Isolation of Naturally Occurring Novel Isoflavonoids

Natural Product Reports c8np00069g

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1 Isolation of naturally occurring novel isoflavonoids: an update Nawaf Al-Maharik* This review covers the literature concerning the isolation and identification of new naturally occurring isoflavonoids from Leguminosae and non-Leguminous species between 2012– 2017.

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1 Isolation of naturally occurring novel isoﬂavonoids: 1 an update† Cite this: DOI: 10.1039/c8np00069g 5 1 Nawaf Al-Maharik * 5

Covering: Jan. 2012 to Dec. 2017 10 10 This review describes the 391 new isoflavonoids isolated and identified from natural sources between Received 31st July 2018 January 2012 and December 2017, commenting on their sources, identification and biological activities. DOI: 10.1039/c8np00069g Due to the length of this review, the synthesis of isoflavonoids is not included. Furthermore, new rsc.li/npr applications of analytical techniques for the isolation and identification of isoflavonoids are also reviewed. 15 15 1. Introduction such as isoavans, isoavanones, isoavanols, isoav-3-enes, 2. Isolation and identication and more complex structures including pterocarpans, rote- 3. Isoavones noids, coumestans, arylcoumarins, coumaronochromones, 2- 3.1. Simple isoavones arylbenzofurans and isoavonoid dimers. Isoavonoids vary in 20 20 3.2. Isoavone glycosides several compounds by modication of their basic skeletons 3.3. Complex isoavones through further hydroxylation, methylation, prenylation, acyl- 4. Pterocarpans ation and glycosylation.1 In plants, isoavonoids occur as 5. Isoavanones aglycones or as glycosides (commonly with glucose, rhamnose     25 6. Iso avans, iso avanols and iso av-3-enes and apiose as the sugar constituent), where the iso avonoid 25 7. Rotenoids glycosides are less prevalent than aglycones. 8. Coumaronochromones Isoavonoids exhibit a wide range of biological activities 9. 3-Arylcoumarins including antioxidant, anticarcinogenic, and antiproliferative 10. Coumestans activities, reduction in osteoporosis and cardiovascular disease, 30 11. 2-Arylbenzofurans and is used the treatment of menopause symptoms.2–5 They are 30 12. Isoavonoid dimers, heterodimers and conjugates classically dened as dietary antioxidants, i.e. compounds that 13. Conclusions may protect against oxidative stress linked to inammation and 14. Species checklist the risk of macromolecule damage by free radicals and related 15. Conicts of interest oxygen and nitrogen-based oxidizing agents.2,3 In contrast to 35 16. Acknowledgements other groups of avonoids, the occurrence of isoavonoids in 35 17. References the plant kingdom is relatively sparse, possibly due to the sporadic incidence of isoavone synthase. The majority of natural isoavonoids (more than 1600 at the end of 2011) have 1. Introduction been reported from the subfamily Papilionoideae of the Legu- 40 40 minosae. However, isoavonoids have also been identied from  Iso avonoids, which are plant secondary metabolites, are non-leguminous plants, including Iridaceae, Moraceae, Lil- characterized by a B-ring attached at the C-3 position of their C- iaceae, Compositae and Melicacea.5 Comprehensive reviews of ring (3-phenylchroman skeleton). This is biogenetically estab- advances on isoavonoid chemistry including their isolation,  lished by the 2-hydroxyiso avanone synthase catalysed aryl modern isolation techniques, biosynthesis and synthesis have 45  1 45 migration of the 2-phenylchroman skeleton of avonoids. been periodically published.6–12 However, the current review is  ff Iso avones are further transformed at di erent phases in plants concerned with the isolation of isoavonoids from Legumino-  ff  to yield een structurally di erent subclasses of iso avonoids, sae and non-leguminous sources, covering the literature published between January 2012 and December 2017 using the 50 Department of Forensic Sciences, Al Istilal University, Jericho, Palestinian Authority. SciFinder, Reaxys and PubMed (http://www.ncbi.nlm.nih.gov/ 50 E-mail: [email protected] entrez/query.fcgi) databases. † Electronic supplementary information (ESI) available. See DOI: 10.1039/c8np00069g

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 1 Natural Product Reports Review

genistein, irilone, and maackiain, with purity greater than 1 2. Isolation and identification 1 95.31% were successfully extracted.13 This section highlights the advances in the separation and A new, reproducible, sensitive and reliable HPLC-DAD identication of isoavonoids from natural sources using approach was used for the quantication of daidzein, genistein, 5 hyphenated analytical techniques. The growing interest in soy glycitein and their corresponding 7-O-glucosides in soy extracts 5 food products due to their biological effects including the without the need for sample pretreatment.14 The approach relation between consumption of isoavone-rich food and showed high selectivity and was linear over the range of 1.5–150 reduction in cancer, has led to the growing demand for the mgmL 1 for all the isoavones. The robustness study found that quantitative and qualitative determination of isoavones in soy the range of recovery was 95–102% and that the ow rate was the 10 foods. The presence of isoavonoids in traditional medicinal only critical factor.14 This method proved to be a suitable and 10 plants has stimulated the growing search for biologically active reliable alternative for quality control of soy extracts. Additionally, compounds from both legume and nonlegume sources. Verardo et al. reported the development of a simple reverse-phase Conventional methods of purifying natural isoavonoids RP-HPLC-DAD using pentauorophenyl particles (PFP) for the involve extraction and separation processes, which are per- separation, determination and quantication of free and bound 15 formed independently. polyphenolic compounds in soy isoavone concentrate.15 The 15 Zhang et al. reported the development of a novel procedure detection (LOD) and quantication limits (QOD) for the major based on ultrasonic-assisted dynamic extraction (UADE) isoavones and their glycoside ranged from 0.028–0.044 mgmL 1 combined with two countercurrent chromatography systems and 0.093–0.157 mgmL 1, respectively.15 A new, simple and cost- (parallel countercurrent chromatography, PCCC).13 This new effective analytical method based on hyphenated matrix solid- 20 20 method was used for fractionation and purication of iso- phase dispersion extraction (MSPD) MSPD-LC-UV/DAD was avones from red clover, offering the possibility for simulta- developed and validated for the simultaneous determination and neous extraction, solvent conguration, purication, and quantication of daidzein, genistein, glycitein and their 7-O-b-D- isolation of the desired compounds. The lower aqueous phase glucopyranoside in soybeans our with linearity within the of the two-phase solvent system, which was prepared by auto- concentration range of 0.02–2.0 mgmL 1.16 The limits of detection 25 25 mating the equipment, was used as the UADE solution and as and quantitation were 0.057 mgmL 1 (genistin and glycitein), the mobile phase for PCCC. Once the extraction and purica- 0.124 mgmL 1 (genistein), 0.190 mgmL 1 (genistin and glycitein), tion steps were completed, the puried sample was pumped and 0.410 mgmL 1 (genistein). A simple and efficient reverse into the countercurrent chromatography 1 (CCC1) column for phase HPLC-UV approach was developed for the simultaneous 30 the rst isolation step. During CCC1 separation, the sample was examination and quantication of nine isoavonoids in the 30 enriched, puried and then pumped into the CCC2 column for Chinese Huangqi-Gegen herbal pair using a Kromasil C18 column the second isolation step. Aer completion of the rst cycle of (4.6 250 mm, i.d.; 5 mm). This method was veried to be linear UADE-PCCC, the second-cycle experiments were performed. for the nine isoavonoids identied.17 Furthermore, a novel Using this sequence, ve target compounds, daidzein, prunetin, method utilizing freezing as an effective clean-up step with ultra- 35 high performance liquid chromatography-tandem mass spec- 35 trometry (SPE-UHPLC-MS/MS triple quadrupole) was applied to quantify the major isoavonoids in 48 lentil samples successfully Nawaf Al-Maharik received his with high recoveries ranging from 54.4–114%.18 Anewultra-high PhD on the Synthesis of pressure liquid chromatography (UV-UPLC™)methodwas 40 Isoavonoid-Derivatives for developed for the fast and reliable quantication of total agly- 40 Immunoassay in 2000 at the conesinsoybeansaer enzymatic hydrolysis applying Helix University of Helsinki (Finland). pomatia digestive juice with a total runtime of 8 minutes. The He subsequently joined the group major isoavones (daidzein, glycitein, and genistein) were sepa- of Lars Engman at Uppsala rated within only three minutes; thus, UV-UPLC™ proved to be 45 45 University (Sweden), and in 2001 superior due to its signicantly shorter runtimes.19 Asensitive, the group of Nigel Botting at St efficient and rapid ultra-high performance liquid chromatography Andrews University (UK) to work coupled with quadrupole-time-of-ight mass spectrometry on the synthesis of 13C-labelled (UHPLC-Q-TOF-MS) was developed and validated for the qualita- 50 polyphenols. In 2006, he began tive determination of chemical constituents including iso- 50 working at Dundee University avonoids in six Chinese herbal medicines.20 HPLC-ESI-Q-TOFMS towards the chemical preparation of GPI anchors and other bio- was demonstrated to be a powerful technique for the identica- logically important carbohydrates. In 2010 he joined David tion of 96 characteristic compounds from the urine sample of O'Hagan's group as a senior researcher at the University of St WZS-miniaturepigsorallyadministratedwithPuerariae lobatae 55 Andrews to work on the synthesis of diastereoisomeric multi-vicinal Radix (PLR) decoction.21 Park et al. reported the development and 55 uoroalkanes. In 2017, he was appointed as an Associate Professor validation of a simple, selective, sensitive, accurate and fast at the Al Istiqlal University, Jericho. His research interests include UHPLC-ESI-MS/MS in combination with one step salting-out- the synthesis and isolation of natural products, and organouorine assisted liquid–liquid extraction (SALLE) for the determination and carbohydrate chemistry. of 12 isoavones in soy milk.22 Thebaselineseparationof12

2 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

 ff 1 iso avones was achieved within 2.5 min, o ering the fastest et al. reported the design of aqueous micellar two-phase systems 1 chromatographic method ever reported. A simple and efficient (AMTPS), Triton X-114 and sodium tartrate pH 5.00 to extract hyphenated ultra-high-pressure liquid chromatography with an isoavones from soy ourwithpreservationoftheproteincontent LTQ-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap- in the treated soy our.32 The integration of solid–liquid and n  – 5 MS ) approach was developed for the separation and identi ca- liquid liquid extraction using AMTPS in aqueous media 5 tion of avonoid constituents of Radix astragali.23 The proposed permitted the recovery of 93% of all isoavones with a purication fragmentation pathways of isoavones, pterocarpans and iso- factor of about 10. The key target of this technique is the reduction avans were explored to trace the isoavonoid derivatives in the of both extractive/separative steps and the use of organic solvents. plant extracts. Based on this strategy, 48 constituents were iden- Ultraltration liquid chromatography-mass spectrometry 10 tied.Thisapproachwasdemonstratedasaneffective means for (UFLC-MS) with a PC 12 cell model was efficiently utilised in the 10 the rapid qualitative determination of polyphenols from natural rapid screening and identication of ligands (isoavones) for resources.23 A hyphenated high-performance thin-layer chroma- lactate dehydrogenase (LDH) from Pueraria lobata owers. tography (HPTLC/UV/VIS) method using basic silica gel TLC Then, a highly unique and effective instrumental system con- equipment was successfully employed for the simultaneous sisting of microwave-assisted extraction (MAE) coupled with 15 recognition of ve compounds, including the major isoavones a solvent concentration tank (SCT) and countercurrent chro- 15 daidzein, genistein and glycitein, aer a single chromatographic matography (CCC) for the continuous extraction and separation run.24 The obtained accuracy and precision of the results using of LDH inhibitors from P. lobata owers was developed. The this method were comparable to that reported for HPLC methods. MAE-CCC method generated seven LDH inhibitors with >90% The certied method is simple, fast, reliable and more cost- purity. The newly UFLC-MS combined with MAE-CCC and 20 20 effective than the other commonly used methods.24 Areliable a PC12 cell model provided an excellent instrument for the and convenient analytical method for the quantication of 14 screening, extraction, and separation of LDH inhibitors from isoavones in various beans, including soybean, red and black complex samples.33 Utilising ionic-liquid-based (1.0 M 1-ethyl-3- bean using UHPLC coupled to a photo diode array (PDA) at methylimidazolium tetrauoroborate) ultrasound-assisted 260 nm was successfully adopted withalimitofdetectionranging extraction (IL-UAE) in the extraction of bioactive compounds 25 25 from 0.03–0.33 mg kg 1 andgoodlinearity(r2 ¼ 0.99).25 A from Belamcanda chinensis, the incubation of the extract with a- structure-guided method based on fast UHPLC-LTQ Orbitrap and glucosidase, and subsequent ultraltration and semi- UHPLC-HRMS/MS was employed in the identication of iso- preparative HPLC resulted in the isolation of four a-glucosi- avonoids in a crude MeOH extract of stem bark of Amphiumas dase inhibitors, namely tectorigenin, iristectorigenin A, irige- 30 pterocarpoids (Leg.). This method was based on fast UHPLC and nin, and irisorentin with purity ranging from 88.97–99.97%.34 30 HRMS/MSinfullscanacquisition.26 Green, simple ultra-high performance supercritical uid fl chromatography (UHPSFC) using supercritical carbon dioxide, 3. Iso avones methanol and phosphoric acid as additives for elution was Among the isoavonoid subclasses, isoavones comprise the 35 successfully used in the quantitative determination of nine iso- largest group of natural isoavonoids with 178 new structures 35  avones in dietary supplements containing Glycine max (soy), isolated and identied during the review period. This number of Trifolium pratense (red glover) and Pueraria lobata (kudzu) in eight new structures demonstrates the diversity present in natural 27 minutes. This method proved to be selective, sensitive, linear products. The presence of isoavonoids in traditional medicinal 2 $ (R 0.9994), and accurate with recovery rates ranging from plants has prompted increasing interest in the search for bioactive 40 – 40 97.6 102.4%. A green, quick and cheap extraction method based compounds. An examination of the oxygenation pattern of on the nontoxic natural deep eutectic solvent (NADES) and 30% aromatic carbons in the isoavone skeletons revealed that all solution of choline chloride : citric acid with a molar ratio of 1 : 1 isoavones can be divided into 55 patterns based on their was successfully adopted by Bajkacz et al. for the extraction of oxygenated carbons. The most abundant oxygenation patterns are daidzein, genistein, daidzin and genistin from soy-containing 0 0 0 0 0 0 0 0 0 0 0 0 0 45 5,7,4 >5,7,2,4 > 5,7,3 ,4 > 5,7,2 ,4 ,5 >7,4 >5,7,3,4 ,5 >7,3,4 > 45 food samples with enrichment factors of up to 598 for iso- 7,20,40 in descending order. Herein, isoavones are treated in  – 28 avones and recoveries in the range of 64.7 99.2%. Addition- three groups, comprising those characterized by simple substi- ffi ally, Li et al. reported the development of a green, e cient and tution patterns (hydroxy, methoxy, methylenedioxy, hydrox- preparative deep eutectic solvent (choline chloride/ethylene ymethyl and acetyl), then isoavone glycosides (43–86, Section 50 glycol with 1 : 2 molar ratio)-based negative pressure cavitation- 3.2) and nally prenylated derivatives (87–181, Section 3.3). 50 assisted extraction (DES-NPCE) followed by microporous resin column chromatography to extract and separate the main iso-  avones, genistein, biochanin A, tectorigenin and prunetin, from 3.1. Simple iso avones Dalbergia odorifera T. Chen leaves with more than 80% yield.29 39 simple isoavones were isolated from plant sources during 55 Based on the eco-friendly liquid–liquid extraction method the review period, among which only 19 compounds were 55 (cloud point extraction) using surfactants adopted by Mirzaei et al. identied from Leguminosae species. The genus Iris is consid- for the extraction of genistein from soybeans30 and on the superior ered to be a rich source of secondary metabolites, such as iso- reverse micelles for the extraction of soy isoavone from soy ours avonoids possessing anti-oxidant, antitumor and antibacterial using surfactant solutions (anionic and non-ionic),31 Cordisco activity.35,36 Fractionation of the methanolic extract of Iris

