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Isolation of naturally occurring novel isoflavonoids:

an update†
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Cite this: DOI: 10.1039/c8np00069g

Nawaf Al-Maharik *

Covering: Jan. 2012 to Dec. 2017

Received 31st July 2018

This review describes the 391 new isoflavonoids isolated and identified from natural sources between
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.

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
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
6. Isoavans, isoavanols and isoav-3-enes and apiose as the sugar constituent), where the isoavonoid
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,
11. 2-Arylbenzofurans and is used the treatment of menopause symptoms.2–5 They are
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
16. Acknowledgements other groups of avonoids, the occurrence of isoavonoids in
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-
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
migration of the 2-phenylchroman skeleton of avonoids.1 been periodically published.6–12 However, the current review is
Isoavones are further transformed at different phases in plants concerned with the isolation of isoavonoids from Legumino-
to yield een structurally different subclasses of isoavonoids, sae and non-leguminous sources, covering the literature pub-
lished between January 2012 and December 2017 using the
Department of Forensic Sciences, Al Istilal University, Jericho, Palestinian Authority. SciFinder, Reaxys and PubMed (http://www.ncbi.nlm.nih.gov/
E-mail: an10@pass.ps
entrez/query.fcgi) databases.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8np00069g

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Natural Product Reports
2. Isolation and identification
This section highlights the advances in the separation and
identication of isoavonoids from natural sources using
hyphenated analytical techniques. The growing interest in soy
food products due to their biological effects including the
relation between consumption of isoavone-rich food and
reduction in cancer, has led to the growing demand for the
quantitative and qualitative determination of isoavones in soy
foods. The presence of isoavonoids in traditional medicinal
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plants has stimulated the growing search for biologically active
compounds from both legume and nonlegume sources.
Conventional methods of purifying natural isoavonoids
involve extraction and separation processes, which are per-
formed independently.
Zhang et al. reported the development of a novel procedure
based on ultrasonic-assisted dynamic extraction (UADE)
combined with two countercurrent chromatography systems
(parallel countercurrent chromatography, PCCC).13 This new
method was used for fractionation and purication of iso-
avones from red clover, offering the possibility for simulta-
neous extraction, solvent conguration, purication, and
isolation of the desired compounds. The lower aqueous phase
of the two-phase solvent system, which was prepared by auto-
mating the equipment, was used as the UADE solution and as
the mobile phase for PCCC. Once the extraction and purica-
tion steps were completed, the puried sample was pumped
into the countercurrent chromatography 1 (CCC1) column for
the rst isolation step. During CCC1 separation, the sample was
enriched, puried and then pumped into the CCC2 column for
the second isolation step. Aer completion of the rst cycle of
UADE-PCCC, the second-cycle experiments were performed.
Using this sequence, ve target compounds, daidzein, prunetin,
Nawaf Al-Maharik received his
PhD on the Synthesis of
Isoavonoid-Derivatives for
Immunoassay in 2000 at the
University of Helsinki (Finland).
He subsequently joined the group
of Lars Engman at Uppsala
University (Sweden), and in 2001
the group of Nigel Botting at St
Andrews University (UK) to work
on the synthesis of 13C-labelled
polyphenols. In 2006, he began
working at Dundee University
towards the chemical preparation of GPI anchors and other bio-
logically important carbohydrates. In 2010 he joined David
O'Hagan's group as a senior researcher at the University of St
Andrews to work on the synthesis of diastereoisomeric multi-vicinal
uoroalkanes. In 2017, he was appointed as an Associate Professor
at the Al Istiqlal University, Jericho. His research interests include
the synthesis and isolation of natural products, and organouorine
and carbohydrate chemistry.
Nat. Prod. Rep.
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Review
genistein, irilone, and maackiain, with purity greater than
95.31% were successfully extracted.13
A new, reproducible, sensitive and reliable HPLC-DAD
approach was used for the quantication of daidzein, genistein,
glycitein and their corresponding 7-O-glucosides in soy extracts
without the need for sample pretreatment.14 The approach
showed high selectivity and was linear over the range of 1.5–150
mg mL
1 for all the isoavones. The robustness study found that
the range of recovery was 95–102% and that the ow rate was the
only critical factor.14 This method proved to be a suitable and
reliable alternative for quality control of soy extracts. Additionally,
Verardo et al. reported the development of a simple reverse-phase
RP-HPLC-DAD using pentauorophenyl particles (PFP) for the
separation, determination and quantication of free and bound
polyphenolic compounds in soy isoavone concentrate.15 The
detection (LOD) and quantication limits (QOD) for the major
isoavones and their glycoside ranged from 0.028–0.044 mg mL
1
and 0.093–0.157 mg mL
1, respectively.15 A new, simple and cost-
effective analytical method based on hyphenated matrix solid-
phase dispersion extraction (MSPD) MSPD-LC-UV/DAD was
developed and validated for the simultaneous determination and
quantication of daidzein, genistein, glycitein and their 7-O-b-D-
glucopyranoside in soybeans our with linearity within the
concentration range of 0.02–2.0 mg mL
1.16 The limits of detection
and quantitation were 0.057 mg mL
1 (genistin and glycitein),
0.124 mg mL
1 (genistein), 0.190 mg mL
1 (genistin and glycitein),
and 0.410 mg mL
1 (genistein). A simple and efficient reverse
phase HPLC-UV approach was developed for the simultaneous
examination and quantication of nine isoavonoids in the
Chinese Huangqi-Gegen herbal pair using a Kromasil C18 column
(4.6  250 mm, i.d.; 5 mm). This method was veried to be linear
for the nine isoavonoids identied.17 Furthermore, a novel
method utilizing freezing as an effective clean-up step with ultra-
high performance liquid chromatography-tandem mass spec-
trometry (SPE-UHPLC-MS/MS triple quadrupole) was applied to
quantify the major isoavonoids in 48 lentil samples successfully
with high recoveries ranging from 54.4–114%.18 A new ultra-high
pressure liquid chromatography (UV-UPLC™) method was
developed for the fast and reliable quantication of total agly-
cones in soybeans aer enzymatic hydrolysis applying Helix
pomatia digestive juice with a total runtime of 8 minutes. The
major isoavones (daidzein, glycitein, and genistein) were sepa-
rated within only three minutes; thus, UV-UPLC™ proved to be
superior due to its signicantly shorter runtimes.19 A sensitive,
efficient and rapid ultra-high performance liquid chromatography
coupled with quadrupole-time-of-ight mass spectrometry
(UHPLC-Q-TOF-MS) was developed and validated for the qualita-
tive determination of chemical constituents including iso-
avonoids in six Chinese herbal medicines.20 HPLC-ESI-Q-TOFMS
was demonstrated to be a powerful technique for the identica-
tion of 96 characteristic compounds from the urine sample of
WZS-miniature pigs orally administrated with Puerariae lobatae
Radix (PLR) decoction.21 Park et al. reported the development and
validation of a simple, selective, sensitive, accurate and fast
UHPLC-ESI-MS/MS in combination with one step salting-out-
assisted liquid–liquid extraction (SALLE) for the determination
of 12 isoavones in soy milk.22 The baseline separation of 12
This journal is © The Royal Society of Chemistry 2019

