminobutyric also been acid found (GABA), in the Mn-SOD, genus Lycium, etc. [121,142,143]. such as Ca, Mg, Zn, Fe, aminoethanesulfonic acid, γ-aminobutyric acid (GABA), Mn-SOD, etc. [121,142,143]. aminoethanesulfonic acid, γ-aminobutyric acid (GABA), Mn-SOD, etc. [121,142,143]. O O OH HO O O HO OH HO HO O OH HO O O OH O OH HO HO O OH O OH O OH HO OH H CHO O O OH OH OH HO 355 p-Hydroxybenzaldehyde O OH OH OH H CHO HO OH OH 354 2-O-(OHβ-D-Glucopyranosyl)- 355 p-Hydroxybenzaldehyde OH 353 Digupigan A OH 354 2-ascorbicO-(β-D-Glucopyranosyl)- acid 353 Digupigan A ascorbic acid Figure 24. Chemical structures of compounds 353–355. Figure 24. Chemical structures of compounds 353–355. Figure 24. Chemical structures of compounds 353–355. 3. Discussion 3. Discussion 3. DiscussionLycium species are of valuable medicinal, nutritional and functional significance, and have been studiedLycium in speciesterms of are their of valuable chemical medicinal, compounds. nutritional Phytochemical and functional investigations significance, on andeight have different been Lycium species are of valuable medicinal, nutritional and functional signiﬁcance, and have been studiedspecies, inhave terms resulted of their in thechemical isolation compounds. of at least Phytochemical355 constituents investigations up to July of on2016. eight Research different on studied in terms of their chemical compounds. Phytochemical investigations on eight different species, species,chemical have compounds resulted inhas the concentrated isolation of mainlyat least on355 L. constituents barbarum and up L.to chinenseJuly of 2016.. Therefore, Research future on have resulted in the isolation of at least 355 constituents up to July of 2016. Research on chemical chemicalphytochemistry compounds research has should concentrated be focused mainly on the on other L. barbarum species inand Lycium L. chinense genus. .In Therefore, addition, diversefuture phytochemistryplant parts (i.e., research the flowers, should leaves, be focused seeds) haveon the al otherso been species testified in Lycium to contain genus. new In constituents,addition, diverse most plantof which parts possess (i.e., the the flowers, novel chemical leaves, seeds) structures. have alPolysaccharidesso been testified play to contain a particularly new constituents, significant role most in of which possess the novel chemical structures. Polysaccharides play a particularly significant role in

Molecules 2017, 22, 911 27 of 33 compounds has concentrated mainly on L. barbarum and L. chinense. Therefore, future phytochemistry research should be focused on the other species in Lycium genus. In addition, diverse plant parts (i.e., the flowers, leaves, seeds) have also been testified to contain new constituents, most of which possess the novel chemical structures. Polysaccharides play a particularly significant role in exerting pharmacological actions. A specific class of polysaccharides, abbreviated as LBP, is used as biomarker in the 2015 Chinese Pharmacopoeia as a measure by which wolfberry is qualified. At present, LBP in products or in pharmacological studies usually are polysaccharide mixtures with heterogeneity and polydispersity. On the other hand, development of new separation, detection techniques will greatly benefit the phytochemical isolation and structural elucidation of LBP. There is a growing recognition that not only the LBP,but also the plant secondary metabolites may have the potential active ingredients, while most of the research on goji berry was LBP rather than small molecule substances, so more intensive studies of goji berry are required to shed some light on these compounds.

Acknowledgments: This research was financially supported by The National Science Fund for Distinguished Young Scholars of China (81325023). Author Contributions: D.Q. and L.H. conceived and designed the paper; D.Q. wrote the paper and L.H. reviewed the paper. Y.Z. and G.Y. discussed the results and commented on the manuscript. All authors read and approved the final manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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