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 3 Natural Product Reports Review

1 germanica rhizomes (Iridaceae), the ornamental herb known as medicinal plants, Al-qudah et al. reported the isolation of a new 1 Irsa distributed worldwide, afforded the new 5,30-dihydroxyisoavone lacking oxygenation at the 40-position, named 30- 6,7,40,50-tetramethoxyisoavone 1, named irigenin S.37 Around the methyl tenuifone 8, and a new isoavone dimer 391 from the same time, Xie et al. reported the isolation and identication of aqueous MeOH extract of Gynandriris sisyrinchium (Iridaceae).42 A  5 another new simple iso avone, iriskashmirianin A 2 and one new phytochemical study of Rosa rugosa buds (Rosaceae), the attrac- 5 isoavone glucoside, germanaism H 63, together with eight tive ower distributed in the temperate areas of Eastern Asia used known isoavones from the MeOH extracts of the rhizome of the as food and Chinese medicinal materials for the treatment of same species.38 Iriskashmirianin A 2 exhibited a cytotoxic effect on stomach ache and diarrhea, led to the isolation of 6,8-dihydroxy- 0 43 the Ehrlich's ascites carcinoma (EAC) cell line with IC50 SD of 4 ,7-dimethoxyisoavone 9 (rosa isoavone). Compound 9 10 20.9 2.7 and 4.3 0.9 mM with the 3-(4,5-dimethylthiazole-2-yl)- exhibited strong cytotoxicity against A549 and PC3 cells with IC50 10 2,5-diphenyltetrazoli-umbromide (MTT) and ATP assay methods, values of 2.6 and 3.2 mM, respectively. respectively.38 MeOH rhizomes extract of the same species afforded two additional new isoavones, namely 8-hydroxyirilone 3 and 8-hydroxyirilone 5-methyl ether 4.39 Both compounds were 15 characterised by the full oxygenation of the A-ring and the pres- 15 ence of 6,7-methylenedioxy-substitution. The isoavones 3 and 4

displayed antioxidant activities with IC50 values of 12.92 and 9.23 ¼ mM, respectively, compared with propyl gallate (IC50 7.11 mM). Moreover, both compounds revealed 66.1% and 78.3% a-amylase 20 20 inhibition activities, respectively, compared to acarbose (96.7%, reference a-amylase inhibitor).39

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Phytochemical examination of the constituents of the 40 heartwood of Pterocarpus soyauxii (Fabaceae), known as zitan or 40 red sandalwood, resulted in the identication of ve new simple isoavones, named pterosonins A–E 10–16, two of which lacked oxygenation at the 40-position, 10 and 11, in addition to 7,8,30- trihydroxy-20,40-dimethoxyisoavone 15 and 6,7,30-trihydroxy- 45 20,40-dimethoxyisoavone 16, which were known as synthetic 45 Fractionation of the MeOH extracts of Iris kashmiriana compounds but never isolated from natural sources.44 Another 0 rhizomes (Iridaceae) afforded the new isoavone isonigricin 5 in new isoavone lacking oxygenation at the C-4 position, namely 0 addition to isoirisolidone, which was isolated from this species 7-hydroxy 3 -methoxyisoavone 17, was isolated from the seeds for the rst time. Isonigricin 5 displayed immunosuppressive of Indigofera heterantha (Fabaceae), which is native to the 50 50 activity, while isoirisolidone showed an immunostimulatory Northwestern Himalayas of Tibet and known as indigo Hima- effect.40 Huang et al. reported the isolation of two new isoavones, layan.45 Fractionation of the MeOH extracts of Pueraria montana namely 6,8,40-trihydroxy-7,30-dimethoxyisoavone 6 and 6,8,40- var. lobata Willd. (Fabaceae), also called Ge Gen in Chinese folk 0 trihydroxy-7-methoxyisoavone 7 by fractionating the MeOH medicine, afforded three new isoavones, namely 7-acetyl-4 ,6- 0 extract of rhizomes of Iris dichotoma (Iridaceae), a perennial herb dimethoxy-isoavone 18, 7-acetyl-4 -hydroxy-6-methoxy- 55 0 55 used in traditional Chinese medicine as “Bai-Shegan” for clearing isoavone 19 and 7-acetyl-6,8-dimethoxy-4 -hydroxy-isoavone heat and detoxication, and eliminating swelling and pain in the 20, together with ve known isoavones.46 The remarkable throat.41 In continuation of an extensive effort on the phyto- feature of these new compounds is the occurrence of an chemical study and biological evaluation of Mediterranean unusual acetyl group at the C-7 position on the A-ring, which

4 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

 1 was reported for the rst time from the genus Pueraria.In appreciated agricultural crops in the world. In addition to its 1 a primary screen, compounds 18 and 19 exhibited high anti- use in the cigarette industry, N. tabacum also contains many tobacco mosaic virus (anti-TMV) activities with inhibition valuable chemical compounds, such as sesquiterpenes, diter- rates of 36.8% and 33.6%, respectively, which were higher than penoids, alkaloids and polyphenols. The utilization of these – 5 that of the positive control. The cytotoxicities of compounds 18 active composites in the leaves and stems of N. tabacum has 5 20 displayed weak inhibitory activities against ve human attracted increasing attentions. Phytochemical investigation of

tumour cell lines (NB4, A549, SHSY5Y, PC3 and MCF7) with IC50 the roots and stems of Nicotiana tabacum resulted in the isola- values ranging from 1.2–3.6 mM.46 The red heartwood of the tion and identication of two new isoavones, named 7- rhizomes of Caragana changduensis (Fabaceae), a species hydroxy-6,30,40,50tetramethoxyisoavone 29 and 6-hydroxy- 10 considered to be traditional Tibetan medicine to treat hyper- 7,30,40,50tetramethoxyisoavone 30, together with seven known 10 tension and menstrual disorder, is rich in avonoids including isoavones.52 Around the same time, Ye et al. reported in isoavonoids. Fractionation of its EtOH extracts yielded two a separate paper the isolation and identication of the new new isoavones, 6,7,20-trihydroxy-4-methoxyisoavone 21 and 30,40,50-trihydroxy-5,7-dimethoxyisoavone 31 from the stems of 7,30-dimethoxy-5-hydroxyisoavone 22.47 Ma et al. reported the the same species.53 It is worth mentioning that the three iso- 15 isolation of an unusual isoavone, hydroisoavone 23, together avones share the 30,40,50-oxygenation pattern in the B-ring. 15 with the unprecedented isoavane coumaronochromone 389 Three additional new isoavones 32–34 were isolated from the from Campylotropis hirtella (Leg.).48 Identication of this acetone extracts of the leaves of N. tabacum, two of which bear remarkable hydroisoavone with a fully saturated B-ring, brings either a methoxycarbonyl- or hydroxymethyl-group at C-8.54 The the total number of naturally occurring hydroisoavones to structures of these compounds were characterised as 7,40- 20 0 20 four.49 In 2009, Ndejouong et al. reported for the rst time the dimethoxy-6-hydroxy-8-methoxycarbonylisoavone 33, 7,4 - isolation of hydroisoavones A–C 24–26 from a culture of highly dimethoxy-6-hydroxy-8-hydroxymethylisoavone 34 and 8,40- Ni-resistant strain of Streptomyces mirabilis from a former dihydroxy-6,7-dimethoxyisoavone 32.54 Compounds 32–34 uranium mining area in China.49 Single crystal X-ray diﬀraction exhibited high anti-tobacco mosaic virus (anti-TMV) activity 25 experiments indicated that the two hydroxyl groups on the B- with inhibition rates of 25.2%, 22.6% and 27.4%, respectively. 25 ring were in the axial position and trans conguration.48

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An unusual isoavone containing epoxide at C-2 and C-3, named vigradiatain 27, was isolated as a minor constituent Phytochemical investigation of the leaves and stems of Quran- (0.026 mg/100 g) from the stems and leaves Vigna radiate L. tea ferruginea (Ochnaceae) led to the isolation of a new isoavone, 50 0 0 0 50 (mung beans) together with the new isoavone glycoside, 5-hydroxy-7,3 ,4 ,5 -trimethoxyisoavone 35, together with three 0 named 20-hydoxydaidzin 60, and 13 known isoavonoids.50 known isoavones.55 Shen et al. obtained 4 -deoxyisoavone, ter- Compound 27 exhibited strong ABTS radical scavenging activ- natin A 36,fromtheEtOHextractofRanunculus ternatus Thunb. ¼ 56 ities (IC50 15.6 3.71 mM). However, the stereochemistry of 27 (Ranunculaceae), a traditional Chinese medicine. Compound 36 55 was not determined. Pruinosanone E 28, a new isoavone, was exhibited moderate cytotoxic activity against HeLa and PANC-1 55 isolated from the roots of the Caragana puinosa (Leg.), a dwarf cells, with IC50 values of 13.88 and 16.78 2 mM, respectively. A shrub distributed in China and Central Asia.51 new isoavone, mexitin 37 together with quercetin and rutin were Nicotiana tabacum L. (Solanaceae), a perennial plant origi- isolated from the aerial part of Argemone mexicana Linn (Papaver- nating from South America, is one of the most commercially aceae).57 In an ongoing phytochemical investigation of Salsola

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  1 tetrandra (Amaranthaceae), a new iso avone lacking the oxygena- 3.2. Iso avone glycosides 1 tion at C-40, designated as 2-dihydroxy-5-methoxy-6,7- Intensive phytochemical investigation on the EtOH extract of methylenedioxy-isoavone 38 (tetranins B), was isolated and the root bark of Ormosia henryi Prain (Leg.) resulted in the identied from the EtOAc extract of its roots.58 Compound 38 isolation and characterisation of a new isoavone glycoside, exhibited a strong antioxidant eﬀect in 1,1-diphenyl-2- 5 designated as ormosinoide 43, and polyprenylated isoavanone 5 picrylhydrazyl (DPPH) free radical assays.58 Examination of the named ormosinol 235.63 Ormosinoide is characterised as ethanolic extract of Eremostachys vicaryi (Labiatae), a plant that a disaccharide b-D-Xylp-(1/6)-b-D-Glcp O-linked at C-7 of the  grows in India, Pakistan and Iran and studied for the rst time, led isoprunetin. The glycoside was found to be inactive as a radical to the isolation of a new isoavone lacking C-40-oxygenation named scavenger. A new isoavone glycoside named caviunin 7-O-[b-D- 10 vicarine 39.59 Pauciisoavone A 40,anewisoavone bearing an 10 apiofuranosyl-(1/6)-b-D-glucopyrano-side] 44, isolated from isobutyl group at 40-O-position, isolated from the leaves of the the ethanolic extract of Dalbergia sissoo leaves (Fabaceae), used Garcinia paucinervis (Chusiaceaea) showed cytotoxicity against the as Chinese folk medicine for the treatment of gonorrhoea, was NB4, SH-SY54, and MCF7 cell lines with IC values of 8.6, 7.5, and 50 found to increase alkaline phosphatase activity and minerali- 9.2 mM, respectively.60 AnewC-methylisoavone bearing methyl zation, consequently resulting in substantial osteogenic 15 groups at C-6 and C-8, isosideroxylin 41,isolatedfromtheEtOAc 15 activity.64 The high activity of 44 was attributed to the apiofur- extractoftheleavesofLeiophyllum buxifolium (Ericaceae), known as anosyl-(1/6)-b-D-glucopyranoside at the 7-O-position of cav- myrtle, showed selective anti-proliferative activity against MDA-MB- 0 iunin.64 Glycitein-7,4 -di-O-b-D-glucoside 45 (ammopiptanoside 230 cells with an IC value of 7.0 4.2 mM.61 0 50 A) and 4 -O-b-D-glucopyranosyl-glycitein 7-a-L-rhamnopyranosyl-  A new chlorine-containing iso avone, named 8-chloro-7-O- / 20 (1 6)-O-b-D-glucopyranoside 46 (ammopiptanoside B) were 20 methylgenistein 42, together with eight known isoavones, one identied as constituents of the EtOH extract of Ammopiptan- of which is 8-clorogenistein, were obtained and identied from 0 thus nanus Cheng f. (Leg.).65 Four new isoavone glucosides, 2 - the metabolites of the Streptomyces strain YIM GS3536, which hydroxy-5-methoxy daidzin (not genistin as mentioned in the was isolated from a soil sample collected from Yunnan Prov- 0 0 original paper) 47, 5,3 -dimethoxy daidzin 48,2-hydroxy gen- 62  25 ince, China. This nding brings the number of chlorine- istein-7-O-gentibioside 49, and 20-hydroxy-5-methoxy daidzein- 25  containing iso avones to six. The chlorination mechanism in 7,40-O-diglucoside 50 were isolated from the MeOH extract of Streptomyces remains vague. The new compound 42 demon- the groundnut of Apios americana Medik (Leg.) using PDA- strated substantial cytotoxicity against human melanoma cell HPLC, a perennial vine native to North America that generates lines (B16) and human leukemia cell lines (HL60) with IC 50 edible tubers.66 The structures of the glycosides 47–50 were values of 17.5 and 19.2 mM, respectively. The MIC values of 42 30 revealed based on 1D- and 2D-NMR as well as HR-ESI-MS 30 for E. coli, Staphylococcus aureus, Bacillus subtilis, and Candida analyses. The bioside 50 selectively inhibited DHT binding to albicans were in the range of 23–35 mM.62 the androgen receptor (AR) in a dose-dependent manner with

an IC50 value of 280 mM. Moreover, the activity of this compound for AR was demonstrated to be antagonistic with an 35 35 assay using cultured LNCaP cells.66 The extract of the vine stems of Millettia dielsiana Harms (Leg.), a Chinese herbal medicine known as Ji-xue-teng, yielded millesianins F 51 and G 52, the 7- O-b-D-apiofuranosyl-(1/6)-b-D-glucopyranoside of cladrastin 67 40 and fujikinetin, respectively. Both structures were elucidated 40 via spectroscopic analysis and chemical methods.67 Wang et al. reported the isolation of two new isoavones, one of which was 00 daidzein-7-O-b-D-{6 -[(E)-but-2-enoyl]}glycoside 53, a crotonylated glucoside of daidzin (600-crotonyldaidzin), from the green 45 vegetable soya beans known as Maodou in China.68 The iden- 45 tication of this compound represents the second documented natural occurrence of a crotonylated isoavone glycoside. Shi et al. reported the identication of a new 7-O-biglycoside, irisolidone-7-O-b-D-glucopyranosyl-(1/6)-b-D-glucopyranoside 54 50 together with 17 known isoavones and isoavone glycosides 50 from the Pueraria lobata ower (Kudzu, Leg.), a traditional Chinese medicine.69 Investigation of the crude MeOH extract P. lobata by dual high resolution a-glucosidase inhibition and radical scavenging proling combined with hyphenated HPLC- 55 HRMS-SPE-NMR resulted in the identication of one C-8 iso- 55 avone glycoside 55,8-C-[a-D-apiofuranosyl-(1/6)]-b-D-glucopyranoside, and new 600-O-malonyl-30-methoxydaidzin 56 together with 23 known isoavonoids.70