Review
isoavones was achieved within 2.5 min, offering the fastest
chromatographic method ever reported. A simple and efficient
hyphenated ultra-high-pressure liquid chromatography with an
LTQ-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-
MSn) approach was developed for the separation and identica-
tion of avonoid constituents of Radix astragali.23 The proposed
fragmentation pathways of isoavones, pterocarpans and iso-
avans were explored to trace the isoavonoid derivatives in the
plant extracts. Based on this strategy, 48 constituents were iden-
tied. This approach was demonstrated as an effective mean for
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the rapid qualitative determination of polyphenols from natural
resources.23 A hyphenated high-performance thin-layer chroma-
tography (HPTLC/UV/VIS) method using basic silica gel TLC
equipment was successfully employed for the simultaneous
recognition of ve compounds, including the major isoavones
daidzein, genistein and glycitein, aer a single chromatographic
run.24 The obtained accuracy and precision of the results using
this method were comparable to that reported for HPLC methods.
The certied method is simple, fast, reliable and more cost-
effective than the other commonly used methods.24 A reliable
and convenient analytical method for the quantication of 14
isoavones in various beans, including soybean, red and black
bean using UHPLC coupled to a photo diode array (PDA) at
260 nm was successfully adopted with a limit of detection ranging
from 0.03–0.33 mg kg
1 and good linearity (r2 ¼ 0.99).25 A
structure-guided method based on fast UHPLC-LTQ Orbitrap and
UHPLC-HRMS/MS was employed in the identication of iso-
avonoids in a crude MeOH extract of stem bark of Amphiumas
pterocarpoids (Leg.). This method was based on fast UHPLC and
HRMS/MS in full scan acquisition.26
Green, simple ultra-high performance supercritical uid
chromatography (UHPSFC) using supercritical carbon dioxide,
methanol and phosphoric acid as additives for elution was
successfully used in the quantitative determination of nine iso-
avones in dietary supplements containing Glycine max (soy),
Trifolium pratense (red glover) and Pueraria lobata (kudzu) in eight
minutes.27 This method proved to be selective, sensitive, linear
(R2 $ 0.9994), and accurate with recovery rates ranging from
97.6–102.4%. A green, quick and cheap extraction method based
on the nontoxic natural deep eutectic solvent (NADES) and 30%
solution of choline chloride : citric acid with a molar ratio of 1 : 1
was successfully adopted by Bajkacz et al. for the extraction of
daidzein, genistein, daidzin and genistin from soy-containing
food samples with enrichment factors of up to 598 for iso-
avones and recoveries in the range of 64.7–99.2%.28 Addition-
ally, Li et al. reported the development of a green, efficient and
preparative deep eutectic solvent (choline chloride/ethylene
glycol with 1 : 2 molar ratio)-based negative pressure cavitation-
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
Dalbergia odorifera T. Chen leaves with more than 80% yield.29
Based on the eco-friendly liquid–liquid extraction method
(cloud point extraction) using surfactants adopted by Mirzaei et al.
for the extraction of genistein from soybeans30 and on the superior
reverse micelles for the extraction of soy isoavone from soy ours
using surfactant solutions (anionic and non-ionic),31 Cordisco
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et al. reported the design of aqueous micellar two-phase systems
(AMTPS), Triton X-114 and sodium tartrate pH 5.00 to extract
isoavones from soy our with preservation of the protein content
in the treated soy our.32 The integration of solid–liquid and
liquid–liquid extraction using AMTPS in aqueous media
permitted the recovery of 93% of all isoavones with a purication
factor of about 10. The key target of this technique is the reduction
of both extractive/separative steps and the use of organic solvents.
Ultraltration liquid chromatography-mass spectrometry
(UFLC-MS) with a PC 12 cell model was efficiently utilised in the
rapid screening and identication of ligands (isoavones) for
lactate dehydrogenase (LDH) from Pueraria lobata owers.
Then, a highly unique and effective instrumental system con-
sisting of microwave-assisted extraction (MAE) coupled with
a solvent concentration tank (SCT) and countercurrent chro-
matography (CCC) for the continuous extraction and separation
of LDH inhibitors from P. lobata owers was developed. The
MAE-CCC method generated seven LDH inhibitors with >90%
purity. The newly UFLC-MS combined with MAE-CCC and
a PC12 cell model provided an excellent instrument for the
screening, extraction, and separation of LDH inhibitors from
complex samples.33 Utilising ionic-liquid-based (1.0 M 1-ethyl-3-
methylimidazolium tetrauoroborate) ultrasound-assisted
extraction (IL-UAE) in the extraction of bioactive compounds
from Belamcanda chinensis, the incubation of the extract with a-
glucosidase, and subsequent ultraltration and semi-
preparative HPLC resulted in the isolation of four a-glucosi-
dase inhibitors, namely tectorigenin, iristectorigenin A, irige-
nin, and irisorentin with purity ranging from 88.97–99.97%.34
3. Isoflavones
Among the isoavonoid subclasses, isoavones comprise the
largest group of natural isoavonoids with 178 new structures
isolated and identied during the review period. This number of
new structures demonstrates the diversity present in natural
products. The presence of isoavonoids in traditional medicinal
plants has prompted increasing interest in the search for bioactive
compounds. An examination of the oxygenation pattern of
aromatic carbons in the isoavone skeletons revealed that all
isoavones can be divided into 55 patterns based on their
oxygenated carbons. The most abundant oxygenation patterns are
5,7,40 > 5,7,20 ,40 > 5,7,30 ,40 > 5,7,20 ,40 ,50 > 7,40 > 5,7,30 ,40 ,50 > 7,30 ,4 >
7,20 ,40 in descending order. Herein, isoavones are treated in
three groups, comprising those characterized by simple substi-
tution patterns (hydroxy, methoxy, methylenedioxy, hydrox-
ymethyl and acetyl), then isoavone glycosides (43–86, Section
3.2) and nally prenylated derivatives (87–181, Section 3.3).
3.1. Simple isoavones
39 simple isoavones were isolated from plant sources during
the review period, among which only 19 compounds were
identied from Leguminosae species. The genus Iris is consid-
ered to be a rich source of secondary metabolites, such as iso-
avonoids possessing anti-oxidant, antitumor and antibacterial
activity.35,36 Fractionation of the methanolic extract of Iris
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Natural Product Reports
germanica rhizomes (Iridaceae), the ornamental herb known as
Irsa distributed worldwide, afforded the new 5,30 -dihydroxy-
6,7,40 ,50 -tetramethoxyisoavone 1, named irigenin S.37 Around the
same time, Xie et al. reported the isolation and identication of
another new simple isoavone, iriskashmirianin A 2 and one new
isoavone glucoside, germanaism H 63, together with eight
known isoavones from the MeOH extracts of the rhizome of the
same species.38 Iriskashmirianin A 2 exhibited a cytotoxic effect on
the Ehrlich's ascites carcinoma (EAC) cell line with IC50  SD of
20.9  2.7 and 4.3  0.9 mM with the 3-(4,5-dimethylthiazole-2-yl)-
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2,5-diphenyltetrazoli-umbromide (MTT) and ATP assay methods,
respectively.38 MeOH rhizomes extract of the same species affor-
ded two additional new isoavones, namely 8-hydroxyirilone 3
and 8-hydroxyirilone 5-methyl ether 4.39 Both compounds were
characterised by the full oxygenation of the A-ring and the pres-
ence of 6,7-methylenedioxy-substitution. The isoavones 3 and 4
displayed antioxidant activities with IC50 values of 12.92 and 9.23
mM, respectively, compared with propyl gallate (IC50 ¼ 7.11 mM).
Moreover, both compounds revealed 66.1% and 78.3% a-amylase
inhibition activities, respectively, compared to acarbose (96.7%,
reference a-amylase inhibitor).39
Fractionation of the MeOH extracts of Iris kashmiriana
rhizomes (Iridaceae) afforded the new isoavone isonigricin 5 in
addition to isoirisolidone, which was isolated from this species
for the rst time. Isonigricin 5 displayed immunosuppressive
activity, while isoirisolidone showed an immunostimulatory
effect.40 Huang et al. reported the isolation of two new isoavones,
namely 6,8,40 -trihydroxy-7,30 -dimethoxyisoavone 6 and 6,8,40 -
trihydroxy-7-methoxyisoavone 7 by fractionating the MeOH
extract of rhizomes of Iris dichotoma (Iridaceae), a perennial herb
used in traditional Chinese medicine as “Bai-Shegan” for clearing
heat and detoxication, and eliminating swelling and pain in the
throat.41 In continuation of an extensive effort on the phyto-
chemical study and biological evaluation of Mediterranean
Nat. Prod. Rep.
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medicinal plants, Al-qudah et al. reported the isolation of a new
isoavone lacking oxygenation at the 40 -position, named 30 -
methyl tenuifone 8, and a new isoavone dimer 391 from the
aqueous MeOH extract of Gynandriris sisyrinchium (Iridaceae).42 A
phytochemical study of Rosa rugosa buds (Rosaceae), the attrac-
tive ower distributed in the temperate areas of Eastern Asia used
as food and Chinese medicinal materials for the treatment of
stomach ache and diarrhea, led to the isolation of 6,8-dihydroxy-
40 ,7-dimethoxyisoavone 9 (rosa isoavone).43 Compound 9
exhibited strong cytotoxicity against A549 and PC3 cells with IC50
values of 2.6 and 3.2 mM, respectively.
Phytochemical examination of the constituents of the
heartwood of Pterocarpus soyauxii (Fabaceae), known as zitan or
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-
20 ,40 -dimethoxyisoavone 16, which were known as synthetic
compounds but never isolated from natural sources.44 Another
new isoavone lacking oxygenation at the C-40 position, namely
7-hydroxy 30 -methoxyisoavone 17, was isolated from the seeds
of Indigofera heterantha (Fabaceae), which is native to the
Northwestern Himalayas of Tibet and known as indigo Hima-
layan.45 Fractionation of the MeOH extracts of Pueraria montana
var. lobata Willd. (Fabaceae), also called Ge Gen in Chinese folk
medicine, afforded three new isoavones, namely 7-acetyl-40 ,6-
dimethoxy-isoavone 18, 7-acetyl-40 -hydroxy-6-methoxy-
isoavone 19 and 7-acetyl-6,8-dimethoxy-40 -hydroxy-isoavone
20, together with ve known isoavones.46 The remarkable
feature of these new compounds is the occurrence of an
unusual acetyl group at the C-7 position on the A-ring, which
This journal is © The Royal Society of Chemistry 2019