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pallidiora.74 The new isoavone 61 could be an artefact formed 30 during the EtOAc fractionation process. Compound 61 dis- 30 played moderate cytotoxicity on three cancer cell lines (CEM-13, MT4, and U-937) using the conventional MTT assays. 0 0 0 5-Hydroxy-6,3 ,4 ,5 -tetramethoxy-7-O-b-D-glucopyranosyl isoavone, iridine S 62, isolated and identied from the MeOH extract of Iris germanica rhizomes growing in Egypt, showed no 35 Continuation of the extensive phytochemical investigation of 35 activity against L51784, PC12 and Hela cell lines.75 Fraction- the extract of Dalbergia velutina roots (Leg.), the creeping plant ation of the EtOH and MeOH extract of the rhizomes of the found in north-eastern Thailand, led to the isolation of a new same species resulted in the identication of 5,30-dihydroxy-40- isoavone glucoside 57, dalvelutinoside, together with ve O-b-D-glucopyranosyl-6,7-methylenedioxyisoavone 63 (germa- other known isoavones, among which were one 7-O-glycoside 40 naism H),38 and iridine A 64 together with 8 known iso- 40 and three C-8 glycosides.71 A bioassay-directed study on the avones.76 Iridine A 64 exhibited strong a-amylase inhibitory MeOH extract of the root of Sophora avescens resulted in the activity with 70% inhibition and moderate antioxidant activity isolation of a new isoavone glycoside 58 together with eight with an IC value of 8.91 mM.76 In continuation of an extensive known isoavone glycosides, which have never been isolated 50 eﬀort on the phytochemical investigation and biological evalu- 45 from this plant. Compound 58 showed moderate SGLT2 45 72 0 ation of Iris pseudacorus L., Tarbeeva et al. reported the isolation inhibitory activity with the IC50 value of 15.3 mM. 7,5 -Dihy- 0 of a new isoavone, 7-O-glucoside 65, lacking oxygenation at the droxy-4-O-glucopyranosyl-2 -methoxyisoavone 59 was isolated C-40 position together with ve known simple isoavones from and identied from the roots of the Tunisian Ononis the root of I. pseudacorus.77 7-O-b-D-Glucopyranosyl-5,8-dihy- angustissima L. (Fabaceae), together with formononetin and its 0   droxy-4 -methoxyiso avone 66 and 7-O-b-D-glucopyranosyl-6- 50 glucoside (Ononin), which were isolated for the rst time from 0 50 0 hydroxy-4 -methoxyisoavone 67 were isolated from the this plant.73 The position of the glucosyl moiety at 4 -OH was rhizomes of Iris kashmeriana Baker.78 Structural identication of conrmed by spotting the correlation in HMBC spectrum 0 0 0 0 00 0 0 the new compounds 66 and 67 was achieved by spectrometry between H-3 -C4 ,H6-C4 and H1 -C4 .73 2 -Hydroxydaidzin 60 coupled with chemical analysis. isolated from the seeds of Vigna radiate L. (mung beans) as 55 EtOH extracts of the aerial parts of Trachelospermum jasmi- 55 a minor constituent (17 mg/100 g) showed high antioxidant ﬀ ¼ noides (Apocynaceae), a traditional Chinese medicine, a orded activity (IC50 8.27 0.47 mM) and very low a-glycosidase 0 0  b D 50  00 the 7,3 -dimethoxyiso avone-5,4 -di-O- - -glucopyranoside 69 inhibitory activity. A new iso avone glycoside named 6 -O- 0 0 (not 7,3 -dimethoxyisoavanone-5,4 -di-O-b-D-glucopyranoside acetylwistin 61 was isolated from the roots of Glycyrrhiza as stated in the original paper) together with four known

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30 inhibitory activities against NO production.83 MeOH extracts of 30 the seeds of Lepidium Sativum (Cruciferae), a plant used in the Middle East as traditional medicine, furnished an uncommon C-7 isoavone glucoside lacking 40-oxygenation, named 5,6- 0 0 dimethoxy-3 ,4 -methylenedioxy-7-C-b-D-glucopyranosyliso- 35 avone 75 together with two known isoavones.84 The structure 35 isoavones.80 Comprehensive phytochemical investigation of of the new C-glycoside was conrmed by observing the the stem bark of Antidesma laciniatum Muell Arg. (Antidesma anomeric proton correlation with C-8, C-7 and C-6 in the HMBC Chevalieri Beilli, Phyllanthaceae), a small tree used in Africa to experiment and chemically by its resistance to acidic hydrolysis. treat miscarriage and intestinal complaints, resulted in the Compound 75 showed high ability to lessen the hepatotoxicity 40 40 isolation chevalierinoside A 70.81 The new isoavonoid glyco- prompted by paracetamol in male rats by reducing the damage  side 70 was determined to be biochanin A 7-O-[a-L-rhamnopyr- and toxicity on the liver cells with signi cant improvement of anosyl-(1/6)-b-D-apiofuranosyl-(1/2)-b-D-glucopyranoside].81 the total antioxidant capacity and restoring the normal liver The structure of 70 was established by interpretation of its functions.84 1 13 45 spectral data, including 1D-NMR ( H, C and DEPT) and 2D- A bioassay-directed fractionation and chemical study of the 45 NMR (COSY, ROESY, TOCSY, HSQC and HMBC).81 In a sepa- MeOH extract of Tilia amurensis trunks (Tiliaceae), a traditional rate report, Djouossi et al. reported the isolation of two addi- Korean medicine to treat cancer and rheumatoid arthritis, tional isoavane glycosides, designated as chevalierinoside B 71 resulted in the isolation and characterization of a new iso- 0 and chevalierinoside C 72, as minor constituents from the same avone, O-biglycoside, orobol 4 -O-b-D-apiofuranosyl-(1/6)-b-D- 50 species using the same extraction procedure.82 The new glyco- glucopyranoside 76, together with three orobol-based O-gluco- 50 85 0 sides were characterised as genistein 7-O-[b-D-apiofuranosyl- sides. In contrast to orobol 4 -O-b-glucopyranoside, the new  (1/2)-b-D-glucopyranoside] 71 and biochanin A 7-O-[b-D-apioiso avone 4-O-biglycoside inhibited the NO production in 82 ¼ furanosyl-(1/2)-b-D-glucopyranoside] 72. Two isoavone lipopolysaccharide-stimulated BV-2 cells (IC50 23.42 mM), 0 glycosides lacking the 4 -oxygenation were reported from the suggesting that the addition of a b-D-apiofuranosyl moiety to the 55 – 0 85 55 EtOH H2O extract of the roots of Achyranthes bidentata (Amar- glycoside at the 4 -O-position may play a role in NO inhibition. anthaceae), which were characterised as achyranthosides A 73 Flaniostatin 77, a new isoavone glycoside in which the glucosyl and B 74.83 Compound 73 bears the unusual methoxymethyl moiety is linked to the isoavone via an ethylene bridge, was group at the C-8 position. Both glycosides exhibited substantial isolated from the leaves of Cudrania tricuspidata (Moraceae).86

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Previously, several isoavones were isolated from microbes cultivated in media containing nutrients such as soybean.90 30 30 Streptomyces is well-known for its capability to biotransform genistein and daidzein, the major isoavones of soybeans, into 8-methyl genistein and 8-methyl daidzein, respectively.91 Recently, Deng et al. reported the isolation and identication of daidzein 7-O-400-anhydro-400,500-didehydroglucuronide 81 and 35 Flaniostatin 77 inhibited tyrosinase activity by 16.5–47.3% at 35 genistein 7-O-a-400-anhydro-400,500-didehydroglucuronide 82 a concentration of 500 mM, and consequently demonstrated as from the MeOH extract of Streptomyces sp. LZ35DgdmAI culture a potential skin whitening agent. In continuation of their study through various chromatography techniques.92 The two new on the anti-obesity effect of Cudrania tricuspidata fruits, Jo et al. isoavone glucuronides may have been formed from the conducted a comparison study of the pancreatic lipase inhibi- soybean daidzein and genistein in the culture media by glu- 40 tory isoavonoids from ripe and unripe fruits of C. tricuspidata, 40 0 curonidation via UDP-glucuronosyltransferases existing in this which lead to the isolation of isoavone 4 -O-glucoside, named strain.92 Furthermore, three new isoavone O-biglycosides, cudracusisoavone 78, and a new prenylated isoavone from named termisoavones A–C 83–85, together with eight known the unripe fruits.87 HPLC analysis showed that the chemical isoavonoids were isolated and identied from termite- composition and the amounts of polyphenols in the unripe and 45 associated Streptomyces sp. RB1 recovered from the cuticle of 45 ripe fruits are different. Furthermore, it was found that the the South African termite, Macrotermes natalensis.93 The struc- unripe fruits had a higher content of total polyphenolics and tures of the new compounds 83–85 were established via spec- displayed stronger pancreatic lipase inhibition compared to the troscopic methods, including 1D and 2D NMR and HR-MS ripe fruits.87 Phytochemical investigations of Shenqi Fuzheng analysis, as well as by chemical methods. Acidic hydrolysis of Injection (SFI), a clinical drug composed of two herbal medi- 50 83–85 afforded the corresponding aglycone (genistein and 50 cines Radix Codonopsis and Radix Astragali used as an adjuvant daidzein) and 3-O-methyl-a-L-rhamnose and rhamnose. Frac- to chemotherapy for cancer treatment in China, led to the tionation of the EtOAc-soluble MeOH extract of germinated isolation and characterization of a new isoavone glycoside soybeans cultivated for one week with the fungus Cordyceps named calycosin 7-O-[a-D-glucopyranosyl(1/4)]-b-D-glucopyr- militaris led to the isolation of a new quercetin 7-O-b-D-glucoside 55 anoside 79.88 A new biochanin A C-8 glycoside, named malay- 55 400-O-methylate (CGLM) 86.94 The new glucoside 86 exhibited sianone B 80, was isolated and characterised from the MeOH inhibitory activity against MUC5AC gene expression by inhib- extract of Mangifera indica leaves (Anacardiaceae) using various iting epidermal growth factor (EGF)-induced p38/ERK MAP chromatography techniques.89 kinase and NF-kB activation.

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1 complexity and diverse bioactivity such as estrogenic and anti- 1 estrogenic isoavonoids. Flemiphilippinin G 87, a new prenylated isoavone, was identied from the roots of Flemingia philippinensis, a shrubby herb growing in tropical and 95  5 subtropical areas. Compound 87 exhibited signi cant cyto- 5 toxicity against MCF-7, A549, and Hep-G2 cells with IC50 values of 4.8–7.3 mM. The bioassay-guided fractionation of the MeOH extract of Vigna vexillata (Fabaceae) led to the isolation and characterisation of two new optically active isoavones, vigvexin a 25 ¼ 10 A 88 and B 89 with ([ ]D 100 and 80 (c 0.2, MeOH), 10 respectively), in which the dihydrofurano is attached to daidzein and genistein at C-7 and C-8.96 Derrisisoavone G 90, a new isoavone with a fused furan ring at the C-8 and C-7 positions

was isolated from the CH2Cl2 extract of dried stems of Derris 15 ferruginea (Fabaceae).97 The position of the dihydrofuran 15 appendage was determined via 2D NMR and a hemi-synthetic method, while the 200S absolute conguration was established a 20 ¼ based on its measured optical rotation of [ ]D 50 (c 0.4, MeOH) and by comparison with other structurally related 20 20 compounds. The estrogenic activity-guided fractionation of the MeOH extract of Flemingia macrophylla (Leg.) roots, a shrubby herb used in folk medicine in East Asia, with silica gel chromatography followed by HPLC led to the isolation and identi-    25 cation of a new iso avone named eminigin 91 together with 25 11 known isoavones.98 Fleminigin 91 displayed only moderate estrogenic activity with an MAC value of 35.31 mM. Flemilati- folin B 92, a new prenylated isoavone, was isolated from the roots of Flemingia latifolia Benth.99 30 30

3.3. Complex isoavones 35 35 Prenylated isoavones comprise the largest group of isoavones with 94 new complex isoavones isolated from plant sources during the review period.

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1 Several studies indicated that the Erythrina genusisarich A comprehensive phytochemical and biological investigation 1 source of bioactive avonoids, especially, isoavones, pter- of the constituents of Glycyrrhiza uralensis (Licorice, Leg.), ocarpans and avanones. The leaves and the bark of Erythrina which is widely used as herbal medicine in China, led to the species are frequently applied as folk medicine to cure a wide isolation and identication of six new isoavonoids, one of   5 range of diseases. Two new prenylated iso avones, erythraddison which is the C-6 prenylated iso avone 109 (glycyuralin F), 5 I, II 93 and 94 and two new isoavanones 220 and 221 were together with 116 known compounds.107 puried by activity-directed isolation from the EtOAc extract of the Four isoavones, among which three were new natural prod- roots of Erythrina addisoniae (Leg.).100 The noteworthy feature of ucts 110–112, were isolated from the leaves Vatairea guianensis the genistein-based compound, erythraddison I 93,isthepres- Aubl´e (Fabaceae), a plant native to the Amazon and known as 10 ence of the 1-OMe group at the isoprenyl moiety attached to the C- “fava bolacha” or “fava de impingem”.108 5,30-Dihydroxy-40- 10 8 position. The C-6 and C-8 isoprenylated isoavones showed methoxy-200,200-dimethylpyrano-(500,600:8,7)-isoavone 110 and 5,7- signicant cytotoxicity against MCF7, MCF7/ADR, and MDA/MB- dihydroxy-30,40-methylenedioxy-8-prenyl-isoavone 111,cited

231 cancer cells with IC50 values of 11.41, 6.75 and 4.57 mM, previously as synthetic compounds, were isolated for rst time respectively. The MeOH extracts of the root, stem bark and leaf of from natural sources. The crude extract of the leaves exhibited 15 15 Erythrina schliebenii, a rare medicinal tree endemic to Tanzania, signicant radical scavenging ability with an IC50 value of 6.2 yielded three new B-ring prenylated isoavones named schliebe- 0.4 mgmL 1, which was close to that of Trolox (positive control). nones A–C 95–97, and one new pterocarpan 208.101 Fractionation of the root extract of the of Chinese herbal medicine

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As part of the BioBioPha project for the large scale screening for drug discovery from non-alkaloidal natural products, Wang 35 et al. recorded the isolation and structural elucidation of four 35 new genistein-based isoprenylated isoavonoids named eryth- rinins D–G 98–101 from the branches of E. arborescens.102 The structure of the pyranoisoavone, anagyroidisoavone A 102a, reported from Laburnum anagyroides and Maclura pomifera has 40 been revised based on the 13C NMR shi for C-100 bearing a – 40 OMe group, which was renamed 100-O-methylerythrinin F 102b.102 The pyranoisoavone 40-prenyloxyderrone 103 obtained

by fractionating the CH2Cl2/MeOH extract of stem bark of Mil- lettia oblata ssp. Teitensis (Leg.) showed antiplasmodial activity 45 45 (13–15 mM) against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum.103

The CH2Cl2/MeOH extract of the leaves from the same species yielded 8-prenylmilldrone 104 together with four new rote- 104 50 noids. As part of the search for new anticancer agents, 50 examination of the hexane-soluble MeOH extract of M. caerulea fruits resulted in the isolation and identication of three new rotenoids and two new 7-O-prenylated isoavones named 7-O- prenylcladrastin 105 and 7-O-prenyl-30,40-dimethylcladrastin 55 106.105 Two additional isoprenylated isoavones of the mil- 55 lesianin series, named millesianin H 107 and I 108, were recorded by bioassay-directed fractionation of the EtOH extract of the stems of M. dielsiana Harms.106

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ff 0 1 Hedysarum multijugum (Leg.) a orded the 3 -isoprenyl- 113 and and K 118 is the occurrence of hydroxyethyl substituents, which 1 6,8-diisoprenyl- 114 derivatives of 20-hydroxybiochanin A, desig- represent the rst two examples of hydroxyethylated natural nated as hedysarimisoavones A 113 and B 114,respectively.109 isoavonoids. Extensive phytochemical studies of the stems of the ethnomedicinal plant D. eriocarpa, Chinese traditional 5 medicine, resulted in the isolation and characterization of three 5 new naturally occurring isoavones, namely derrubo 5-methyl ether 119, 5,7-di-methoxy-40-hydroxy-6-(3-methyl-2-butenyl)- isoavone 120, and the previously synthesised 5,7-dihydroxy-40- O-(3-methyl-2-butenyl)-isoavone 121.111 Compounds 119 and 10 120 displayed inhibitory effects on the Candida guilliermondii, C. 10 albicans and M. gypseum microbial strains. Isoprenylated and geranylated isoavonoids are typical constituents of Campylotropis species, a trend reected in the new isolated compounds 122–132.112,114,115 The bioassay- 15 directed fractionation of the EtOH extracts of Campylotropis 15 hirtella (Leg.) resulted in the isolation and characterization of two new geranylated isoavones designated 5,7,40-trihydroxy-30- [6,7-dihydroxy-3,7-dimethyl-2E-octenyl]isoavone 122 and 3- [10,40-dihydroxycyclohexyl]-6-geranyl-5,7-dihydroxyisoavone 20 20 123, in addition to two new isoavanones 226 and 227 and one new coumaronochromone 301.112 The linkage of the cyclo- hexane moiety to the chromenone in compound 123 was established by HMBC correlation, and the 10-OH in equatorial 0 25 and 4 -OH in the axial positions were determined by HMBC and 25 NOESY correlations and coupling constant data. It is worth noting that isoavone 123 bears 1,4-dihydroxycyclohexyl instead of the aromatic B-ring. This type of isoavone derivative has never been reported from plant sources, with only a few 30 isoavone derivatives isolated from bacterial strains.113 Further 30  Derris species (Leg.), a rich source of iso avonoids, is widely phytochemical examination of the EtOH roots extract of C. distributed in the tropical and subtropical regions of Africa and hirtella afforded seven additional new geranylated isoavones  Asia. The majority of Derris iso avonoids are isoprenylated, 124–130 (not nine as reported), two new isoavans, one iso- a trend revealed in the new examples documented herein. avanone and one new coumestan 312.114 The new isoavones 35 35

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Phytochemicals of the genus Derris showed a broad spectrum displayed only weak to moderate antibacterial activities against of biological activities, including insecticidal, antimicrobial, and four Gram-positive bacteria and ve Gram-negative bacteria.114 antioxidant activities. Phytochemical examination of the twigs The further identication of a new C-30 geranylated isoavone 55 0 55 and leaves of the EtOH extract of Derris robusta resulted in the 131 and new 3 -O-geranylted isoavone, hirtellanine M 132, isolation and identication of four new prenylated isoavones from the roots of the same species was described in two sepa- named derrisisoavones H–K 115–118, together with a new iso- rate reports.115,116 The new prenylated isoavone 131 displayed avan 254.110 The remarkable feature of derrisisoavones J 117 signicant and dose-dependent inhibitory eﬀects on the

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15 15 inuenza A1(H1N1) virus NA.115 The structural feature of almost concentration. 40-Hydroxy-20-methylalpinumisoavone 134 iso- all the isoavones from this species is that the geranyl moiety is lated and characterised by the bioassay-directed fractionation located on the B-ring at the C-30 position. of the EtOH extract of the Chinese folk medicine Crotalaria ferruginea (Leg.) exhibited cytotoxicity against

20 phosphodiesterase-4 (PDE4) with an IC50 value of 4.59 0.50 20 mM.118 A new furanoisoavone, neoraudiol 135, was separated

by a bioassay-directed assay from the n-hexane/CHCl3 extract of the tuberous root of Neorautanenia mitis Verdcourt, a sub- shrubby plant grown in rocky soil in Africa.119 Compound 135 25 exhibited high antimicrobial activity on two Gram-positive 25 bacterial strains and fungi with an MIC in the range of 51.4– 58.8 mM. 5,7,30-Trihydroxy-40-methoxy-8-prenylisoavone 136 was isolated from the leaves of Vatairea guianensis Aubl. (Fabaceae), together with two known isoavones lupiwighteone 30 0 0 30 and 5,7,4 -trihydroxy-3 -methoxy-8-prenylisoavone.120 Lupi- wighteone was reported for the rst time from the genus Vatairea. Compound 136 exhibited weak antifungal activity

against Candida dubliniensis and C. parapsilosis with IC50 values m 35 of 173.8 and 21.7 M. 35

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50 50 In a voltage clamp assay with Xenopus laevis oocytes, the CH Cl extract of roots and tubers of Adenocarpus cincinnatus 2 2 Two new prenylisoavones named pachyloisoavones A 137 (Leg.) improved the GABA-induced chloride current (IGABA) and B 138, and a pterocarpan 211 were isolated from the vine through receptors of the subtype a1b2g2s by 126.5 25.1% at stems and leaves of the Chinese herbal medicine Millettia 55 100 mgmL 1,aﬀording a new prenylated isoavone 133 and 55 pachyloba (Leg.).121 The absolute conguration of 138 was three new pterocarpans 187–189 in addition to ve known iso- elucidated using the calculated electronic circular dichroism avonoids.117 The 8-prenyl isoavone 133 displayed high inu- (ECD). ence and potentiate on IGABA by 560.34 387.06% at 100 mM

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 13 Natural Product Reports Review

ﬀ 1 pruinosa (Leg.) displayed strong inhibitory e ects on NO 1 125 production with an IC50 value of 1.93 mM. Examination of Amorpha fruticosa fruits, a North American native shrub, resulted in the isolation of C-8-geranyl isoavones 145 and  5 146,oneC-6-geranyl iso avone 147, one new glycoside 68 and 5 three new rotenoids 293–295.79 Compounds 145 and 146 displayed moderate antibacterial activities against E. faecalis and E. faecium bacteria with MIC values ranging from 12.5– 50 mM.79 10 10

15 15

20 20 Phytochemical investigation on the constituent of the seeds and fruits of Psoralea corylifolia (Leg.), traditionally used for the treatment of various inammatory diseases, resulted in the identication of 7,40-dihydroxy-30,50-diprenylisoavone 139,122 25 25 7-O-isoprenylneobava-isoavone 140,7-O-isoprenylcorylifol 141 and 7-O-methylcorylifol 142, as new prenylated isoavones described in two separate reports.122,123 The latter compound showed a signicant inhibition eﬀect against the generation of the superoxide anion (O \ ) (IC ¼ 10.89 mM) by human 30 2 50 30 neutrophils in response to N-formyl-L-methionyl-L-leucyl-L- phenylalanine, cytochalasin B (fMLP/CP).123 Three new iso- avonoids, among which one dipyranoisoavone named pre- The bioactivity-directed fractionation of the active CHCl - catorin C 143, were isolated from the CH Cl root extract of 3 2 2 soluble extract of the root bark of Sphenostylis marginata ssp. Rhynchosia precatoria (Humb. & Bonpl. ex Willd., Fabaceae).124 35 Erecta (Leg.) led to the isolation of one new isoavone, 35 Compound 143 showed weak antimycobacterial activity with an sphenostylisin H 148, three new 3-phenylcoumarins 307–310 IC value of 149.36 mM. 50 and three complex dimeric isoavonoids 372–374.126 The new isoavone displayed strong hydroxyl radical scavenging activity with an ED value of 2.2 mM, and showed very potent 40 50 40 inhibitory activity on NF-kB p65 with an IC50 value of 0.23 mM.126 The plants of the Ficus genus have attracted great attention due to their wide range of biological properties. In continuation of an extensive program on the phytochemical 45 investigation and biological evaluation of Hawaiian plants, 45 sixnewcomplexisoavones 149–154 were isolated from the fruits of Ficus benjamina (Moraceae).127 The structures of all the new compounds except that of 150 are based on genistein. The compounds were assigned via a combination of spectro- 50 scopic methods and comparison with the NMR data of other 50 compounds. The bioassay-directed fractionation of the fruits of Ficus tikoua Bur., a wood plant wide-spread in southern China and India, resulted in the identication of a new antifungal pyr- 55 anoisoavone named 5,30,40-trihydroxy-200,200-dimethylpyrano 55 (500,600:7,8) isoavone 155, together with wighteone and lupiwighteone.128 Pruinosanone B 144 isolated together with the new iso- avanone 241 (Pruinosanone C) from the roots of Caragana

14 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

1 As part of a continuing research program dedicated to 1 nding neuroprotective compounds from higher plants, the EtOAc soluble MeOH extract of Maclura tricuspidata (formerly known as Cudrania tricuspidata, Moraceae), a traditional  5 herb in Korea, was found to display signi cant neuro- 5 protective against SH-SY5Y cell death induced by 6-hydrox- 1 130 ydopamine (6-OHDA) with an IC50 value of 7.7 mgmL . Based on this result, extensive phytochemical investigation of the MeOH extract of Maclura tricuspidata resulted in the 10 isolation of een prenylated isoavones and three iso- 10 avone dimers together with 31 known isoavones described in two separate reports.130,131 Hiep et al. reported the isolation of cudraisoavones 157–166, among which nine are preny- latedatC-6andC-8eitherasfreeprenylorcyclisedasafur- 15 ano, dihydrofurano or pyrano moiety and derivatives of 15 genistein, from the EtOAc soluble extract of the fruits of M. tricuspidata.130 Compounds 162, 164 and 165 exhibited neuroprotective activity against 6-OHDA-induced cell death in

neuroblastoma cells with IC50 values of 9.2, 4.5, and 0.5 mM, 20 20 respectively. Further investigation of the EtOAc soluble extract of the same species led to the isolation of eight additional prenylated isoavones named cudraisoavones L– P, T 167–171, 174,4-O-methylcudraisoavone O 172 and 4-O-   131 25 methylcudraiso avone 173 and three iso avone dimers. 25 The structural feature common to the isolated compounds is Phytochemical investigation of the Malcuna genus revealed that they all have a tetra-substituted A-ring and they are that prenylated avonoids are its foremost components.129 derived from genistein. The unusual C-8 benzylated iso- Oyama et al. reported the identication of the linear dihy- avones 165 and 170–173 were only reported from this 30 drofurano pyranoisoavone 156 from the fruits of Maclura species. Structural elucidation of the new compound was 30 tinctoria (Moraceae), a tree grown in the tropical forests of accomplished via spectroscopic and chemical methods. Central and South America.129 Structural elucidation of Snatzke's method, using dimolybdenum tetraacetate as an compound 156 was established via the HMQC and HMBC auxiliary chromophore, was employed to determine the techniques and comparison with the closely related ulexin D, absolute conguration. 35 identied from Ulex airensis, varying by the presence of a 5- 35 129 OCH3 instead of 5-OH group in ulexin D.

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Fractionation of the MeOH extract of Cudrania tricuspidata leaves led to the isolation a new prenylated isoavone named 55 cudraisoavone L 175, together with eight known isoavones.132 55 The remarkable feature of this new compound is the unprecedented presence of a hydroxyethyl attached to the C-atom in the isoavone skeleton. The new isoavone 175 showed signicant

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 15 Natural Product Reports Review

m 1 cytotoxicity against NO production with an IC50 value of 10 M. 1 A new isoavone with an isoprenyl group at C-8 and the uncommon hydroxyethyl group at C-6, named cudraisoavone M 176, was obtained from the EtOH extract of 5 Cudrania cochinchinensis (Moraceae) and from Derris robusta 5 (Leg.).133 This compound showed weak cytotoxicity against ve human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7 and SW-480).

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35 35 In ongoing research on the phytochemical and biological activities of medicinal plants from the genus Polygala,Venzke et al. reported the isolation and characterization of four pyranoisoavones 177–180, among which compounds 178–180 40 are known synthetic compounds, from Polygala molluginifolia, 40 a small herb grown along the Atlantic Forest of Southern Brazil.134 Compounds 177–180 displayed moderate inhibition activity towards the acetylcholinesterase enzyme, and iso-

avones 178 and 180 showed the best eﬀects with IC50 values 45 of 68 and 84 mM, respectively, due to the presence of the free 45 hydroxyl groups at positions 30 and 40 in the isoavone scaf- fold. Furthermore, the addition of a second dimethylpyran ring attached to A-ring also improved the inhibition value 4. Pterocarpans signicantly. These results indicate that both the hydropho- 50 bicity and the presence of a catechol group play signicant Pterocarpans are the second largest subclass of isoavonoids aer 50 rolesintheabilityoftheisoavones to inhibit acetylcholin- isoavones. They are known as phytoalexins and exhibit a range of esterase. EtOH extracts of the rhizomes of Cyperus rotundus biological activities. 32 new pterocarpans were isolated between (Cyperaceae), used in traditional Chinese medicine as an 2012–2017, and most of them were isolated from Leguminosae antidepressant and anti-inammatory, aﬀorded a new C-30 species. Pterocarpans contain two stereocenters (C-6a and C-11a) 55 prenylated isoavone, 5,7,40-trihydrox-20-methoxy-30-pre- and only two congurations were reported from nature. 55 nylisoavone 181.135 In the search for new bioactive metabolites, reinvestigation of the constituents of the 70% methanolic extract of the whole plant of Clinopodium urticifolium (182 g) (Lamiaceae) resulted in the