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was reported for the rst time from the genus Pueraria. In
a primary screen, compounds 18 and 19 exhibited high anti-
tobacco mosaic virus (anti-TMV) activities with inhibition
rates of 36.8% and 33.6%, respectively, which were higher than
that of the positive control. The cytotoxicities of compounds 18–
20 displayed weak inhibitory activities against ve human
tumour cell lines (NB4, A549, SHSY5Y, PC3 and MCF7) with IC50
values ranging from 1.2–3.6 mM.46 The red heartwood of the
rhizomes of Caragana changduensis (Fabaceae), a species
considered to be traditional Tibetan medicine to treat hyper-
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tension and menstrual disorder, is rich in avonoids including
isoavonoids. Fractionation of its EtOH extracts yielded two
new isoavones, 6,7,20 -trihydroxy-4-methoxyisoavone 21 and
7,30 -dimethoxy-5-hydroxyisoavone 22.47 Ma et al. reported the
isolation of an unusual isoavone, hydroisoavone 23, together
with the unprecedented isoavane coumaronochromone 389
from Campylotropis hirtella (Leg.).48 Identication of this
remarkable hydroisoavone with a fully saturated B-ring, brings
the total number of naturally occurring hydroisoavones to
four.49 In 2009, Ndejouong et al. reported for the rst time the
isolation of hydroisoavones A–C 24–26 from a culture of highly
Ni-resistant strain of Streptomyces mirabilis from a former
uranium mining area in China.49 Single crystal X-ray diffraction
experiments indicated that the two hydroxyl groups on the B-
ring were in the axial position and trans conguration.48
An unusual isoavone containing epoxide at C-2 and C-3,
named vigradiatain 27, was isolated as a minor constituent
(0.026 mg/100 g) from the stems and leaves Vigna radiate L.
(mung beans) together with the new isoavone glycoside,
named 20 -hydoxydaidzin 60, and 13 known isoavonoids.50
Compound 27 exhibited strong ABTS radical scavenging activ-
ities (IC50 ¼ 15.6  3.71 mM). However, the stereochemistry of 27
was not determined. Pruinosanone E 28, a new isoavone, was
isolated from the roots of the Caragana puinosa (Leg.), a dwarf
shrub distributed in China and Central Asia.51
Nicotiana tabacum L. (Solanaceae), a perennial plant origi-
nating from South America, is one of the most commercially
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appreciated agricultural crops in the world. In addition to its
use in the cigarette industry, N. tabacum also contains many
valuable chemical compounds, such as sesquiterpenes, diter-
penoids, alkaloids and polyphenols. The utilization of these
active composites in the leaves and stems of N. tabacum has
attracted increasing attentions. Phytochemical investigation of
the roots and stems of Nicotiana tabacum resulted in the isola-
tion and identication of two new isoavones, named 7-
hydroxy-6,30 ,40 ,50 tetramethoxyisoavone 29 and 6-hydroxy-
7,30 ,40 ,50 tetramethoxyisoavone 30, together with seven known
isoavones.52 Around the same time, Ye et al. reported in
a separate paper the isolation and identication of the new
30 ,40 ,50 -trihydroxy-5,7-dimethoxyisoavone 31 from the stems of
the same species.53 It is worth mentioning that the three iso-
avones share the 30 ,40 ,50 -oxygenation pattern in the B-ring.
Three additional new isoavones 32–34 were isolated from the
acetone extracts of the leaves of N. tabacum, two of which bear
either a methoxycarbonyl- or hydroxymethyl-group at C-8.54 The
structures of these compounds were characterised as 7,40 -
dimethoxy-6-hydroxy-8-methoxycarbonylisoavone 33, 7,40 -
dimethoxy-6-hydroxy-8-hydroxymethylisoavone 34 and 8,40 -
dihydroxy-6,7-dimethoxyisoavone 32.54 Compounds 32–34
exhibited high anti-tobacco mosaic virus (anti-TMV) activity
with inhibition rates of 25.2%, 22.6% and 27.4%, respectively.
Phytochemical investigation of the leaves and stems of Quran-
tea ferruginea (Ochnaceae) led to the isolation of a new isoavone,
5-hydroxy-7,30 ,40 ,50 -trimethoxyisoavone 35, together with three
known isoavones.55 Shen et al. obtained 40 -deoxyisoavone, ter-
natin A 36, from the EtOH extract of Ranunculus ternatus Thunb.
(Ranunculaceae), a traditional Chinese medicine.56 Compound 36
exhibited moderate cytotoxic activity against HeLa and PANC-1
cells, with IC50 values of 13.88 and 16.78 2 mM, respectively. A
new isoavone, mexitin 37 together with quercetin and rutin were
isolated from the aerial part of Argemone mexicana Linn (Papaver-
aceae).57 In an ongoing phytochemical investigation of Salsola
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Natural Product Reports
tetrandra (Amaranthaceae), a new isoavone lacking the oxygena-
tion at C-40 , designated as 2-dihydroxy-5-methoxy-6,7-
methylenedioxy-isoavone 38 (tetranins B), was isolated and
identied from the EtOAc extract of its roots.58 Compound 38
exhibited a strong antioxidant effect in 1,1-diphenyl-2-
picrylhydrazyl (DPPH) free radical assays.58 Examination of the
ethanolic extract of Eremostachys vicaryi (Labiatae), a plant that
grows in India, Pakistan and Iran and studied for the rst time, led
to the isolation of a new isoavone lacking C-40 -oxygenation named
vicarine 39.59 Pauciisoavone A 40, a new isoavone bearing an
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isobutyl group at 40 -O-position, isolated from the leaves of the
Garcinia paucinervis (Chusiaceaea) showed cytotoxicity against the
NB4, SH-SY54, and MCF7 cell lines with IC50 values of 8.6, 7.5, and
9.2 mM, respectively.60 A new C-methylisoavone bearing methyl
groups at C-6 and C-8, isosideroxylin 41, isolated from the EtOAc
extract of the leaves of Leiophyllum buxifolium (Ericaceae), known as
myrtle, showed selective anti-proliferative activity against MDA-MB-
230 cells with an IC50 value of 7.0  4.2 mM.61
A new chlorine-containing isoavone, named 8-chloro-7-O-
methylgenistein 42, together with eight known isoavones, one
of which is 8-clorogenistein, were obtained and identied from
the metabolites of the Streptomyces strain YIM GS3536, which
was isolated from a soil sample collected from Yunnan Prov-
ince, China.62 This nding brings the number of chlorine-
containing isoavones to six. The chlorination mechanism in
Streptomyces remains vague. The new compound 42 demon-
strated substantial cytotoxicity against human melanoma cell
lines (B16) and human leukemia cell lines (HL60) with IC50
values of 17.5 and 19.2 mM, respectively. The MIC values of 42
for E. coli, Staphylococcus aureus, Bacillus subtilis, and Candida
albicans were in the range of 23–35 mM.62
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3.2. Isoavone glycosides
Intensive phytochemical investigation on the EtOH extract of
the root bark of Ormosia henryi Prain (Leg.) resulted in the
isolation and characterisation of a new isoavone glycoside,
designated as ormosinoide 43, and polyprenylated isoavanone
named ormosinol 235.63 Ormosinoide is characterised as
a disaccharide b-D-Xylp-(1/6)-b-D-Glcp O-linked at C-7 of the
isoprunetin. The glycoside was found to be inactive as a radical
scavenger. A new isoavone glycoside named caviunin 7-O-[b-D-
apiofuranosyl-(1/6)-b-D-glucopyrano-side] 44, isolated from
the ethanolic extract of Dalbergia sissoo leaves (Fabaceae), used
as Chinese folk medicine for the treatment of gonorrhoea, was
found to increase alkaline phosphatase activity and minerali-
zation, consequently resulting in substantial osteogenic
activity.64 The high activity of 44 was attributed to the apiofur-
anosyl-(1/6)-b-D-glucopyranoside at the 7-O-position of cav-
iunin.64 Glycitein-7,40 -di-O-b-D-glucoside 45 (ammopiptanoside
A) and 40 -O-b-D-glucopyranosyl-glycitein 7-a-L-rhamnopyranosyl-
(1/6)-O-b-D-glucopyranoside 46 (ammopiptanoside B) were
identied as constituents of the EtOH extract of Ammopiptan-
thus nanus Cheng f. (Leg.).65 Four new isoavone glucosides, 20 -
hydroxy-5-methoxy daidzin (not genistin as mentioned in the
original paper) 47, 5,30 -dimethoxy daidzin 48, 20 -hydroxy gen-
istein-7-O-gentibioside 49, and 20 -hydroxy-5-methoxy daidzein-
7,40 -O-diglucoside 50 were isolated from the MeOH extract of
the groundnut of Apios americana Medik (Leg.) using PDA-
HPLC, a perennial vine native to North America that generates
edible tubers.66 The structures of the glycosides 47–50 were
revealed based on 1D- and 2D-NMR as well as HR-ESI-MS
analyses. The bioside 50 selectively inhibited DHT binding to
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
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
and fujikinetin, respectively.67 Both structures were elucidated
via spectroscopic analysis and chemical methods.67 Wang et al.
reported the isolation of two new isoavones, one of which was
daidzein-7-O-b-D-{600 -[(E)-but-2-enoyl]}glycoside 53, a crotony-
lated glucoside of daidzin (600 -crotonyldaidzin), from the green
vegetable soya beans known as Maodou in China.68 The iden-
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, iri-
solidone-7-O-b-D-glucopyranosyl-(1/6)-b-D-glucopyranoside 54
together with 17 known isoavones and isoavone glycosides
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-
HRMS-SPE-NMR resulted in the identication of one C-8 iso-
avone glycoside 55, 8-C-[a-D-apiofuranosyl-(1/6)]-b-D-gluco-
pyranoside, 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