16 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

0 0 1 isolation of 22.8 mg of the new pterocarpan (3S,4S)-3 -methoxy-4 - The bioassay-directed fractionation of the EtOAc extracts of 1 hydroxy-7,8-methylenedioxylpterocarpan 182 together with four Pachyrhizus erosus roots (bengkoang, Fabaceae), a tropical and known pterocarpans.136 The new compound exhibited strong subtropical plant used as a skin whitening material in Indo-  cytotoxicity against PC3 cells with an IC50 value of 3.5 mM. nesia, resulted in the identi cation of a new pterocarpan, 141 5 Examination of the constituents of Pueraria alopecuroides designated as 8,9-furanypterocarpan-3-ol 186. The new pter- 5 tuberous roots (Leg.), a plant close to P. mirica,resultedinthe ocarpan displayed signicant tyrosinase inhibitory activity with

isolation and identication of one new pterocarpan 3-O-glyco- an IC50 value of 7.49 mM. However, the absolute congurations 137 side, ()-tuberosin-3-O-b-D-glucopyranoside 183. at C-6a and C-11a for 186 were not determined. The CH2Cl2 extract of the roots and tubers of Adenocarpus cincinnatus (Ball) 10 Maire (Fabaceae), grown in Morocco, potentiated the GABA- 10 induced chloride anion current by 126.5 25.1% at 100 mM and yielded three new pterocarpans 187–189 via bioassay- directed fractionation.117 Structural elucidation was accomplished via ESI-TOF-MS and 1D and 2D NMR spectroscopy, and 15 the absolute conguration 6aR,11aR was determined via elec- 15 tronic circular dichroism (ECD) spectroscopy. Compounds 187

and 189 potentiated IGABA by 488.57 268.6% and 453.87 141.03%, respectively. Two new pterocarpans, (6aR,11aR)-3- methylmaackiapterocarpan B 190 and 2-hydroxy-3-methoxy-8,9- 20 20 methylenedioxy-1-prenyl-(6aR,11aR)-pterocarpan 191, were isolated and identied as minor constituents from the rhizomes and roots of Sophora tonkinensis (Leg.).142 (6aR,11aR)-Maackiain- 3-O-b-D-{[(E)-but-2-enoyl]}glucopyranoside 192 (Sophoratonkin), 25 a new pterocarpan glycoside, isolated by bioassay-guided frac- 25 tionation from S. tonkinensis showed inhibitory activity against ¼ 143 LPS NO production (IC50 33.0 mM). The occurrence of the (2E)-but-2-enoyl moiety at C-600 as an acylating group in natural Maackia amurensis (Leg.), which is used as folk medicine for isoavonoids has been only encountered once previously.10 the treatment of cancer, is rich in prenylated isoavones and Separation of the chemical constituents of G. uralensis resulted 30 pterocarpans.138 Fractionation of the n-BuOH extracts of M. 30 in the identication of a new pterocarpan with the (6aR,11aR) amurensis roots by column chromatography on Toyopearl HW- absolute conguration, named glycyuralin B 193, in addition to 50F sorbent led to the isolation of a new pterocarpan glycoside, ve isoavonoids.107 namely (6aR,11aR)-medicarpin-3-O-gentiobioside 184 together with six other new isoavonoids.138 Structural elucidation of the 35 35 new compound was accomplished via HPLC-PDA-MS, 1H–1H- COSY, HSQC and HMBC analyses. Compound 184 displayed noteworthy antioxidant activity, which accounts for its hep- atoprotective property. Entsandwicensin 185, a new pterocarpan 40 obtained from the roots of Dalea formosa (Leg.), displayed anti- 40 fungal growth inhibitory activity.139 The NMR data of the new compound was similar to that of the known pterocarpan, sand- wicensin.140 Its (6aS,11aS)conguration was established by comparing its experimental CD spectrum with that of sandwi- 45 censin, which is opposite and similar in magnitude. 45

50 50

In the search of drug leads from natural sources, BioBioPha reported the identication pterocarpadiols A–D 194–197,veryrare 55 6a,11b-dihydroxypterocarpans, inadditiontoelevenknownpter- 55 ocarpans from Derris robusta.144 A remarkable feature of the new pterocarpans is the unusual occurrence of a hydroxyl group at C- 11b. Structural elucidation and the conguration at C-6a and C-

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 17 Natural Product Reports Review

146 1 11b were determined via the HMBC, HMQC and ROESY NMR with three known pterocarpans. These compounds were also 1 4 – techniques. The clear ROESY correlation in DMSO-d6 of 6a-OH given another trivial name (kaennavelutinans A C). Compound H-11a revealed the cis fusion of the B and C ring junction, while 203 displayed good cytotoxicity against KB and HeLa cells with 4 correlation of 11b-OH H-11a and H6a indicated the a-orienta- IC50 values of 8.22 and 5.99 mM, respectively; whereas, 144 5 tion of the hydroxyl group at C-11b. The optical rotation values compounds 201 and 202 showed only moderate activities. 5 for the four new pterocarpans were 484.0, 397.0, 507.0,and 476.0 respectively, and accordingly their absolute congurations were assigned as 6aS,11aR,11bS. Isolation of compounds 194–197 brings the number of natural 6a,11b-dihydroxypterocarpans to 10 six,144 all of which were isolated from Leguminosae plants. 10 (6aR,11aR)-3-Hydroxy-9-methoxypterocarpan 8-O-a-D-ribofurano- side 198, with a rare glycosidic ribose, and medicarpin 3-O-b-D- glucopyranoside 6ʹ-acetate 199 were isolated from the whole plant of Gueldenstaedtia verna (Leg.), a traditional Chinese medicine.145 15 Compound 199 was also reported as a trace constituent of Sophora 15 tonkinensis.142 The (6aR,11aR)absoluteconguration of both compounds was determined by optical rotation comparison of their experimental ECD spectra and X-ray diﬀraction analysis.

20 20

25 25 The bioassay-directed isolation of the MeOH extract of Apoptanesia paniculata roots (Fabaceae) using a blood-based bioassay for the growth inhibition of P. falciparum led to the isolation of two simple pterocarpans named apoplanesia- 30 30 carpans A 204 and B 205.147 Both compounds did not display antiplasmodial and antiproliferative activity. The MeOH extract from the stem bark of E. schliebenii yielded a new pterocarpan with the 6aR,11aR relative conguration, 3-hydroxy-10-(2,3- 35 dihydroxy-3-methylbutyl)-9-methoxypterocarpan 206, in addi- 35 tion to three new isoavones 95–97.101

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Peng et al. reported the isolation and identication of the new 10-hydroxy-9-methoxypterocarpan named Pruinosanone D 200 from C. pruinosa roots together with one new isoavone 45 28.51 They considered Pruinosanone D 200 as an isoavan and 45 gave it the following name (3R,4R,200S)-8-(2-methoxybut-1-en-yl)- 4,20,7,200-diepoxy-30-hydroxy-40-methoxyisoavan.51 Pruinosa- none D 200 displayed high inhibitory eﬀects on NO production

with an IC50 value of 0.62 mM, which proved to be better than 50 that of the positive control (aminoguanidine 20.13 mM). Thus, 50 this compound can be considered as a lead candidate for anti- inammatory drug improvement. The Dalbergia genus is a rich source of secondary metabolites, Fractionation of the CH Cl /MeOH extract of the root bark of   2 2 especially pterocarpans, iso avanes, iso avones, and iso- Millettia dura and M. micans resulted in the identication of one 55  55 avanones. Three new C-4 geranylated pterocarpans with the new pterocarpan from each species, named 3-O-prenylmaackiain  – – (6aR,11aR)absolutecon guration, velucarpins A C 201 203,were 207 and micanspterocarpan 208, respectively.148 The 6aR,11aR reported from the CH2Cl2 extracts of Dalbergia velutina roots, absolute conguration of both compounds was derived from the “ ” famously known as Khruea khang khwai in Thailand, together cis conguration of their B/C ring, which was validated by the

18 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

1 strong NOE observed between H-6a and H-11a and the great 1  a 25 ¼ negative speci crotationof[ ]D 129.6 and 134.3 ,respectively, and positive Cotton effect at 288 nm in their ECD spectra. Examination of the vine stems of M. pachyloba afforded the new 5 pyranopterocarpan, pachylobin A 209, together with two new pre- 5 nylated isoavones 137 and 138.121 Theabsoluteconguration of 209 was established by comparing its negative Cotton effect in its 25 CD curve ([a]D ¼30.71 , MeOH) at 223 nm with that of known compounds. Aeschynocarpin 210 isolated from Aeschynomene fas- 10 cicularis (Fabaceae) is considered to be the rst reported pter- 10 ocarpaninthegenusAeschynomene.149 A new pterocarpan glycoside, glycinol-3-O-b-D-glucopyranoside 211,isolatedfromthe MeOHextractoftheaerialpartsofDucrosia ismaelis (Apiaceae) Two new isoavanone bearing a methoxycarbonyl group at displayed potent peroxyl radical-scavenging capacities with an the C-5 position, (3R)-7,20,40-trihydroxy-30-methoxy-5- 15 0 15 ORAC value of 22.79 0.90 mM,whichisstrongerthanthatof methoxycarbonyl-isoavanone 214 and (3R)-7,2 -dihydroxy- 150 0 0 Trolox (24.83 0.12 mM). Two new pterocarpans bearing dihy- 3 ,4 -dimethoxy-5-methoxycarbonylisoavanone 215, were iso- droisopropenylfuryl attached at C-2 and C-3 having the 6aR, 11aR lated from Cassia siamea stem (Leg.).152 Compound 215  and 13S con gurations, named seputhecarpan A 212 and B 213, exhibited potential anti-TMV activity with an inhibition rate of respectively,inadditiontoanewisoavanone were obtained from 20 24.6%. The bioassay-directed fractionation of the EtOAc soluble 20 the MeOH extract of Polychidium contortum,aBotswananfolk fraction of the MeOH extract of Dalbergia odorifera T. heartwood 151 medicine. Pterocarpans 212 and 213 showed weak antioxidant (Leg.) led to the isolation and characterisation of two new 0 0 inhibitory activity with EC50 values of 611 and 88.7 mM, simple isoavanones, (3R)-3,7-dihydroxy-2 ,4 -dimethoxyiso- respectively. avanone 216 (not 3S as mentioned in the original paper) and 0 0 0 25 (3S)-7-hydroxy-2 ,4 ,5 -trimethoxyisoavanone 217.153 Their 25 absolute conguration was determined by CD spectroscopy, which showed a negative Cotton effect at 341 nm (n / p*). Furthermore, two 3-hydroxyisoavanones having the 3S absolute conguration, kenusanone F 7-methyl ether 218 and 30 sophoronol-7-methyl ether 219, were identied from the MeOH 30 extract of D. melanoxylon bark, which is used as traditional Chinese medicine for cleaning wounds.154 Compound 218 displayed inhibitory effects on mycobacterium tuberculosis by 96% with an MIC value of 80 mM, while both isoavanones were 35 inactive against P. falciparum.154 35

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5. Isoﬂavanones 55 55 Isoavanones are rare compared to isoavones and even to pterocarpans, with 31 new structures isolated and characterised during the period covered by this review. All of the new iso- The bioassay-directed fractionation of the EtOAc soluble avanones were isolated from Leguminosae sources. extract of Erythrina addisoniae roots aﬀorded four new

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 19 Natural Product Reports Review

   1 iso avones, two of which were prenylated iso avanones named enantio-enriched iso avanones, an observation that was sup- 1 Erythraddison III 220 and IV 221.100 The 3S absolute conguration ported by the absence of optical activity. The major compound, of both isoavanones was deduced fromthenegativeCottoneffect sedonans A 223, exhibited high growth inhibitory activity against of CD as well as from their negative optical rotations. Compounds C. albicans and C. glabrata with MIC values of 40.7 and 20.6 mM,  5 220 and 221 showed strong inhibitory activity against the PTP1B respectively. Two new iso avanones 226 and 227 were isolated 5 enzyme with IC50 values of 4.6 (stronger than that of tamoxifen) and identied from the C. hirtella roots together with two new and 13.8 mM, respectively. A new uncommon isoavanone, 5,7- isoavones 122 and 123 and one new pterocarpan.112 Compound dihydroxy-20,4-dimethoxy-50-formylisoavanone (erycaffra E) 222, 226 was identied as (3R)-6,30-di(3-hydroxy-3-methylbutyl)-20- was isolated from the stem bark of E. caffra, a tree native to South methoxy-5,7,40-trihydroxyisoavanone based on the data obtained 10 Africa used to treat sores, toothaches, tuberculosis, and arthritis, from HMBC NMR and from the positive Cotton effect at 310 nm 10 together with three prenylated isoavones.155 This compound and negative Cotton effect at 294 nm in its CD spectrum. On the represents the rstreportofanisoavanone bearing a formyl other hand, compound 6,30-di(3-hydroxy-3-methylbutyl)-5,7,20,40- substituent. The structure of the compound was determined using tetrahydroxyisoavanone 227 wasisolatedasaracemicmixture. 1D and 2D NMR spectroscopic data and conrmed by the obser- 15 vation of a retro-Diels–Alder fragment at m/z 152, while the 3R 15 absolute conguration was assigned by comparison of its specic rotation with literature values.

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Further examination of the roots of C. hirtella yielded three new C-30 geranylated isoavanones 228–230 reported in two separate 35 35 papers,114,116 among which compound 230 bears the uncommon methoxycarbonyl group attached to the C-6 position.116 The absolute conguration at C-3 in compound 229 was assigned as 3S based on the positive Cotton effectat325nmandnegativeeffect 40 at 295 nm its the CD spectrum. In the case of compound 230,its 40 CD spectrum presented no Cotton effectat320nm,suggestingits occurrence as a racemate. The numbering and some information in the original paper were confusing and misleading.114

45 45

50 The fractionation of the MeOH extract of Dalea formosa Torr 50 (Fabaceae) roots by silica gel VLC, Sephadex LH-20, and gradient chromatography over silica gel aﬀorded three new isoavonones, sedonans A–C 223–225,threenewisoavans 251–253,andanew pterocarpan entsandwicensin 185.139 The 3S absolute congura- 55 55 tion of compound 224 was determined by comparison of the experimental ECD data (n / p* and p / p* electronic transition) with that of known 3-hydroxyisoavanones. The ECD spectra of compounds 223 and 225 lacked the Cotton eﬀectofthe

20 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

m 1 Examination of the CH2Cl2 root extract of Mucuana pruri- tumor cell lines with IC50 values of 3.1 and 2.5 M, respec- 1 ens (Fabaceae), traditional Indian medicine, afforded two new tively, while compound 238 showed cytotoxicity against the  pyranoiso avanones named mucunone A 231 and B 232,and PC3 cell line with an IC50 value of only 3.6 mM. Phytochemical one new simple isoavanone named mucunone C 233.156 The investigation of the Ptychlobium contortum roots resulted in 5 proximity of the optical rotation of mucunone A 231 to zero the isolation of the uncommon a,a-dimethylallyl-substituted 5 29 ([a]D ¼2.53) and the insignicant Cotton effect in its CD isoavanone having the 3S conguration, designated sepu- spectrum indicated its racemic nature. A negative Cotton theisoavone 239, in addition to two new pterocarpans 212 effect in their CD spectra at 328 nm (3S-conguration) and and 213.151 The new compound 239 showed weak antibacte- a positive Cotton effectat327nm(3R-conguration) were rial and a-glycosidase inhibitory activity and moderate anti- 156 10 observed for compounds 232 and 233, respectively. Des- oxidant activity with an EC50 value of 68.5 mM. Seventeen 10 modianone H 234,anewfuranoisoavanone, isolated via the isoavonoids including the unprecedented 3,7,40-trihydroxy- bioactivity-directed fractionation of the EtOAc soluble extract 2-methoxy-30-geranylisoavanone 240 were isolated from the of Lespedeza maximowiczii leaves (Leg.) showed signicant roots of Psoralea Corylifolia (Fabaceae).122 The structural inhibitory effects on mushroom tyrosinase activity with an feature of 240 istheoccurrenceofanacetalmoiety(2- 15 157 15 IC50 value of 1 mM. methoxy) and the presence of a 3-hydroxyl group. No clear Cotton effect for 240 was observed at 325 nm, which is attributed to the n / p* transition of the 4-CO group, and as aresulttheabsoluteconguration at C-2 and C-3 was not dened. (3R,200S)-8-(2-Methylbut-1-en-4-yl)-7,200-epoxy-20- 20 0 0 20 hydroxy-3 ,4 -dimethoxyisoavanone 241 (pruinosanone C) isolated from the EtOH extract of Caragana pruinosa roots (Leg.) suppressed the NO release in LPS-induced RAW 264.7 125 cells with an IC50 value of 1.58 mM. 25 25