during the EtOAc fractionation process. Compound 61 dis-
played moderate cytotoxicity on three cancer cell lines (CEM-13,
MT4, and U-937) using the conventional MTT assays.
5-Hydroxy-6,30 ,40 ,50 -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
Continuation of the extensive phytochemical investigation of
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
naism H),38 and iridine A 64 together with 8 known iso-
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 IC50 value of 8.91 mM.76 In continuation of an extensive
known isoavone glycosides, which have never been isolated
effort on the phytochemical investigation and biological evalu-
from this plant. Compound 58 showed moderate SGLT2
ation of Iris pseudacorus L., Tarbeeva et al. reported the isolation
inhibitory activity with the IC50 value of 15.3 mM.72 7,50 -Dihy-
of a new isoavone, 7-O-glucoside 65, lacking oxygenation at the
droxy-4-O-glucopyranosyl-20 -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
droxy-40 -methoxyisoavone 66 and 7-O-b-D-glucopyranosyl-6-
glucoside (Ononin), which were isolated for the rst time from
hydroxy-40 -methoxyisoavone 67 were isolated from the
this plant.73 The position of the glucosyl moiety at 40 -OH was
rhizomes of Iris kashmeriana Baker.78 Structural identication of
conrmed by spotting the correlation in HMBC spectrum
the new compounds 66 and 67 was achieved by spectrometry
between H-30 -C40 , H60 -C40 and H100 -C40 .73 20 -Hydroxydaidzin 60
coupled with chemical analysis.
isolated from the seeds of Vigna radiate L. (mung beans) as
EtOH extracts of the aerial parts of Trachelospermum jasmi-
a minor constituent (17 mg/100 g) showed high antioxidant
noides (Apocynaceae), a traditional Chinese medicine, afforded
activity (IC50 ¼ 8.27  0.47 mM) and very low a-glycosidase
the 7,30 -dimethoxyisoavone-5,40 -di-O-b-D-glucopyranoside 69
inhibitory activity.50 A new isoavone glycoside named 600 -O-
(not 7,30 -dimethoxyisoavanone-5,40 -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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isoavones.80 Comprehensive phytochemical investigation of
the stem bark of Antidesma laciniatum Muell Arg. (Antidesma
Chevalieri Beilli, Phyllanthaceae), a small tree used in Africa to
treat miscarriage and intestinal complaints, resulted in the
isolation chevalierinoside A 70.81 The new isoavonoid glyco-
side 70 was determined to be biochanin A 7-O-[a-L-rhamnopyr-
anosyl-(1/6)-b-D-apiofuranosyl-(1/2)-b-D-glucopyranoside].81
The structure of 70 was established by interpretation of its
spectral data, including 1D-NMR (1H, 13C and DEPT) and 2D-
NMR (COSY, ROESY, TOCSY, HSQC and HMBC).81 In a sepa-
rate report, Djouossi et al. reported the isolation of two addi-
tional isoavane glycosides, designated as chevalierinoside B 71
and chevalierinoside C 72, as minor constituents from the same
species using the same extraction procedure.82 The new glyco-
sides were characterised as genistein 7-O-[b-D-apiofuranosyl-
(1/2)-b-D-glucopyranoside] 71 and biochanin A 7-O-[b-D-apio-
furanosyl-(1/2)-b-D-glucopyranoside] 72.82 Two isoavone
glycosides lacking the 40 -oxygenation were reported from the
EtOH–H2O extract of the roots of Achyranthes bidentata (Amar-
anthaceae), which were characterised as achyranthosides A 73
and B 74.83 Compound 73 bears the unusual methoxymethyl
group at the C-8 position. Both glycosides exhibited substantial
Nat. Prod. Rep.
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inhibitory activities against NO production.83 MeOH extracts of
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-
dimethoxy-30 ,40 -methylenedioxy-7-C-b-D-glucopyranosyliso-
avone 75 together with two known isoavones.84 The structure
of the new C-glycoside was conrmed by observing the
anomeric proton correlation with C-8, C-7 and C-6 in the HMBC
experiment and chemically by its resistance to acidic hydrolysis.
Compound 75 showed high ability to lessen the hepatotoxicity
prompted by paracetamol in male rats by reducing the damage
and toxicity on the liver cells with signicant improvement of
the total antioxidant capacity and restoring the normal liver
functions.84
A bioassay-directed fractionation and chemical study of the
MeOH extract of Tilia amurensis trunks (Tiliaceae), a traditional
Korean medicine to treat cancer and rheumatoid arthritis,
resulted in the isolation and characterization of a new iso-
avone, O-biglycoside, orobol 40 -O-b-D-apiofuranosyl-(1/6)-b-D-
glucopyranoside 76, together with three orobol-based O-gluco-
sides.85 In contrast to orobol 40 -O-b-glucopyranoside, the new
isoavone 4-O-biglycoside inhibited the NO production in
lipopolysaccharide-stimulated BV-2 cells (IC50 ¼ 23.42 mM),
suggesting that the addition of a b-D-apiofuranosyl moiety to the
glycoside at the 40 -O-position may play a role in NO inhibition.85
Flaniostatin 77, a new isoavone glycoside in which the glucosyl
moiety is linked to the isoavone via an ethylene bridge, was
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
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
Flaniostatin 77 inhibited tyrosinase activity by 16.5–47.3% at
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-
tory isoavonoids from ripe and unripe fruits of C. tricuspidata,
curonidation via UDP-glucuronosyltransferases existing in this
which lead to the isolation of isoavone 40 -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
associated Streptomyces sp. RB1 recovered from the cuticle of
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-
83–85 afforded the corresponding aglycone (genistein and
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
anoside 79.88 A new biochanin A C-8 glycoside, named malay-
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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complexity and diverse bioactivity such as estrogenic and anti-

estrogenic isoavonoids. Flemiphilippinin G 87, a new preny-
lated isoavone, was identied from the roots of Flemingia
philippinensis, a shrubby herb growing in tropical and
subtropical areas.95 Compound 87 exhibited signicant cyto-
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 88 and B 89 with ([a]25 D ¼
100 and
80 (c 0.2, MeOH),
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respectively), in which the dihydrofurano is attached to daid-

zein 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
ferruginea (Fabaceae).97 The position of the dihydrofuran
appendage was determined via 2D NMR and a hemi-synthetic
method, while the 200 S absolute conguration was established
based on its measured optical rotation of [a]20 D ¼
50 (c 0.4,
MeOH) and by comparison with other structurally related
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 chro-
matography followed by HPLC led to the isolation and identi-
cation of a new isoavone named eminigin 91 together with
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

3.3. Complex isoavones

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

The phytochemical composition of Flemingia philippinensis

has attracted increasing attention due to its structural

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Several studies indicated that the Erythrina genus is a rich
source of bioactive avonoids, especially, isoavones, pter-
ocarpans and avanones. The leaves and the bark of Erythrina
species are frequently applied as folk medicine to cure a wide
range of diseases. Two new prenylated isoavones, erythraddison
I, II 93 and 94 and two new isoavanones 220 and 221 were
puried by activity-directed isolation from the EtOAc extract of the
roots of Erythrina addisoniae (Leg.).100 The noteworthy feature of
the genistein-based compound, erythraddison I 93, is the pres-
ence of the 1-OMe group at the isoprenyl moiety attached to the C-
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A comprehensive phytochemical and biological investigation
of the constituents of Glycyrrhiza uralensis (Licorice, Leg.),
which is widely used as herbal medicine in China, led to the
isolation and identication of six new isoavonoids, one of
which is the C-6 prenylated isoavone 109 (glycyuralin F),
together with 116 known compounds.107
Four isoavones, among which three were new natural prod-
ucts 110–112, were isolated from the leaves Vatairea guianensis
Aublé (Fabaceae), a plant native to the Amazon and known as
“fava bolacha” or “fava de impingem”.108 5,30 -Dihydroxy-40 -

8 position. The C-6 and C-8 isoprenylated isoavones showed
signicant cytotoxicity against MCF7, MCF7/ADR, and MDA/MB-
231 cancer cells with IC50 values of 11.41, 6.75 and 4.57 mM,
respectively. The MeOH extracts of the root, stem bark and leaf of
Erythrina schliebenii, a rare medicinal tree endemic to Tanzania,
yielded three new B-ring prenylated isoavones named schliebe-
nones A–C 95–97, and one new pterocarpan 208.101
methoxy-200 ,200 -dimethylpyrano-(500 ,600 :8,7)-isoavone 110 and 5,7-
dihydroxy-30 ,40 -methylenedioxy-8-prenyl-isoavone 111, cited
previously as synthetic compounds, were isolated for rst time
from natural sources. The crude extract of the leaves exhibited
signicant radical scavenging ability with an IC50 value of 6.2 
0.4 mg mL
1, which was close to that of Trolox (positive control).
Fractionation of the root extract of the of Chinese herbal medicine

As part of the BioBioPha project for the large scale screening

for drug discovery from non-alkaloidal natural products, Wang
et al. recorded the isolation and structural elucidation of four
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
been revised based on the 13C NMR shi for C-100 bearing a –
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
(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-
noids.104 As part of the search for new anticancer agents,
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
106.105 Two additional isoprenylated isoavones of the mil-
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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Hedysarum multijugum (Leg.) afforded the 30 -isoprenyl- 113 and
6,8-diisoprenyl- 114 derivatives of 20 -hydroxybiochanin A, desig-
nated as hedysarimisoavones A 113 and B 114, respectively.109
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Derris species (Leg.), a rich source of isoavonoids, is widely
distributed in the tropical and subtropical regions of Africa and
Asia. The majority of Derris isoavonoids are isoprenylated,
a trend revealed in the new examples documented herein.
Phytochemicals of the genus Derris showed a broad spectrum
of biological activities, including insecticidal, antimicrobial, and
antioxidant activities. Phytochemical examination of the twigs
and leaves of the EtOH extract of Derris robusta resulted in the
isolation and identication of four new prenylated isoavones
named derrisisoavones H–K 115–118, together with a new iso-
avan 254.110 The remarkable feature of derrisisoavones J 117
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and K 118 is the occurrence of hydroxyethyl substituents, which
represent the rst two examples of hydroxyethylated natural
isoavonoids. Extensive phytochemical studies of the stems of
the ethnomedicinal plant D. eriocarpa, Chinese traditional
medicine, resulted in the isolation and characterization of three
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
120 displayed inhibitory effects on the Candida guilliermondii, C.
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-
directed fractionation of the EtOH extracts of Campylotropis
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
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
and 40 -OH in the axial positions were determined by HMBC and
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
isoavone derivatives isolated from bacterial strains.113 Further
phytochemical examination of the EtOH roots extract of C.
hirtella afforded seven additional new geranylated isoavones
124–130 (not nine as reported), two new isoavans, one iso-
avanone and one new coumestan 312.114 The new isoavones
displayed only weak to moderate antibacterial activities against
four Gram-positive bacteria and ve Gram-negative bacteria.114
The further identication of a new C-30 geranylated isoavone
131 and new 30 -O-geranylted isoavone, hirtellanine M 132,
from the roots of the same species was described in two sepa-
rate reports.115,116 The new prenylated isoavone 131 displayed
signicant and dose-dependent inhibitory effects on the
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inuenza A1(H1N1) virus NA.115 The structural feature of almost
all the isoavones from this species is that the geranyl moiety is
located on the B-ring at the C-30 position.
In a voltage clamp assay with Xenopus laevis oocytes, the
CH2Cl2 extract of roots and tubers of Adenocarpus cincinnatus
(Leg.) improved the GABA-induced chloride current (IGABA)
through receptors of the subtype a1b2g2s by 126.5  25.1% at
100 mg mL
1, affording a new prenylated isoavone 133 and
three new pterocarpans 187–189 in addition to ve known iso-
avonoids.117 The 8-prenyl isoavone 133 displayed high inu-
ence and potentiate on IGABA by 560.34  387.06% at 100 mM
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concentration. 40 -Hydroxy-20 -methylalpinumisoavone 134 iso-
lated and characterised by the bioassay-directed fractionation
of the EtOH extract of the Chinese folk medicine Crotalaria
ferruginea (Leg.) exhibited cytotoxicity against
phosphodiesterase-4 (PDE4) with an IC50 value of 4.59  0.50
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
exhibited high antimicrobial activity on two Gram-positive
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
and 5,7,40 -trihydroxy-30 -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
of 173.8 and 21.7 mM.
Two new prenylisoavones named pachyloisoavones A 137
and B 138, and a pterocarpan 211 were isolated from the vine
stems and leaves of the Chinese herbal medicine Millettia
pachyloba (Leg.).121 The absolute conguration of 138 was
elucidated using the calculated electronic circular dichroism
(ECD).
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pruinosa (Leg.) displayed strong inhibitory effects on NO