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ArareC-triisoprenylated isoavanone, designated as ormosinol 235, isolated from the root bark of Ormosia henryi (Leg.), a Chinese traditional medicine for the treatment of 45 swelling and inammation, displayed substantial scavenging 45

activity against DPPH radicals with an IC50 value of 28.5 mM and signicant inhibitory activity against three cancer cell 75% of all antibacterial molecules are of natural product lines (A549, LAC and HepG2) with IC values of 4.25, 522 and 50 origin. Recently, an extensive study designed to assess the anti- 7.05 mM.63 7,20,40-Trihydroxy-6-(3-methylbut-2-en-1yl) mycobacterial activity of traditional medicinal plant extracts used 50 isoavanone 236 was obtained via an HPLC-based activity 50 by the Mayo population against Tuberculosis (TB) and respiratory proling method from the CH Cl extract of Adenocarpus 2 2 diseases was carried out. The CH Cl root extract of Rhynchosia cincinnatus roots and tubers (Leg.).117 Two new isoavanones 2 2 precatoria (Fabaceae) yielded two newly identied anti- bearing methoxycarbonyl groups, (3R)-7-hydroxy-40-methoxy- mycobacterial prenylated isoavanones named precatorin A 242 5-methoxycarbonylisoavanone 237 and (3R)-8-hydroxy-40- 55 and precatorin B 243, in addition to a new isoavone named 55 methoxy-7-methoxycarbonylisoavanone 238,togetherwith precatoren C 143.124 Assignment of the (3R) absolute conguration seven known isoavanones were isolated from 70% aqueous of 242 and 243 was carried out by ab initio computational analysis acetone extracts of Desmodium oxyphyllum (Leg.).158 of their ECD spectra. Precatorin A 242 and B 243 inhibited the Compound 237 exhibited cytotoxicity on the NB4 and SHSY5Y

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 21 Natural Product Reports Review

m   1 growth of M. tuberculosis with an MIC value of 163 Mandkilled Iso avans, iso avenes and 3-arylcoumarin are characteristic 1 the bacteria with an MBC value of 297 mM. (3S)-7-Hydroxy-4- metabolites of the plants of the Glycyrrhiza genus. A new isoavan 0 0 0 methoxyisoavanone 3 -b-D-glucopyranoside 244 isolated from bearingaprenylgroupatC-6andhavinga5,7,2,4 -oxygenation the aerial part extracts and exudate of Ononis angustissima Lam, pattern named (3S)iconisoavan 248 wasrecordedasaconstit- 163 5 a plant widespread in the Sahara, through antioxidant-directed uent of the roots of Glycyrrhiza iconica. The new compound 248 5 fractionation, showed moderate antioxidant activity.159 exhibited potent activity against Salmonella typhimurium with an MIC value of 21.6 mM. In a combined phytochemical and biological 6. Isoflavans, isoflavanols and isoflav- approach to identify the active components of Licorice, 122 compounds, among which two new isoavans named Glycyuralin 10 3-enes A 249 and C 250, and four other new isoavonoids were isolated 10 and characterised from Glycyrrhiza uralensis roots and rhizomes.107 Isoavans are isoavones with a fully reduced C-ring and constitute the h largest subgroup of isoavonoids. Many isoavans were discovered by challenging plant tissues with 6,13 15 fungi or abiotic elicitors and act as phytoalexins in legumes. 15 The most common oxygenation pattern of aromatic carbons in isoavans is 7,20,40 > 5,7,20,40 > 7,20,30,40 > 7,20,30,40,50. Isoavans are almost equally divided between simple and prenylated ones, and all of them were found in plants from the Leguminosae 20 family. The C-3 absolute conguration was established by 20 optical activity measurements or by comparison of experimental electronic circular dichroism (ECD) data with either that of known isoavans or with computational simulated spectra. 600-O-Acetyl-(3R)-7,20-dihydroxy-30,40-dimethoxyisoavan-7-O-b- 25 D-glucopyranoside 245,anewisoavan glycoside, was isolated and 25 identied from the roots of Astragalus membranaceus var. mon- gholicus (Fabaceae).160 Fractionation of the antiprotozoal active

CH2Cl2/MeOH (1 : 1) extract of Abrus precatorius aerial parts (Fabaceae), a shrub originating from India, resulted in the isola- 30 tion and identication of a new isoavan quinone, abruquinone I 30 246, one new isoavanol 263 together with two known isoavan quinones and one known isoavanol.161 A year later, a highly oxygenated isoavan named abruquinone L 247 together with two new isoavanols 264 and 265 were isolated from the whole plant 35 35 ofthesamespecies.162 The 3R absolute conguration of the iso- avan 247 was determined by comparing its experimental ECD The MeOH extract of Dalea formosa roots (Fabaceae) aﬀorded spectrum with the data calculated for 3R and 3S.Compound246 six new prenylated isoavonoids, including three new isoavans and 247 displayed strong in vitro activity against T. b. rhodesiense with the 7,8,20,40-oxygenation pattern, designated as sedonans with IC values of 0.3 and 0.2 mM, respectively.161,162 40 50 D–F 251–253.139 Theabsolutecongurations of isoavans 251 and 40 253 were assigned as 3S by comparison of their experimental ECD spectrawiththatofknownisoavans, while the absolute cong- uration of compound 252 wasassignedas3R based on its CD spectrum. Compounds 251–253 exhibited antifungal activity 45 45 against S. cerevisae strains (the double knockout PDR1 and PDR3 as well as the triple knockout of PDR5, SNQ2 and YOR1).

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22 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

– 166 1 The fractionation of the EtOH extract of Derris robusta twigs and simii with 52 70.3% inhibition. A remarkable feature of 262 is 1 leaves, a rich source of isoavonoids, especially prenylated pter- the unexpected occurrence of a hept-2-enyl substituent at C-8 ocarpans and isoavones, yielded a new simple isoavan named 6- and the unusual presence of a formyl moiety at C-20. hydroxyisosativan 254, in addition to four new isoavones 115– In the search for new natural compounds possessing 110 5 118. The structure of 6-hydroxyisosativan 254 was inferred from antitrypanosomal activity, Hata et al., in two separate reports, 5 the 1D and 2D NMR techniques, while its relative conguration described the identication of three new isoavanols, abru-

wasdeterminedas3R by comparison of its negative rotation value quinone H 263,J264 and K 265,fromtheCH2Cl2/MeOH (1 : 1) (11.7, MeOH) with that of 3R vestitol derivatives.164 Wang et al. extract of Abrus precatorius (Fabaceae) together with the new reported the isolation of two new isoavans, (3R)-7,40-dihydroxyisoavans 246 and 247.161,162 The absolute congurations of 10 8,20,30-trimethoxyisoavan 255 and (3R)-7,20,40-trihydroxy-8,30- compounds 263–265 were determined to be (3S,4S), (3S,4R), 10 dimethoxyisoavan 256 from the EtOH extracts of Spatholobus and (3S,4R), respectively, by comparing their experimental suberectus (Leg.) and (3R)-7,20,40-trihydroxy-5-methoxyisoavan 257 ECD spectra with data calculated for (3S,4S)and(3S,4R). from the EtOH extracts of Flemingia macrophylla (Leg.).133 Two new These three isoavonols strongly inhibited T. b. rhodesiense 0 0 0 0 0 5,7,2 ,4 ,5 -oxygenated isoavans, designated as (3R)-4 ,5 -dihy- with IC50 values ranging from 0.11–12.0 mM. Rugosa- 15 droxy-5,7,20-trimethoxy-6-(3-methylbut-2-enyl)isoavan 258 avonoids D 266 and E 267,twonew4-isoavanols isolated 15 and (3R)-7,20,40-trihydroxy-5,50-dimethoxy-6-(3-hydroxyisoprenyl) from the MeOH extracts of Rosa rugose buds (Rosaceae), dis- isoavan 259, together with other nine new isoavonoids were played weak cytotoxicity on ve human tumor cell lines (NB4, isolated from the roots of C. hirtella.114 A549, SHSY5Y, PC3, and MCF7).167 The new cordifoliavanes The strong cytotoxicities of numerous pterocarpans and A 268 and B 269 isolated form the extracts of Codonopsis 20 20 isoavones reported from D. velutina147 encouraged further cordifolioidea (Campanulaceae), a herb used as food in China, search for more bioactive compounds from this species. Frac- using silica gel column chromatography followed by HPLC

tionation of the CH2Cl2 extract of D. velutina roots led to the showed weak anti-HIV activities with EC50 values of 5.26 and identication of two new C-8 geranylated isoavans, devel- 2.25 m mL 1, respectively.168  25 utinanes A 260 and B 261, having 3S and 3R absolute con gu- 25 rations, respectively, as revealed from their CD spectra.165 Both compounds displayed moderate cytotoxicity against ve human – cancer cells with IC50 values ranging from 4.69 33.19 mM. A new isoavan named colutin 262 reported from the EtOAc soluble 30 fraction of Colutea armata (Fabaceae), showed signicant anti- 30 fungal activity against Trichophyton schoen leinii, Aspergillus niger, Pseudallescheria boydri, Candida albican and Trichophyton

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45 45 As part of ongoing search for biologically potent secondary metabolites from Turkish medicinal plants, a new isoavene prenylated at C-6, iconisoavene 270, was identied from the methanolic root extract of Glycyrrhiza iconica together with the 50 new isoavan 248.163 50

7. Rotenoids 55 55 In contrast to the fact that almost all known natural rotenoids comprise an isoprenoid-derived substituent usually at the C-8 position and sometimes at the C-10 position,9 a literature review indicated that plants of the family Nyctaginaceae are

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 23 Natural Product Reports Review

 1 important sources of simple rotenoids, some of which possess a trans B/C junction and its absolute con guration was 1 a methyl group at the C-10 position. established as 6aR,12aR.OblarotenoidC285 exhibited weak activity against the human breast cancer cell line MDA-MB-

231 with an IC50 value of 93.8 mM. 5 5

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Do et al. reported the identication of three new rotenoids, Boeravinone K 271, 10-demethylboeravinone C 11-O-b-D-glu- 20 20 copyranoside 272 (boeravinone N) and 6-boeravinone M 273 (6-demethylboeravinone G) together with two new coumaronochromones 299 and 300 from the aerial part of Boerhaavia erecta L.169 In the search of COX inhibitory components from  25 Indian medicinal plants, ve optically inactive simple rote- 25 noids, boeravinone K–O 274–278, together with four known rotenoids were identied via fractionation of the methanolic extract of Boerhaavia diﬀusa L. (Nyctaginaceae) roots.170 The new compounds 274–278 displayed only moderate anti- 30 inammatory activities. Bioactivity-directed fractionation of 30 the EtOAc extract of Mirabilis himalaica (Nyctaginaceae), Tibetan folk medicine for the treatment of uterine cancer, led to the isolation of mirabijalone E 279, which is fully oxidized at C-6, a new rotenoid that showed cytotoxicity against A549 1 171 35 cells (IC50 ¼ 2.7 mgmL ). Another new C-10 methylated 35 rotenoid named abronione 280 was isolated from Abronia nana (Nyctaginaceae) together with three known rotenoids.172

Fractionation of the CH2Cl2/MeOH extract of Millettia usaramensis ssp. usaramensis root (Leg.), a shrub used in Kenyan 40 traditional medicine as an antidote against snake bites, 40 showed cytotoxic activities against MDB-MB-231 cells with an 1 IC50 value of 11.63 mgmL and afforded 12-dihydrousarar- otenoid B 281 and C 282.173 The identication of compounds 281 and 282 brings the number of rotenoids bearing hydroxyl 45 45 groups at C-12 and C-12a to three. The trans-geometry of the B/C ring junction of 281 was derived from the strong NOEs and from the coupling constants while the (6aR,12R,12aR) congurations of the 12a-dihydrorotenoids was established  a 20 50 by the high positive speci crotationof[ ]D +96 and positive 50 ECD Cotton effect at 295 nm and by comparing these data with that of the 12-dihydrorotenoids174 isolated previously The CHCl3-soluble MeOH extract of M. caerulea fruits fromthesamespecies.Fournewrotenoids,oblarotenoids ff – –  (Graham) Baker showed e ective cytotoxicity against the HT- A D 283 286,andanewiso avone 104 were isolated from the ¼ 1 29 human colon cancer cell line (IC50 2.0 mgmL )and 55 leaves of M. oblata ssp. teitensis.104 Oblarotenoids A 283,B284 55 yielded three new rotenoids named caeruleanone A–C 287– and C 285 have cis B/C fusion and (6aR,12aR), (6aR,12aS)and 289, together with eleven known rotenoids.175 Caeruleanone A (6aS,12aS), respectively, as indicated from their ECD spectra 287 represents the rst example of a rotenoid in which the D- and specic optical rotation, while oblarotenoid A 286 had ring aromaticity is disturbed, while compound 288 presents

24 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

 1 the rst example of a naturally occurring rotenoid bearing C- 1  d and O-prenyl moieties on the D-ring. The chemical shi sof H 6.64, 6.54, and 6.53 ppm for H-1, H-6a and H12a in the new compounds, respectively, suggested their relative congura- – 5 tion, which indicated a cis B/C junction (6.4 6.8 ppm) versus 5 the deshielded trans form (7.6–7.9 ppm). The zero specic rotation and X-ray diﬀraction analysis conrmed the cis- racemate conguration of the unprecedented rotenoid 287. Rotenoid 288 showed strong mitochondrial transmembrane ¼ 10 inhibition (IC50 0.07 mM) and quinone reductase (QR) 10 induction activities, while 289 only exhibited QR induction activity. The lack of bioactivity of the unusual rotenoid 287 may be attributed to the disruption of the aromaticity in its D- ring. Fractionation of the n-hexane-soluble MeOH extract of 15 the same plant using silica gel chromatography led to the 15 isolation and identication of ve new isoavonoids, including three prenylated rotenoids designated as ()-caeruleanone D 290,()-3-deoxycaeruleanone D 291,and()-3- hydroxycaeruleanone A 292.105 Thisisthefourthreportofthe 20 20 occurrence of the unusual geminal diisoprenyl moiety causing the disturbance of the aromaticity group in iso- avonoids.105,175–177 All such modied structures were isolated from the Millettia genus species. It is well known that pre- 25 nylation of rotenoids occurs once the formation of the A/B/C/ 25 Dringsystemiscompleted.6 Dimethylallyl diphosphate (DMAPP) is the source for the isoprene unit being integrated at the D-ring.6 Based on these results, an anticipated biogenetic route for the D-ring substitution of rotenoids 287, 288 0 30 and 292 was proposed from rot-2 -enonic acid, as depicted in 30 Scheme 1.

Chromatographic fractionation of the CH2Cl2–MeOH extract of Amorpha fruticosa fruits (Fabaceae) using vacuum-liquid chromatography led to the isolation of nine new iso- 35 avonoids, among which were the three prenylated rotenoids 3- 35

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Scheme 1 Anticipated biogenetic pathways for the D-ring prenylations of 287, 288 and 292.