production with an IC50 value of 1.93 mM.125 Examination of
Amorpha fruticosa fruits, a North American native shrub,
resulted in the isolation of C-8-geranyl isoavones 145 and
146, one C-6-geranyl isoavone 147, one new glycoside 68 and
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
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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
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 (O2
) (IC50 ¼ 10.89 mM) by human
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 CHCl3-
catorin C 143, were isolated from the CH2Cl2 root extract of
soluble extract of the root bark of Sphenostylis marginata ssp.
Rhynchosia precatoria (Humb. & Bonpl. ex Willd., Fabaceae).124
Erecta (Leg.) led to the isolation of one new isoavone,
Compound 143 showed weak antimycobacterial activity with an
sphenostylisin H 148, three new 3-phenylcoumarins 307–310
IC50 value of 149.36 mM.
and three complex dimeric isoavonoids 372–374.126 The new
isoavone displayed strong hydroxyl radical scavenging
activity with an ED50 value of 2.2 mM, and showed very potent
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
investigation and biological evaluation of Hawaiian plants,
six new complex iso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-
scopic methods and comparison with the NMR data of other
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-
anoisoavone named 5,30 ,40 -trihydroxy-200 ,200 -dimethylpyrano
(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

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Phytochemical investigation of the Malcuna genus revealed
that prenylated avonoids are its foremost components.129
Oyama et al. reported the identication of the linear dihy-
drofurano pyranoisoavone 156 from the fruits of Maclura
tinctoria (Moraceae), a tree grown in the tropical forests of
Central and South America.129 Structural elucidation of
compound 156 was established via the HMQC and HMBC
techniques and comparison with the closely related ulexin D,
identied from Ulex airensis, varying by the presence of a 5-
OCH3 instead of 5-OH group in ulexin D.129
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As part of a continuing research program dedicated to
nding neuroprotective compounds from higher plants, the
EtOAc soluble MeOH extract of Maclura tricuspidata (formerly
known as Cudrania tricuspidata, Moraceae), a traditional
herb in Korea, was found to display signicant neuro-
protective against SH-SY5Y cell death induced by 6-hydrox-
ydopamine (6-OHDA) with an IC50 value of 7.7 mg mL
1.130
Based on this result, extensive phytochemical investigation
of the MeOH extract of Maclura tricuspidata resulted in the
isolation of een prenylated isoavones and three iso-
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-
lated at C-6 and C-8 either as free prenyl or cyclised as a fur-
ano, dihydrofurano or pyrano moiety and derivatives of
genistein, from the EtOAc soluble extract of the fruits of M.
tricuspidata.130 Compounds 162, 164 and 165 exhibited neu-
roprotective activity against 6-OHDA-induced cell death in
neuroblastoma cells with IC50 values of 9.2, 4.5, and 0.5 mM,
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-
methylcudraisoavone 173 and three isoavone dimers.131
The structural feature common to the isolated compounds is
that they all have a tetra-substituted A-ring and they are
derived from genistein. The unusual C-8 benzylated iso-
avones 165 and 170–173 were only reported from this
species. Structural elucidation of the new compound was
accomplished via spectroscopic and chemical methods.
Snatzke's method, using dimolybdenum tetraacetate as an
auxiliary chromophore, was employed to determine the
absolute conguration.
Fractionation of the MeOH extract of Cudrania tricuspidata
leaves led to the isolation a new prenylated isoavone named
cudraisoavone L 175, together with eight known isoavones.132
The remarkable feature of this new compound is the unprece-
dented presence of a hydroxyethyl attached to the C-atom in the
isoavone skeleton. The new isoavone 175 showed signicant
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cytotoxicity against NO production with an IC50 value of 10 mM.

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
Cudrania cochinchinensis (Moraceae) and from Derris robusta
(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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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 pyr-
anoisoavones 177–180, among which compounds 178–180
are known synthetic compounds, from Polygala molluginifolia,
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
of 68 and 84 mM, respectively, due to the presence of the free
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-
bicity and the presence of a catechol group play signicant Pterocarpans are the second largest subclass of isoavonoids aer
roles in the ability of the iso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)
prenylated isoavone, 5,7,40 -trihydrox-20 -methoxy-30 -pre- and only two congurations were reported from nature.
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

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isolation of 22.8 mg of the new pterocarpan (3S,4S)-30 -methoxy-40 -
hydroxy-7,8-methylenedioxylpterocarpan 182 together with four
known pterocarpans.136 The new compound exhibited strong
cytotoxicity against PC3 cells with an IC50 value of 3.5 mM.
Examination of the constituents of Pueraria alopecuroides
tuberous roots (Leg.), a plant close to P. mirica, resulted in the
isolation and identication of one new pterocarpan 3-O-glyco-
side, (
)-tuberosin-3-O-b-D-glucopyranoside 183.137
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Maackia amurensis (Leg.), which is used as folk medicine for
the treatment of cancer, is rich in prenylated isoavones and
pterocarpans.138 Fractionation of the n-BuOH extracts of M.
amurensis roots by column chromatography on Toyopearl HW-
50F sorbent led to the isolation of a new pterocarpan glycoside,
namely (6aR,11aR)-medicarpin-3-O-gentiobioside 184 together
with six other new isoavonoids.138 Structural elucidation of the
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
obtained from the roots of Dalea formosa (Leg.), displayed anti-
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-
censin, which is opposite and similar in magnitude.
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The bioassay-directed fractionation of the EtOAc extracts of
Pachyrhizus erosus roots (bengkoang, Fabaceae), a tropical and
subtropical plant used as a skin whitening material in Indo-
nesia, resulted in the identication of a new pterocarpan,
designated as 8,9-furanypterocarpan-3-ol 186.141 The new pter-
ocarpan displayed signicant tyrosinase inhibitory activity with
an IC50 value of 7.49 mM. However, the absolute congurations
at C-6a and C-11a for 186 were not determined. The CH2Cl2
extract of the roots and tubers of Adenocarpus cincinnatus (Ball)
Maire (Fabaceae), grown in Morocco, potentiated the GABA-
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 accom-
plished via ESI-TOF-MS and 1D and 2D NMR spectroscopy, and
the absolute conguration 6aR,11aR was determined via elec-
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-
methylenedioxy-1-prenyl-(6aR,11aR)-pterocarpan 191, were iso-
lated 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),
a new pterocarpan glycoside, isolated by bioassay-guided frac-
tionation from S. tonkinensis showed inhibitory activity against
LPS NO production (IC50 ¼ 33.0 mM).143 The occurrence of the
(2E)-but-2-enoyl moiety at C-600 as an acylating group in natural
isoavonoids has been only encountered once previously.10
Separation of the chemical constituents of G. uralensis resulted
in the identication of a new pterocarpan with the (6aR,11aR)
absolute conguration, named glycyuralin B 193, in addition to
ve isoavonoids.107
In the search of drug leads from natural sources, BioBioPha
reported the identication pterocarpadiols A–D 194–197, very rare
6a,11b-dihydroxypterocarpans, in addition to eleven known pter-
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-
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11b were determined via the HMBC, HMQC and ROESY NMR with three known pterocarpans.146 These compounds were also
techniques. The clear ROESY correlation in DMSO-d6 of 6a-OH 4 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
correlation of 11b-OH 4 H-11a and H6a indicated the a-orienta- IC50 values of 8.22 and 5.99 mM, respectively; whereas,
tion of the hydroxyl group at C-11b.144 The optical rotation values compounds 201 and 202 showed only moderate activities.
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
six,144 all of which were isolated from Leguminosae plants.
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(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
Compound 199 was also reported as a trace constituent of Sophora
tonkinensis.142 The (6aR,11aR) absolute conguration of both
compounds was determined by optical rotation comparison of
their experimental ECD spectra and X-ray diffraction analysis.

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-
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-
dihydroxy-3-methylbutyl)-9-methoxypterocarpan 206, in addi-
tion to three new isoavones 95–97.101

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
28.51 They considered Pruinosanone D 200 as an isoavan and
gave it the following name (3R,4R,200 S)-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
that of the positive control (aminoguanidine 20.13 mM). Thus,
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 CH2Cl2/MeOH extract of the root bark of
especially pterocarpans, isoavanes, isoavones, and iso- Millettia dura and M. micans resulted in the identication of one
avanones. Three new C-4 geranylated pterocarpans with the new pterocarpan from each species, named 3-O-prenylmaackiain
(6aR,11aR) absolute con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

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strong NOE observed between H-6a and H-11a and the great
 
D ¼
129.6 and
134.3 , respec-
negative specic rotation of [a]25
tively, and positive Cotton effect at 288 nm in their ECD spectra.
Examination of the vine stems of M. pachyloba afforded the new
pyranopterocarpan, pachylobin A 209, together with two new pre-
nylated isoavones 137 and 138.121 The absolute conguration of
209 was established by comparing its negative Cotton effect in its

CD curve ([a]25D ¼
30.71 , MeOH) at 223 nm with that of known
compounds. Aeschynocarpin 210 isolated from Aeschynomene fas-
cicularis (Fabaceae) is considered to be the rst reported pter-
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ocarpan in the genus Aeschynomene.149 A new pterocarpan

glycoside, glycinol-3-O-b-D-glucopyranoside 211, isolated from the
MeOH extract of the aerial parts of Ducrosia ismaelis (Apiaceae)
displayed potent peroxyl radical-scavenging capacities with an
ORAC value of 22.79  0.90 mM, which is stronger than that of
Trolox (24.83  0.12 mM).150 Two new pterocarpans bearing dihy-
droisopropenylfuryl attached at C-2 and C-3 having the 6aR, 11aR
and 13S congurations, named seputhecarpan A 212 and B 213,
respectively, in addition to a new isoavanone were obtained from
the MeOH extract of Polychidium contortum, a Botswanan folk
medicine.151 Pterocarpans 212 and 213 showed weak antioxidant
inhibitory activity with EC50 values of 611 and 88.7 mM,
respectively.
Two new isoavanone bearing a methoxycarbonyl group at
the C-5 position, (3R)-7,20 ,40 -trihydroxy-30 -methoxy-5-
methoxycarbonyl-isoavanone 214 and (3R)-7,20 -dihydroxy-
30 ,40 -dimethoxy-5-methoxycarbonylisoavanone 215, were iso-
lated from Cassia siamea stem (Leg.).152 Compound 215
exhibited potential anti-TMV activity with an inhibition rate of
24.6%. The bioassay-directed fractionation of the EtOAc soluble
fraction of the MeOH extract of Dalbergia odorifera T. heartwood
(Leg.) led to the isolation and characterisation of two new
simple isoavanones, (3R)-3,7-dihydroxy-20 ,40 -dimethoxyiso-
avanone 216 (not 3S as mentioned in the original paper) and
(3S)-7-hydroxy-20 ,40 ,50 -trimethoxyisoavanone 217.153 Their
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 abso-
lute conguration, kenusanone F 7-methyl ether 218 and
sophoronol-7-methyl ether 219, were identied from the MeOH
extract of D. melanoxylon bark, which is used as traditional
Chinese medicine for cleaning wounds.154 Compound 218 dis-
played inhibitory effects on mycobacterium tuberculosis by
96% with an MIC value of 80 mM, while both isoavanones were
inactive against P. falciparum.154

5. Isoflavanones
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

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isoavones, two of which were prenylated isoavanones named
Erythraddison III 220 and IV 221.100 The 3S absolute conguration
of both isoavanones was deduced from the negative Cotton effect
of CD as well as from their negative optical rotations. Compounds
220 and 221 showed strong inhibitory activity against the PTP1B
enzyme with IC50 values of 4.6 (stronger than that of tamoxifen)
and 13.8 mM, respectively. A new uncommon isoavanone, 5,7-
dihydroxy-20 ,4-dimethoxy-50 -formylisoavanone (erycaffra E) 222,
was isolated from the stem bark of E. caffra, a tree native to South
Africa used to treat sores, toothaches, tuberculosis, and arthritis,
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together with three prenylated isoavones.155 This compound
represents the rst report of an isoavanone bearing a formyl
substituent. The structure of the compound was determined using
1D and 2D NMR spectroscopic data and conrmed by the obser-
vation of a retro-Diels–Alder fragment at m/z 152, while the 3R
absolute conguration was assigned by comparison of its specic
rotation with literature values.
The fractionation of the MeOH extract of Dalea formosa Torr
(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, three new isoavans 251–253, and a new
pterocarpan entsandwicensin 185.139 The 3S absolute congura-
tion of compound 224 was determined by comparison of the
experimental ECD data (n / p* and p / p* electronic transi-
tion) with that of known 3-hydroxyisoavanones. The ECD spectra
of compounds 223 and 225 lacked the Cotton effect of the
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enantio-enriched isoavanones, an observation that was sup-
ported by the absence of optical activity. The major compound,
sedonans A 223, exhibited high growth inhibitory activity against
C. albicans and C. glabrata with MIC values of 40.7 and 20.6 mM,
respectively. Two new isoavanones 226 and 227 were isolated
and identied from the C. hirtella roots together with two new
isoavones 122 and 123 and one new pterocarpan.112 Compound
226 was identied as (3R)-6,30 -di(3-hydroxy-3-methylbutyl)-20 -
methoxy-5,7,40 -trihydroxyisoavanone based on the data obtained
from HMBC NMR and from the positive Cotton effect at 310 nm
and negative Cotton effect at 294 nm in its CD spectrum. On the
other hand, compound 6,30 -di(3-hydroxy-3-methylbutyl)-5,7,20 ,40 -
tetrahydroxyisoavanone 227 was isolated as a racemic mixture.
Further examination of the roots of C. hirtella yielded three new
C-30 geranylated isoavanones 228–230 reported in two separate
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 effect at 325 nm and negative effect
at 295 nm its the CD spectrum. In the case of compound 230, its
CD spectrum presented no Cotton effect at 320 nm, suggesting its
occurrence as a racemate. The numbering and some information
in the original paper were confusing and misleading.114
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Examination of the CH2Cl2 root extract of Mucuana pruri-
ens (Fabaceae), traditional Indian medicine, afforded two new
pyranoisoavanones named mucunone A 231 and B 232, and
one new simple isoavanone named mucunone C 233.156 The
proximity of the optical rotation of mucunone A 231 to zero
D ¼
2.53) and the insignicant Cotton effect in its CD
([a]29
spectrum indicated its racemic nature. A negative Cotton
effect in their CD spectra at 328 nm (3S-conguration) and
a positive Cotton effect at 327 nm (3R-conguration) were
observed for compounds 232 and 233, respectively.156 Des-
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modianone H 234, a new furanoisoavanone, isolated via the
bioactivity-directed fractionation of the EtOAc soluble extract
of Lespedeza maximowiczii leaves (Leg.) showed signicant
inhibitory effects on mushroom tyrosinase activity with an
IC50 value of 1 mM.157
A rare C-triisoprenylated isoavanone, designated as
ormosinol 235, isolated from the root bark of Ormosia henryi
(Leg.), a Chinese traditional medicine for the treatment of
swelling and inammation, displayed substantial scavenging
activity against DPPH radicals with an IC50 value of 28.5 mM
and signicant inhibitory activity against three cancer cell
lines (A549, LAC and HepG2) with IC50 values of 4.25, 522 and
7.05 mM.63 7,20 ,40 -Trihydroxy-6-(3-methylbut-2-en-1yl)
isoavanone 236 was obtained via an HPLC-based activity
proling method from the CH2Cl2 extract of Adenocarpus
cincinnatus roots and tubers (Leg.).117 Two new isoavanones
bearing methoxycarbonyl groups, (3R)-7-hydroxy-40-methoxy-
5-methoxycarbonylisoavanone 237 and (3R)-8-hydroxy-40-
methoxy-7-methoxycarbonylisoavanone 238, together with
seven known isoavanones were isolated from 70% aqueous
acetone extracts of Desmodium oxyphyllum (Leg.).158
Compound 237 exhibited cytotoxicity on the NB4 and SHSY5Y
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tumor cell lines with IC50 values of 3.1 and 2.5 mM, respec-
tively, while compound 238 showed cytotoxicity against the
PC3 cell line with an IC50 value of only 3.6 mM. Phytochemical
investigation of the Ptychlobium contortum roots resulted in
the isolation of the uncommon a,a-dimethylallyl-substituted
isoavanone having the 3S conguration, designated sepu-
theisoavone 239, in addition to two new pterocarpans 212
and 213.151 The new compound 239 showed weak antibacte-
rial and a-glycosidase inhibitory activity and moderate anti-
oxidant activity with an EC50 value of 68.5 mM. Seventeen
isoavonoids including the unprecedented 3,7,40 -trihydroxy-
2-methoxy-30 -geranylisoavanone 240 were isolated from the
roots of Psoralea Corylifolia (Fabaceae).122 The structural
feature of 240 is the occurrence of an acetal moiety (2-
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
a result the absolute conguration at C-2 and C-3 was not
dened. (3R,200 S)-8-(2-Methylbut-1-en-4-yl)-7,200 -epoxy-20 -
hydroxy-30 ,40 -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
cells with an IC50 value of 1.58 mM.125
75% of all antibacterial molecules are of natural product
origin. Recently, an extensive study designed to assess the anti-
mycobacterial activity of traditional medicinal plant extracts used
by the Mayo population against Tuberculosis (TB) and respiratory
diseases was carried out. The CH2Cl2 root extract of Rhynchosia
precatoria (Fabaceae) yielded two newly identied anti-
mycobacterial prenylated isoavanones named precatorin A 242
and precatorin B 243, in addition to a new isoavone named
precatoren C 143.124 Assignment of the (3R) absolute conguration
of 242 and 243 was carried out by ab initio computational analysis
of their ECD spectra. Precatorin A 242 and B 243 inhibited the
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growth of M. tuberculosis with an MIC value of 163 mM and killed
the bacteria with an MBC value of 297 mM. (3S)-7-Hydroxy-4-
methoxyisoavanone 30 -b-D-glucopyranoside 244 isolated from
the aerial part extracts and exudate of Ononis angustissima Lam,
a plant widespread in the Sahara, through antioxidant-directed
fractionation, showed moderate antioxidant activity.159
6. Isoflavans, isoflavanols and isoflav-
3-enes
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Isoavans, isoavenes and 3-arylcoumarin are characteristic
metabolites of the plants of the Glycyrrhiza genus. A new isoavan
bearing a prenyl group at C-6 and having a 5,7,20 ,40 -oxygenation
pattern named (3S) iconisoavan 248 was recorded as a constit-
uent of the roots of Glycyrrhiza iconica.163 The new compound 248
exhibited potent activity against Salmonella typhimurium with an
MIC value of 21.6 mM. In a combined phytochemical and biological
approach to identify the active components of Licorice, 122
compounds, among which two new isoavans named Glycyuralin
A 249 and C 250, and four other new isoavonoids were isolated