This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 25 Natural Product Reports Review

ﬀ 1 O-demethyldalbinol 293, 6a,12a-dehydro-3-O-demethylamor- (Leg.), a Thai traditional medicine, a orded two new furano 1 phigenin 294 and (6aR,12aR,50R)-amorphigenin 295.79 None of coumaronochromones designated as apioisoavone 303 and the new rotenoids displayed antibacterial activity against S. isoapioisoavone 304 together with een known isoavones.180 aureus ATCC137094 and ATCC25923. The two compounds diﬀer only in the site of the attached iso- 0 5 propenyl dihydrofuran moiety. 5-Methoxy-2,5,7,4 - 5 8. Coumaronochromones tetrahydroxycoumarono-chromone 305 isolated from the EtOAc soluble methanolic extract of Apios americana roots (Leg.) using Only 11 new examples, 296–306, of this uncommon isoavonoid silica gel column chromatography, C-18 and Sephadex displayed subclass were isolated and identied from Leguminosae and inhibitory activity on soluble epoxide hydrolase (sEH) with non-Leguminosae families during the review period. 10 a dose-dependent IC50 value of 43.2 0.4 mM and acted as 10 a competitive inhibitor (21.0 0.8 mM).181 An additional simple coumaronochromone named suaeglaucin A 306 was isolated from the herb of Suaeda glauca (Bunge, Chenopodiaceae) together with ve known isoavonoids.182 15 15

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35 Screening of the bioactive EtOAc extract of the whole fresh 35 fruits of Ficus benjamina var. nuda (Moraceae) resulted in the isolation of two new coumaranochroman-4-ones 296 and 297 in addition to six new isoavones 149–154.127 The absolute conguration at C-2, and C-3 for both compounds was not re- 9. 3-Arylcoumarins 40 ported. Fractionation of the EtOH extract of Derris elliptica 40 aerial parts (Leg.), a climbing shrub distributed in Southeast Four new 3-phenylcoumarins named sphenostylisin D–G 307–310, Asia, led to the isolation and identication of 6,40-dihydroxy- together with one new complex isoavone 148 and three new 7,50-dimethoxycoumaronchromone 298.178 Boeravinone L 299 complex dimeric isoavonoids, sphenostylisins A–C 372–374, (trivial name: 10-demethylboeravinone J) and (2S,3S)-5,7,40- were isolated from the bioactive chloroform-soluble MeOH extract 45 0 45 trihydroxy-2,3-dihydrocoumaronochromone 4 -O-b-D-glucopyr- of Sphenostylis marginata ssp. erecta root bark (Fabaceae) using anoside (Boeravinone O) 300 were identied from the EtOAc a bioactivity-directed isolation approach.126 The structures of the extract of the Boerhaavia erecta L. aerial parts (Nyctaginaceae) new compounds were determined via detailed spectroscopic together with three new rotenoids 271–273.169 40,50-Dihydroxy-5,7- analysis, including NMR and HRESIMS analyses. Sphenostylisin – – ﬀ 50 dimethoxy-6-(3-methylbut-2-enyl) coumaronochromone 301 iso- E G 308 310 are isomers with di erent arrangements only in their 50 lated from Campylotropis hirtella root (Leg.) displayed inhibitory respective side chain at C-6. These side chains are thought to be

eﬀects on B and T lymphocyte activity with IC50 values of 0.28 and derived from an a,a-dimethylallyl group through oxidation, rear- 1.55 mM, respectively.112 In the search for bioactive compounds rangement, and cyclization.126 This is the rstreportofthepres- from medicinal plants of Yunnan, China, a new coumar- ence of the unusual side chains among the naturally occurring 3- 0 0 55 onochromone, 2,2 -epoxy-4 -methoxy-3,7-dihydroxy-isoavanone phenylcoumarins.126 Su et al. reported the isolation of pterosonin 55 302, was isolated and identied from the Horseldia pandur- F 311 from the EtOH extract of heartwood of P. soyauxii together ifolia trunk (Myristicaceae).179 Compound 302 was tested for its with seven new natural isoavones 10–16.44 Compound 311 dis- cytotoxicity against ve human tumour lines with no activity. played cytotoxicity against A549, Panc-28, and HCT-116 cells with

Examination of the EtOH extract of the tuber of Apios taiwanianus GI50 values of 7.39, 25, and 19.17 mM, respectively.

26 | Nat. Prod. Rep.,2018,xx,1–40 This journal is © The Royal Society of Chemistry 2018 Review Natural Product Reports

1 Plants of the genus Morus (Moraceae) are substantial sources 1 of isoprenylated polyphenolics with diﬀerent structures, such as arylbenzofurans and Diels–Alder adducts (50 compounds), which exhibit vital bioactivities related with anti-diabetes and anti-  5 in ammation. Most of the 2-arylbenzofurans were isolated from 5 the genus Morus (Moraceae). Three new 2-arylbenzofuran possessing one isoprenyl and one geranyl group, named wittifurand H 314,I315 and U 316, were isolated from the EtOH extract of Morus wittiorum stem bark.184 Compound 315 exhibited strong 10 anti-inhibitory activity and selective cytotoxicity against the 10

human gastric cancer cell line BGC-823 with an IC50 value of 1.45 mM. Fractionation of the bioactive constituents of M. mesozygia (Moraceae), a small-sized tree distributed in the tropical African forest, yielded a new 2-arylbenzofuran derivative named 15 10. Coumestans (+)-dimethylsmoracin O 317.185 (20R)-20,30-Dihydro-20-(1-hydroxy- 15

Only two examples of this isoavonoid subclass were isolated and identied during the review period. Phytochemical examination of C. hirtella roots aﬀorded one new coumestan, 2,40,50-trihydroxy- 20 5-methoxy-2-(3-methyl-2-butenyl)-coumestan 312, seven iso- 20 avones 124–130 and two new isoavans 258 and 259.114 Frac- tionation of the constituents of F. philippinensis (Leg.) roots by several types of column chromatography on silica gel, Sephadex LH-20 and ODS aﬀorded one new pterocarpoid named deme- 25 thylwedelolactone 313, which displayed antiproliferative activity 25 183 against PC-3 cells with an IC50 value of 8.33 0.12 mM.

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This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep.,2018,xx,1–40 | 27 Natural Product Reports Review

0 0 1 1methylethyl)-2,6 -bibenzofuran-6,4 -diol 318 and 5,6-dimethoxy- monoterpenoid 2-arylbenzofurans 320 and 321 displayed the 1 2-(3-hydroxy-5-methoxyphenyl)benzofuran 319 are new iso- highest inhibition. Purication of the cell culture of M. alba, avonoids isolated from the stems of M. notabilis.186 a Chinese traditional medicine, led to the identication of a 2- Phytochemical investigation of the constituents of the EtOH arylbenzofuran bearing an oxacycloheptene attached to the A-ring 188 5 root bark extracts of Morus alba var. tatarica (Moraceae) led to the named 5-dehydroxy-moracin U 330. 5 isolation and identication of ten new B-ring geranylated 2-aryl- Further phytochemical investigation on the M. alba roots benzofurans 320–329 together with four known ones.187 It is aﬀorded six additional new prenylated 2-arylbenzofurans, two noteworthy that all the new compounds possess the 6,30,50- moracin O-glycosides 331 and 332 and moracin P glycosides oxygenation pattern. The relative structures of the new compounds 333–336.189 The new 2-arylbenzofuran O-glycosides displayed 10 were established based on HMBC, HSQC, NOESY and ROESY signicant protective eﬀects on doxorubicin-induced cell death 10  ¼ – 0 spectroscopic data analysis and the absolute con gurations of (IC50 9.5 2.6 39.5 7.2 mM), among which moracin P-3 -O- compounds 320, 322, 323 and 328 were determined via the b-D-glucopyranoside 336 showed the highest activity. Earlier,

induced ECD of the formed [Rh2(OCOCF3)] complex and Snatzke's albafuran D 337, another new C-4 geranylated 2-arylbenzofuran, method. Compounds 320, 321,and324–326 exhibited moderate was isolated and identied from the same source.190 15 15 inhibitory activities against a-reductase with IC50 values ranging Four new benzofuran-type stilbene glycosides 338–341 were from 11.9 1.3–33.1 1.9 mM, among which the two isolated from Cortex Mori Radicis, the root bark of some Morus species (e.g., M. alba, M. mongolica, M. cathayana, and M. aus- tralis) together with eight known benzofuran-type stilbenes.191 The new compounds were characterised as moracin P glyco- 20 20 sides and moracin O, namely the glycosides as (9R)-moracin P 0 3 -O-a-L-arabinopyranoside 338,(9R)-moracin P 9-O-b-D-gluco- 0 pyranoside 339,(9R)-moracin P 3 -O-b-D-glucopyranoside 340 and (9R)-moracin O 10-O-b-D-glucopyranoside 341 based on the 25 spectroscopic and chemical analysis. 25 Continuous chemical investigations on the root bark of M. alba (Sang-Bai-Pi) led to the isolation of thirteen Diels–Alder adducts and four 2-arylbenzofurans, among which, the two Diels–Alder adducts, Albasins A 342 and B 343, and the 2-aryl- 30 benzofuran, Albasin C 344 were reported for the rst time.192 30 Albasins A 342 and B 343 are believed to be biogenetic Diels– Alder products of intermolecular [4 + 2] cycloaddition from chalcone (dienophile) and a dehydrogeranylated 2-arylbenzofuran moiety (diene).192 Compound 342 was assigned as a trans– 35 trans adduct with the absolute conguration of 300R,400R, and 35 00  a 25 ¼ 5 S by the negative speci c rotation of [ ]D 217.7 and the negative Cotton eﬀect around 339 nm, while adduct 343 was assigned as a cis–trans with the absolute conguration of 300S, 00 00 25 4 R, and 5 S by the positive specic rotation [a]D ¼ +440.0 and 40 the positive Cotton eﬀect around 319 nm. The three new 40 compounds 342–344 displayed inhibitory activities against

PTP1B with IC50 values of 1.59 0.66, 5.12 2.66 and 7.13

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ﬀ 25 2.46 mM, respectively, where compound 342 was more e ective 25 ¼ than the positive control (oleanolic acid, IC50 3.31 0.02 mM).192 Leavigasin C 345, a C-7 geranylated 2-arylbenzofuran, was isolated from the twigs of M. laevigata.193 Three new bioactive C-5 prenylated 2-arylbenzofurans named regiafuran 30 A–C 346–348 were isolated and identied from the stem bark 30 Chlorophora regia (Moraceae), a Ghanaian medicinal plant distributed across West Africa, which showed remarkable free

radical scavenging activities with IC50 values of 5.6, 6.8 and 12.0 mM, respectively.194 35 Phytochemical study of the EtOAc extract of Artocarpus 35 gomezianus root bark (Moraceae) led to the isolation of two new 2-arylbenzofurans, namely 13-O-methyllakoochin B 349 and artogomezianin 350, together with six known compounds.195 Artogomezianin 350 displayed high a-gluco- 40 40 sidase inhibitory activity with an IC50 value of 18.25 0.10 mM. Fractionation and purication of the EtOH extracts of the fruits of Livistona chinensis (Arecaceae), a species of the subtropical palm tree of east Asia, led to the identication of 2-(30-hydroxy-50-methoxyphenyl)-3-hydroxymethyl-7-methoxy- 45 45 2,3-dihydrobenzofuran-5-carboxylic acid 351 and 7-hydroxy- 5,40-dimethoxy-2-arylbenzofuran 352.196 Compound 351 and 352 exhibited anti-proliferative activity on four cell lines Continuous examination of the constituents of G. uralensis (HL-60, Mata, HepG2, and CNE-1) with IC50 values ranging (Fabaceae) roots and stolons led to the isolation of two new 2- – m 50 from 7.7 82.7 M. Phytochemical investigation of the aryl-3-methylbenzofurans, namely neoglycybenzofuran 355 and 50 aqueous acetone extracts of the whole plant of Arundina its 20-O-methyl ether 356 (40-O-methylglycybenzofuran), as gramnifolia (bamboo orchid, Orchidaceae), a plant used in minor constituents.198 Neoglycybenzofuran 355 exhibited anti- Chinese folk medicine as a diuretic agent, led to the isolation VRE eﬀects with MICs of 45 mM. Glycyuralin E 357, a new 2- of two new 2-arylbenzofurans named graminiphenols F 353 arylbenzofuran containing the uncommon hydroxymethyl 197 0 55 and G 354. The 4 -O-methylated compound 354 displayed substituent at C-3, was isolated from G. uralensis Fish together 55 anti-HIV-1 activity with therapeutic index values above with ve other new isoavonoids.107 The bioassay-guided 100 : 1.

ﬀ 1 fractionation of the EtOH extract of C. hirtella root a orded the Chromatographic studies on the EtOAc-soluble MeOH 1 3,7-dihydroxy 2-arylbenzofuran 358 and the C-3 formyl 2-aryl- extract of Daphne oleoides (Thymelaeaceae), a plant grown in benzofuran 359.115 Superbanone 360, a new 2-aryl-3- northern Pakistan, led to the isolation and identication of two   00 benzofuranone, was isolated and identi ed from the CH2Cl2 new symmetrical biiso avones, 8,8 -bi-6-hydorxyorobol 361 and 00 0 200 – 5 extract of the tube roots of Butea superba Roxb. (Fabaceae), 8,8 -bi-6,2 -dihydroxygenistein 362. An additional three C-8 5 known as Red Kwao Khruea and used as Thai traditional medicine.199 Superbanone 360 represents the rst example of a naturally occurring compound in the 2-methoxy- benzofuranone class. However, since only small amounts of 10 this material was isolated, the absolute congurations at C-2 in 10 360 was not determined. The new compound did not exhibit a- glucosidase and antimalarial inhibitory activities.

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12. Isoﬂavonoid dimers, heterodimers and conjugates 40 40 This diverse group covers structures formed between two similar or diﬀerent isoavonoids as well as between iso- avonoids and other type of natural products.