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
fungi or abiotic elicitors and act as phytoalexins in legumes.6,13
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
family. The C-3 absolute conguration was established by
optical activity measurements or by comparison of experi-
mental 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-
D-glucopyranoside 245, a new isoavan glycoside, was isolated and
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-
tion and identication of a new isoavan quinone, abruquinone I
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
of the same species.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. Compound 246
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 IC50 values of 0.3 and 0.2 mM, respectively.161,162
D–F 251–253.139 The absolute congurations of isoavans 251 and
253 were assigned as 3S by comparison of their experimental ECD
spectra with that of known isoavans, while the absolute cong-
uration of compound 252 was assigned as 3R based on its CD
spectrum. Compounds 251–253 exhibited antifungal activity
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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Review
The fractionation of the EtOH extract of Derris robusta twigs and
leaves, a rich source of isoavonoids, especially prenylated pter-
ocarpans and isoavones, yielded a new simple isoavan named 6-
hydroxyisosativan 254, in addition to four new isoavones 115–
118.110 The structure of 6-hydroxyisosativan 254 was inferred from
the 1D and 2D NMR techniques, while its relative conguration
was determined as 3R by comparison of its negative rotation value
(
11.7, MeOH) with that of 3R vestitol derivatives.164 Wang et al.
reported the isolation of two new isoavans, (3R)-7,40 -dihydroxy-
8,20 ,30 -trimethoxyisoavan 255 and (3R)-7,20 ,40 -trihydroxy-8,30 -
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dimethoxyisoavan 256 from the EtOH extracts of Spatholobus
suberectus (Leg.) and (3R)-7,20 ,40 -trihydroxy-5-methoxyisoavan 257
from the EtOH extracts of Flemingia macrophylla (Leg.).133 Two new
5,7,20 ,40 ,50 -oxygenated isoavans, designated as (3R)-40 ,50 -dihy-
droxy-5,7,20 -trimethoxy-6-(3-methylbut-2-enyl)isoavan 258
and (3R)-7,20 ,40 -trihydroxy-5,50 -dimethoxy-6-(3-hydroxyisoprenyl)
isoavan 259, together with other nine new isoavonoids were
isolated from the roots of C. hirtella.114
The strong cytotoxicities of numerous pterocarpans and
isoavones reported from D. velutina147 encouraged further
search for more bioactive compounds from this species. Frac-
tionation of the CH2Cl2 extract of D. velutina roots led to the
identication of two new C-8 geranylated isoavans, devel-
utinanes A 260 and B 261, having 3S and 3R absolute congu-
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
fraction of Colutea armata (Fabaceae), showed signicant anti-
fungal activity against Trichophyton schoen leinii, Aspergillus
niger, Pseudallescheria boydri, Candida albican and Trichophyton
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simii with 52–70.3% inhibition.166 A remarkable feature of 262 is
the unexpected occurrence of a hept-2-enyl substituent at C-8
and the unusual presence of a formyl moiety at C-20 .
In the search for new natural compounds possessing
antitrypanosomal activity, Hata et al., in two separate reports,
described the identication of three new isoavanols, abru-
quinone H 263, J 264 and K 265, from the CH2Cl2/MeOH (1 : 1)
extract of Abrus precatorius (Fabaceae) together with the new
isoavans 246 and 247.161,162 The absolute congurations of
compounds 263–265 were determined to be (3S,4S), (3S,4R),
and (3S,4R), respectively, by comparing their experimental
ECD spectra with data calculated for (3S,4S) and (3S,4R).
These three isoavonols strongly inhibited T. b. rhodesiense
with IC50 values ranging from 0.11–12.0 mM. Rugosa-
avonoids D 266 and E 267, two new 4-isoavanols isolated
from the MeOH extracts of Rosa rugose buds (Rosaceae), dis-
played weak cytotoxicity on ve human tumor cell lines (NB4,
A549, SHSY5Y, PC3, and MCF7).167 The new cordifoliavanes
A 268 and B 269 isolated form the extracts of Codonopsis
cordifolioidea (Campanulaceae), a herb used as food in China,
using silica gel column chromatography followed by HPLC
showed weak anti-HIV activities with EC50 values of 5.26 and
2.25 m mL
1, respectively.168
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
new isoavan 248.163
7. Rotenoids
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
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important sources of simple rotenoids, some of which possess
a methyl group at the C-10 position.
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a trans B/C junction and its absolute conguration was
established as 6aR,12aR. Oblarotenoid C 285 exhibited weak
activity against the human breast cancer cell line MDA-MB-
231 with an IC50 value of 93.8 mM.

Do et al. reported the identication of three new rotenoids,

Boeravinone K 271, 10-demethylboeravinone C 11-O-b-D-glu-
copyranoside 272 (boeravinone N) and 6-boeravinone M 273
(6-demethylboeravinone G) together with two new coumar-
onochromones 299 and 300 from the aerial part of Boerhaavia
erecta L.169 In the search of COX inhibitory components from
Indian medicinal plants, ve optically inactive simple rote-
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-
inammatory activities. Bioactivity-directed fractionation of
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
cells (IC50 ¼ 2.7 mg mL
1).171 Another new C-10 methylated
rotenoid named abronione 280 was isolated from Abronia
nana (Nyctaginaceae) together with three known rotenoids.172
Fractionation of the CH2Cl2/MeOH extract of Millettia usar-
amensis ssp. usaramensis root (Leg.), a shrub used in Kenyan
traditional medicine as an antidote against snake bites,
showed cytotoxic activities against MDB-MB-231 cells with an
IC50 value of 11.63 mg mL
1 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
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

by the high positive specic rotation of [a]20
D +96 and positive
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
from the same species. Four new rotenoids, oblarotenoids
(Graham) Baker showed effective cytotoxicity against the HT-
A–D 283–286, and a new isoavone 104 were isolated from the
29 human colon cancer cell line (IC50 ¼ 2.0 mg mL
1) and
leaves of M. oblata ssp. teitensis.104 Oblarotenoids A 283, B 284
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

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the rst example of a naturally occurring rotenoid bearing C-

and O-prenyl moieties on the D-ring. The chemical shis of dH
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-
tion, which indicated a cis B/C junction (6.4–6.8 ppm) versus
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
inhibition (IC50 ¼ 0.07 mM) and quinone reductase (QR)
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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
the same plant using silica gel chromatography led to the
isolation and identication of ve new isoavonoids,
including three prenylated rotenoids designated as (
)-caer-
uleanone D 290, (
)-3-deoxycaeruleanone D 291, and (
)-3-
hydroxycaeruleanone A 292.105 This is the fourth report of the
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-
nylation of rotenoids occurs once the formation of the A/B/C/
D ring system is completed.6 Dimethylallyl diphosphate
(DMAPP) is the source for the isoprene unit being integrated
at the D-ring.6 Based on these results, an anticipated bioge-
netic route for the D-ring substitution of rotenoids 287, 288
and 292 was proposed from rot-20 -enonic acid, as depicted in
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-
avonoids, among which were the three prenylated rotenoids 3-

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

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O-demethyldalbinol 293, 6a,12a-dehydro-3-O-demethylamor-
phigenin 294 and (6aR,12aR,50 R)-amorphigenin 295.79 None of
the new rotenoids displayed antibacterial activity against S.
aureus ATCC137094 and ATCC25923.
8. Coumaronochromones
Only 11 new examples, 296–306, of this uncommon isoavonoid
subclass were isolated and identied from Leguminosae and
non-Leguminosae families during the review period.
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Screening of the bioactive EtOAc extract of the whole fresh
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-
ported. Fractionation of the EtOH extract of Derris elliptica
aerial parts (Leg.), a climbing shrub distributed in Southeast
Asia, led to the isolation and identication of 6,40 -dihydroxy-
7,50 -dimethoxycoumaronchromone 298.178 Boeravinone L 299
(trivial name: 10-demethylboeravinone J) and (2S,3S)-5,7,40 -
trihydroxy-2,3-dihydrocoumaronochromone 40 -O-b-D-glucopyr-
anoside (Boeravinone O) 300 were identied from the EtOAc
extract of the Boerhaavia erecta L. aerial parts (Nyctaginaceae)
together with three new rotenoids 271–273.169 40 ,50 -Dihydroxy-5,7-
dimethoxy-6-(3-methylbut-2-enyl) coumaronochromone 301 iso-
lated from Campylotropis hirtella root (Leg.) displayed inhibitory
effects on B and T lymphocyte activity with IC50 values of 0.28 and
1.55 mM, respectively.112 In the search for bioactive compounds
from medicinal plants of Yunnan, China, a new coumar-
onochromone, 2,20 -epoxy-40 -methoxy-3,7-dihydroxy-isoavanone
302, was isolated and identied from the Horseldia pandur-
ifolia trunk (Myristicaceae).179 Compound 302 was tested for its
cytotoxicity against ve human tumour lines with no activity.
Examination of the EtOH extract of the tuber of Apios taiwanianus
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(Leg.), a Thai traditional medicine, afforded two new furano
coumaronochromones designated as apioisoavone 303 and
isoapioisoavone 304 together with een known isoavones.180
The two compounds differ only in the site of the attached iso-
propenyl dihydrofuran moiety. 5-Methoxy-2,5,7,40 -
tetrahydroxycoumarono-chromone 305 isolated from the EtOAc
soluble methanolic extract of Apios americana roots (Leg.) using
silica gel column chromatography, C-18 and Sephadex displayed
inhibitory activity on soluble epoxide hydrolase (sEH) with
a dose-dependent IC50 value of 43.2  0.4 mM and acted as
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
9. 3-Arylcoumarins
Four new 3-phenylcoumarins named sphenostylisin D–G 307–310,
together with one new complex isoavone 148 and three new
complex dimeric isoavonoids, sphenostylisins A–C 372–374,
were isolated from the bioactive chloroform-soluble MeOH extract
of Sphenostylis marginata ssp. erecta root bark (Fabaceae) using
a bioactivity-directed isolation approach.126 The structures of the
new compounds were determined via detailed spectroscopic
analysis, including NMR and HRESIMS analyses. Sphenostylisin
E–G 308–310 are isomers with different arrangements only in their
respective side chain at C-6. These side chains are thought to be
derived from an a,a-dimethylallyl group through oxidation, rear-
rangement, and cyclization.126 This is the rst report of the pres-
ence of the unusual side chains among the naturally occurring 3-
phenylcoumarins.126 Su et al. reported the isolation of pterosonin
F 311 from the EtOH extract of heartwood of P. soyauxii together
with seven new natural isoavones 10–16.44 Compound 311 dis-
played cytotoxicity against A549, Panc-28, and HCT-116 cells with
GI50 values of 7.39, 25, and 19.17 mM, respectively.
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Plants of the genus Morus (Moraceae) are substantial sources