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00  – – – – 1 C-8 biiso avones, dapholidins A C 363 365, were reported methoxyformononetin (afromosin) linked by a C-7 O C-7 ether 1 203 from the EtOAc-soluble fraction of the MeOH extract of the bridge. The CHCl3-soluble MeOH extract of the root bark of same plant.201 As part of a plan for the discovery of new eﬀective Sphenostylis marginata E. Mey. ssp. erecta (Baker f.) Verdc. [syn: tyrosinase inhibitors from natural products, Hu et al. reported Dolichos erectus Baker f.; Sphenostylis erecta (Baker f.) Hutch. ex  5 the isolation and identi cation of two new 2-arylbenzofuran Baker f.], a medicinal plant used as an antiseptic and for the 5 dimers named morusyunnansin A 366 and B 367 from the EtOH treatment of abdominal pain and fever in some African coun- extract of M. yunnanensis leaves (Moraceae).202 The two mono- tries, aﬀorded three heterodimeric compounds having two mers of 2-arylbenzofuran dimers are joined by their carbon characteristic novel carbon skeletons, named sphenostylisins atoms through the isoprenoid linker. Three genistein-based A–C 372–374, in addition to ve new isoavonoids.126 The 10 isoavone dimers named cudraisoavones Q–S 368–370, connectivity of either the 3-phenylcoumarin A subunit in 10 together with eight new isoavones were isolated and charac- sphenostylisin A 372 or the isoavan subunit in sphenostylisin terised from the EtOAc-soluble MeOH extracts of the fruits of C 374 with morachalcone B subunits was determined by HMBC Maclura tricuspidata (previously known as Cudrania tricuspi- techniques to be C–C-linked on C-30 to C-200 of the benzofuran data).131 The fragment ion peak at m/z 337 [M + H 336]+ ob- unit. Morachalcone B is a chalcone fused with furan at C-alpha 15 tained from retro Diels–Alder-type fragmentation in EISMS of and C-2. Sphenostylisin B 273 comprises the 3-phenylcoumarin 15 compound 368, in addition to COSY and HMBC spectra, sug- C–C-linked at C-50 via a methylene group linker to C-30 of 2- gested that the two isoavone subunits were linked at C-6 by arylbenzofuran. The new dimers 372–374 showed strong 131  a monoterpene (dihydropyran). The two iso avone subunits hydroxyl radical scavenging activity with ED50 values ranging in the uncommon dimers 369 were linked at C-6 via a trans from 0.71–0.91 mM and displayed very potent NF-kB p65 20 20 double bond attached to C-6 of one isoavone unit and to the C- inhibitory activity. Sphenostylisin A 372 was found to be a very

1 in dihydropyran, which is attached to C-6 and 7-O in the other potent NF-kB p65 inhibitor with an IC50 value of 6 nM, which isoavone unit, as revealed by HMBC and COSY spectra. The was >10 times more potent than the positive control (rocagla- absolute congurations of the compounds were determined by mide).126 This powerful inhibition activity can be attributed to 25 employing ECD spectroscopy in combination with quantum- the carbonyl group (C-2) of the lactone as well as to the carbonyl 25 chemical ECD calculations. group in the benzofuran unit, which are both present in 372 but Fractionation of Amphimas pterocarpoides root extracts (Leg.), one of them is absent in 373 and 374.126 The structures of grown in tropical Africa and used as traditional medicine in dimers 372–374 were established by 2D NMR spectroscopic data Cameroon, led to the isolation and identication of a new iso- and conrmed by tandem mass spectroscopy (ESIMS/MS). The 30 avone dimer named amphiisoavone 371, which was derived dimer 372 did not break signicantly through carbon–carbon 30 from 7-hydroxy-5,6,40-trimethoxyisoavone and 6- bond scission when collision-induced dissociation (CID) was

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1 employed, and thus, only one major fragment peak from the tonkinensis roots showed moderate radical scavenging activi- 1 parent ion (m/z 697.22 [M + Na]+) was observed at m/z 679.22 [M ties.204 Shandougenine A 375 is a unique dimeric 2-arylbenzo- + – 0 +Na H2O] . This may be produced through a proton rear- furan with a C-3 C-5 linkage, while shandougenine B 376 rangement similarly to a McLaﬀerty rearrangement, followed by represents the rst naturally occurring 2-arylbenzofuran dimer – 5 cyclization to form the pyrane ring and loss of one water with a C-3 C-3 linkage. 5 molecule, as indicated in Scheme 2. On the other hand, the Twelve heterodimers, hirtellanones A–L 377–388, composed dimer 373 was disconnected at the methylene group to yield the of 2-an arylbenzofuran unit joined to either an isoavan, iso- 2-arylbenzofuran fragment 373a with an m/z 333.14 [M + Na avone or isoavanone unit, were isolated from the EtOH + 205 C21H18O5] fragment and a quinone methide fragment 373b extract of Campylotropis hirtella (Fabaceae). The natural + 126  10 with m/z 373.14 [M + Na C19H18O4] . occurrence of 2-arylbenzofurans attached to iso avonoids has 10 Two 2-arylbenzofuran dimers, shandougenine A 375 and B rarely been reported, with only eight such compounds previ- 376, isolated from the antioxidative EtOH extract of Sophora ously extracted from Lespedeza cyrtobotrya Miq. and L.

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Scheme 2 Tandem MS fragmentation pathway for compounds 372 and 373.

 206,207   1 oribunda. Each dimer is linked via a carbonyl bridge, double bond in the iso avonoid (iso avone) moiety may be 1 which is vital in initiating the phenol oxidative coupling reac- essential for immunosuppressive activity. Further examination tion the at C-30 of the isoavanone or isoavan to the C-8 of the of the extract of C. hirtella led to the isolation and identication 2-arylbenzofuran. Most of the compounds displayed immuno- of the rst isoavan-coumaronochromone dimer reported to ﬀ  48 5 suppressive e ects on Con A and LPS-induced splenocyte date, 389, together with an unusual iso avone 23. The 5 proliferation in vitro. The heterodimer 384, an isoavone linked proposed biosynthetic pathway suggested that the unusual

to 2-arylbenzofuran, showed the highest activity with IC50 values dimer 389 was derived from hirtellanone C 381 reported from of 3.68 mM for T lymphocyte and 1.79 mM for B lymphocyte the same plant via a sequence Michael addition-type reaction, suppression. These results revealed that the occurrence of a 2,3- as depicted in Scheme 3.48 10 10

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Scheme 3 Proposed biosynthetic pathway for dimer 389.

25 25 Phytochemical investigation of the antibacterial and anti- rare C-8 methylated formononetin 7-O-a-L-rhamnopyrano- fungal active MeOH extract of Chlorophytum tuberosum Roxb side. Gynandrinone 391, another new isoavone dimer, iso- roots (Asparagales), used by indigenous people of India to lated from the MeOH extract of Gynandriris sisyrinchium cure various ailments, led to the isolation of a bis- (Iridaceae) displayed signicant antioxidant activity with an  42  30 iso avonoid glycoside characterized as bis(8-methyl- IC50 value of 41.8 mM. The iso avone dimer is derived from 30 0 00 0 0 4 methoxy-7-O-a-L-rhamnopyranoside)-C-5–C-5 -bisiso- 2 ,3 -dimethyl tenuifone and irisolidone linked by the C-5–O– avone 390.208 This symmetrical dimer is derived from the C-7 ether bridge.

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Scheme 4 Suggested biosynthetic pathway for compounds 392–394.

35 35 Phytochemical study of the twigs and leaves of Belamcanda families. In the search for biologically active compounds, chinensis (Iridaceae), Chinese traditional medicine for the Campylotropis hirtella (Franch) Schindl. (Leg.) aﬀorded the treatment of throat ailments, resulted in the identication of highest number of isoavonoids (36 new isoavonoids), fol- three unprecedented spiroiridals attached to isoavones at the lowed by Maclura tricuspidata with 24 isoavonoids and Morus – – 209  40 C-8 position named belamcandanins A C 392 394. The rela- alba with 17 new iso avonoids during the review period. 40 tive congurations of the spiroiridals were determined by ana- Bioactivity-guided fractionation of plant extracts resulted in the lysing their 1H–1H coupling and their NOE and ROESY data. The isolation of several very potent bioactive isoavonoids that can anti-relationship of H-80/H-90 and H-90/H-100 was conrmed by be potential lead drug candidates. The isoavone dimers 372– their 10.8 Hz coupling constants. The biosynthetic pathway for 374 extracted from Sphenostylis marginata subsp. erecta (Baker 45 the unusual compounds was suggested starting from the f.) Verdc showed eﬀective hydroxyl radical scavenging activity 45 – biogenic belamcanda 395, as depicted in Scheme 4. The latter with ED50 values ranging from 0.71 0.91 mM, as well as very may undergo deacetylation and hydrogenation followed by potent inhibitory activity on NF-kB p65 with IC50 values ranging oxidation to produce the intermediate i, which was subjected to from 0.006–1.5 mM, of which sphenostylisin A 372 was found to

nucleophilic attack by the isoavone to offer intermediate ii. be the most effective NF-kB p65 inhibitor with an IC50 value of 50 Dehydration followed by hydrogenation would produce 6 nM, which was >10 times more powerful than the positive 50 compounds 392–394. control, rocaglamide.126 The C-benzylated complex isoavone 165 extracted from Maclura tricuspidata displayed neuroprotective activity with 6-OHDA induced cell death in neuro- ¼ 130 13. Conclusions blastoma cells (IC50 0.5 mM). The pterocarpan, 55 55 pruinosanone D 200, isolated from Caragana pruinosa displayed 391 novel isoavonoids were isolated and characterised during high inhibitory activity against NO production with an IC the review period, including 237 isoavonoids from 74 Legu- 50 value of 0.62 mM, which was found to be superior to that of the minosae species, 74 from 14 the Moraceae species, 18 from six positive control (aminoguanidine 20.13 mM).51 The rotenoid, Iridaceae species and 56 isoavonoids from 28 different plant

18 P. Vila-Donat, G. Caprioli, F. Maggi, M. Ricciutelli, 1 caeruleanone A 288, isolated from Millettia caerulea fruits 1 (Graham) Baker displayed strong mitochondrial trans- E. Torregiani, S. Vittori and G. Sagratini, Food Chem., ¼ 175 – membrane inhibition (IC50 0.07 mM). Coumar- 2015, 174, 487 494. onochromone 301 isolated from Campylotropis hirtella (Leg.) 19 G. Fiechter, I. Opacak, B. Raba and H. K. Mayer, Food Res.  – 5 showed strong inhibitory in uence on B lymphocyte activity Int., 2013, 50, 586 592. 5 112 with the IC50 value of 0.28 mM. Thus, further investigations on 20 Y. Tao, Y. Jiang, W. Li and B. Cai, Anal. Methods, 2016, 8, pharmacology and chemistry, as well as toxicological research, 4211–4219, DOI: 10.1039/c6ay00732e. should be carried out for better validation of the therapeutic 21 Q. L. Zhou, Y. F. Wang, D. H. Yang, F. Xu, X. Zhao, L. Zhang, potential of complex isoavonoids, especially isoavonoid J. Liang and X. W. Yang, Biomed. Chromatogr., 2013, 27, 10 dimers, and coumaronochromones. 1208–1218. 10 22 H. J. Park and M. Y. Jung, Food Chem., 2017, 229, 797–804. 14. Species checklist 23 J. Zhang, X.-J. Xu, W. Xu, J. Huang, D.-Y. Zhu and X.-H. Qiu, J. Chromatogr. Sci., 2014, 1–8, DOI: 10.1093/chromsci/ See ESI.† bmu155. 15 24 E. Shawky and S. M. Sallam, J. Chromatogr. Sci., 2017, 1–7, 15 15. Conﬂicts of interest DOI: 10.1093/chromsci/bmx062. 25 Y. S. Shim, W. J. Yoon, J. B. Hwang, H. J. Park, D. Seo and The author declares no conicts of interest. J. Ha, Food Chem., 2015, 187, 391–397. 26 J. Tchoumtchoua, D. Njamen, J. C. Mbanya, 20 20 16. Acknowledgements A. L. Skaltsounis and M. Halabalaki, J. Mass Spectrom., 2013, 48, 561–575. The Author thanks Miss Ahlam Awawdeh for valuable advice on 27 M. Ganzera, J. Pharm. Biomed. Anal., 2015, 107, 364–369, IT. DOI: 10.1016/j.jpba.2015.01.013. – 25 28 S. Bajkacz and J. Adamek, Talanta, 2017, 168, 329 335. 25 17. References 29 L. Li, J. Z. Liu, M. Luo, W. Wang, Y. Y. Huang, T. Eﬀerth, H. M. Wang and Y. J. Fu, J. Chromatogr. B: Anal. Technol. 1 R. A. Dixon and G. M. Pasinetti, Plant Physiol., 2010, 154, Biomed. Life Sci., 2016, 1033,40–48, DOI: 10.1016/ 453–457. j.jchromb.2016.08.005. 30 2 E. Miadokova, Interdiscip. Toxicol., 2009, 2, 211–218. 30 M. Mirzaei, A. K. Naeini and M. Behzadi, J. AOAC Int., 2012, 30 3 R. J. Reiter, S. D. Paredes, A. Kormaz, M.-J. Jou and 95, 845–849. D.-X. Tan, Interdiscip. Toxicol., 2008, 1, 137–149. 31 X. Zhao, Z. Wei, F. Du and J. Zhu, Appl. Biochem. Biotechnol., 4 R. Scarpato, L. Paganucci, A. Bertoli, L. Fiore, L. Pistelli and 2010, 162, 2087–2097. G. Federico, Phytother. Res., 2008, 22, 1650–1654. 32 E. Cordisco, C. N. Haidar, E. R. Coscueta, B. B. Nerli and 35 5 T. Sabudak and N. Guler, Phytother. Res., 2009, 23, 439–446. L. P. Malpiedi, Food Chem., 2016, 213, 514–520. 35 6 D. M. X. Donnelly and G. M. Boland, Nat. Prod. Rep., 1995, 33 S. Li, S. Li, C. Liu, C. Liu and Y. Zhang, J. Chromatogr. B: 12, 321–328. Anal. Technol. Biomed. Life Sci., 2017, 1048, 111–120, DOI: 7 G. M. Boland and D. M. X. Donnelly, Nat. Prod. Rep., 1998, 10.1016/j.jchromb.2017.02.009. 15, 241–260. 34 S. Li, S. Li, Y. Huang, C. Liu, L. Chen L and Y. Zhang, J. Sep. 40 8 J. B. Harborne and H. Baxter, The Handbook of natural Sci., 2017, 40, 2565–2574, DOI: 10.1002/jssc.201700258. 40 avonoids, John Wiley and Sons, Chichester, 1999, vol. 2. 35 C. P. Jiang, H. Ding, D. H. Shi, Y. R. Wang, E. G. Li and 9 N. C. Veitch, Nat. Prod. Rep., 2007, 24, 417–464. J. H. Wu, World J. Gastroenterol., 2012, 18, 1753. 10 N. C. Veitch, Nat. Prod. Rep., 2009, 26, 776–802. 36 J. Reynaud, D. Guilet, R. Terreux, M. Lussignol and 11 N. C. Veitch, Nat. Prod. Rep., 2013, 30, 988–1027. N. Walchshofer, Nat. Prod. Rep., 2005, 22, 504. 45 45 12 J. Reynaud, D. Guilet, R. Terreux, M. Lussignol and 37 S. R. M. Ibrahim, G. A. Mohamed and N. M. Al-Musayeib, N. Walchshofer, Nat. Prod. Rep., 2005, 22, 504–515. Molecules, 2012, 17, 2587–2598, DOI: 10.3390/ 13 Y. Zhang, C. Liu, Y. Pan, Y. Qi, Y. Li and S. Li, Anal. Bioanal. molecules17032587. Chem., 2015, 407, 4597–4606. 38 G.-Y. Xie, X.-Y. Qin, R. Liu, Q. Wang, B.-B. Lin, G.-K. Wang, 50 14 J. C. Gasparetto, F. S. F. Smolarek, T. M. G. de Francisco, G.-K. Xu, R. Wen and M.-J. Qin, Nat. Prod. Res., 2013, 27, 50 L. C. Miranda, R. Pontarolo and P. F. Siqueira, J. Am. Oil 2173–2177. Chem. Soc., 2012, 89, 1211–1222, DOI: 10.1007/s11746-012- 39 S. R. M. Ibrahim, G. A. Mohamed, M. F. Zayed and 2030-1. S. A. Ross, Bioorg. Chem., 2017, 70, 192–198. 15 V. Verardo, Y. Riciputi, A. G. Frenich and M. F. Caboni, Food 40 N. Nazir, Biomedicine & Preventive Nutrition, 2013, 3, 151– 55 Chem., 2015, 185, 239–244. 157. 55 16 A. Aresta, P. Cotugno, F. Massari and C. Zambonin, J. Food 41 L. Huang, W. Ma, Y. Liu, Y. Peng and P. Xiao, Chem. Nat. Qual., 2017, 3,1–5, DOI: 10.1155/2017/8049039. Compd., 2014, 50, 430–432. 17 X.-P. Meng, Z.-P. Wang, W.-M. Li, H. Fan and Y.-F. Wang, Adv. J. Food Sci. Technol., 2015, 7, 173–176.

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