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-
inammation. Most of the 2-arylbenzofurans were isolated from
the genus Morus (Moraceae). Three new 2-arylbenzofuran pos-
sessing one isoprenyl and one geranyl group, named wittifurand
H 314, I 315 and U 316, were isolated from the EtOH extract of
Morus wittiorum stem bark.184 Compound 315 exhibited strong
anti-inhibitory activity and selective cytotoxicity against the
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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
10. Coumestans (+)-dimethylsmoracin O 317.185 (20 R)-20 ,30 -Dihydro-20 -(1-hydroxy-

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-
5-methoxy-2-(3-methyl-2-butenyl)-coumestan 312, seven iso-
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-
thylwedelolactone 313, which displayed antiproliferative activity
against PC-3 cells with an IC50 value of 8.33  0.12 mM.183

11. 2-Arylbenzofurans

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1methylethyl)-2,60 -bibenzofuran-6,40 -diol 318 and 5,6-dimethoxy-
2-(3-hydroxy-5-methoxyphenyl)benzofuran 319 are new iso-
avonoids isolated from the stems of M. notabilis.186
Phytochemical investigation of the constituents of the EtOH
root bark extracts of Morus alba var. tatarica (Moraceae) led to the
isolation and identication of ten new B-ring geranylated 2-aryl-
benzofurans 320–329 together with four known ones.187 It is
noteworthy that all the new compounds possess the 6,30 ,50 -
oxygenation pattern. The relative structures of the new compounds
were established based on HMBC, HSQC, NOESY and ROESY
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spectroscopic data analysis and the absolute congurations of
compounds 320, 322, 323 and 328 were determined via the
induced ECD of the formed [Rh2(OCOCF3)] complex and Snatzke's
method. Compounds 320, 321, and 324–326 exhibited moderate
inhibitory activities against a-reductase with IC50 values ranging
from 11.9  1.3–33.1  1.9 mM, among which the two
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monoterpenoid 2-arylbenzofurans 320 and 321 displayed the
highest inhibition. Purication of the cell culture of M. alba,
a Chinese traditional medicine, led to the identication of a 2-
arylbenzofuran bearing an oxacycloheptene attached to the A-ring
named 5-dehydroxy-moracin U 330.188
Further phytochemical investigation on the M. alba roots
afforded six additional new prenylated 2-arylbenzofurans, two
moracin O-glycosides 331 and 332 and moracin P glycosides
333–336.189 The new 2-arylbenzofuran O-glycosides displayed
signicant protective effects on doxorubicin-induced cell death
(IC50 ¼ 9.5  2.6–39.5  7.2 mM), among which moracin P-30 -O-
b-D-glucopyranoside 336 showed the highest activity. Earlier,
albafuran D 337, another new C-4 geranylated 2-arylbenzofuran,
was isolated and identied from the same source.190
Four new benzofuran-type stilbene glycosides 338–341 were
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-
sides and moracin O, namely the glycosides as (9R)-moracin P
30 -O-a-L-arabinopyranoside 338, (9R)-moracin P 9-O-b-D-gluco-
pyranoside 339, (9R)-moracin P 30 -O-b-D-glucopyranoside 340
and (9R)-moracin O 10-O-b-D-glucopyranoside 341 based on the
spectroscopic and chemical analysis.
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-
benzofuran, Albasin C 344 were reported for the rst time.192
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-arylbenzo-
furan moiety (diene).192 Compound 342 was assigned as a trans–
trans adduct with the absolute conguration of 300 R, 400 R, and
500 S by the negative specic rotation of [a]25 
D ¼
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 300 S,
400 R, and 500 S by the positive specic rotation [a]25 
D ¼ +440.0 and
the positive Cotton effect around 319 nm. The three new
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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2.46 mM, respectively, where compound 342 was more effective

than the positive control (oleanolic acid, IC50 ¼ 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
A–C 346–348 were isolated and identied from the stem bark
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
Phytochemical study of the EtOAc extract of Artocarpus
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-
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-
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-
from 7.7–82.7 mM. Phytochemical investigation of the aryl-3-methylbenzofurans, namely neoglycybenzofuran 355 and
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
and G 354.197 The 40 -O-methylated compound 354 displayed substituent at C-3, was isolated from G. uralensis Fish together
anti-HIV-1 activity with therapeutic index values above with ve other new isoavonoids.107 The bioassay-guided
100 : 1.

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fractionation of the EtOH extract of C. hirtella root afforded the Chromatographic studies on the EtOAc-soluble MeOH
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
benzofuranone, was isolated and identied from the CH2Cl2 new symmetrical biisoavones, 8,800 -bi-6-hydorxyorobol 361 and
extract of the tube roots of Butea superba Roxb. (Fabaceae), 8,800 -bi-6,20 -dihydroxygenistein 362.200 An additional three C-8–
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
this material was isolated, the absolute congurations at C-2 in
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360 was not determined. The new compound did not exhibit a-
glucosidase and antimalarial inhibitory activities.

12. Isoflavonoid dimers, heterodimers

and conjugates
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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Review
C-800 biisoavones, dapholidins A–C 363–365, were reported
from the EtOAc-soluble fraction of the MeOH extract of the
same plant.201 As part of a plan for the discovery of new effective
tyrosinase inhibitors from natural products, Hu et al. reported
the isolation and identication of two new 2-arylbenzofuran
dimers named morusyunnansin A 366 and B 367 from the EtOH
extract of M. yunnanensis leaves (Moraceae).202 The two mono-
mers of 2-arylbenzofuran dimers are joined by their carbon
atoms through the isoprenoid linker. Three genistein-based
isoavone dimers named cudraisoavones Q–S 368–370,
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together with eight new isoavones were isolated and charac-
terised from the EtOAc-soluble MeOH extracts of the fruits of
Maclura tricuspidata (previously known as Cudrania tricuspi-
data).131 The fragment ion peak at m/z 337 [M + H
336]+ ob-
tained from retro Diels–Alder-type fragmentation in EISMS of
compound 368, in addition to COSY and HMBC spectra, sug-
gested that the two isoavone subunits were linked at C-6 by
a monoterpene (dihydropyran).131 The two isoavone subunits
in the uncommon dimers 369 were linked at C-6 via a trans
double bond attached to C-6 of one isoavone unit and to the C-
1 in dihydropyran, which is attached to C-6 and 7-O in the other
isoavone unit, as revealed by HMBC and COSY spectra. The
absolute congurations of the compounds were determined by
employing ECD spectroscopy in combination with quantum-
chemical ECD calculations.
Fractionation of Amphimas pterocarpoides root extracts (Leg.),
grown in tropical Africa and used as traditional medicine in
Cameroon, led to the isolation and identication of a new iso-
avone dimer named amphiisoavone 371, which was derived
from 7-hydroxy-5,6,40 -trimethoxyisoavone and 6-
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methoxyformononetin (afromosin) linked by a C-7–O–C-7 ether
bridge.203 The CHCl3-soluble MeOH extract of the root bark of
Sphenostylis marginata E. Mey. ssp. erecta (Baker f.) Verdc. [syn:
Dolichos erectus Baker f.; Sphenostylis erecta (Baker f.) Hutch. ex
Baker f.], a medicinal plant used as an antiseptic and for the
treatment of abdominal pain and fever in some African coun-
tries, afforded three heterodimeric compounds having two
characteristic novel carbon skeletons, named sphenostylisins
A–C 372–374, in addition to ve new isoavonoids.126 The
connectivity of either the 3-phenylcoumarin A subunit in
sphenostylisin A 372 or the isoavan subunit in sphenostylisin
C 374 with morachalcone B subunits was determined by HMBC
techniques to be C–C-linked on C-30 to C-200 of the benzofuran
unit. Morachalcone B is a chalcone fused with furan at C-alpha
and C-2. Sphenostylisin B 273 comprises the 3-phenylcoumarin
C–C-linked at C-50 via a methylene group linker to C-30 of 2-
arylbenzofuran. The new dimers 372–374 showed strong
hydroxyl radical scavenging activity with ED50 values ranging
from 0.71–0.91 mM and displayed very potent NF-kB p65
inhibitory activity. Sphenostylisin A 372 was found to be a very
potent NF-kB p65 inhibitor with an IC50 value of 6 nM, which
was >10 times more potent than the positive control (rocagla-
mide).126 This powerful inhibition activity can be attributed to
the carbonyl group (C-2) of the lactone as well as to the carbonyl
group in the benzofuran unit, which are both present in 372 but
one of them is absent in 373 and 374.126 The structures of
dimers 372–374 were established by 2D NMR spectroscopic data
and conrmed by tandem mass spectroscopy (ESIMS/MS). The
dimer 372 did not break signicantly through carbon–carbon
bond scission when collision-induced dissociation (CID) was
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employed, and thus, only one major fragment peak from the
parent ion (m/z 697.22 [M + Na]+) was observed at m/z 679.22 [M
+ Na
H2O]+. This may be produced through a proton rear-
rangement similarly to a McLafferty rearrangement, followed by
cyclization to form the pyrane ring and loss of one water
molecule, as indicated in Scheme 2. On the other hand, the
dimer 373 was disconnected at the methylene group to yield the
2-arylbenzofuran fragment 373a with an m/z 333.14 [M + Na

C21H18O5]+ fragment and a quinone methide fragment 373b
with m/z 373.14 [M + Na
C19H18O4]+.126
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Two 2-arylbenzofuran dimers, shandougenine A 375 and B
376, isolated from the antioxidative EtOH extract of Sophora
Scheme 2 Tandem MS fragmentation pathway for compounds 372 and 373.
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tonkinensis roots showed moderate radical scavenging activi-
ties.204 Shandougenine A 375 is a unique dimeric 2-arylbenzo-
furan with a C-3–C-50 linkage, while shandougenine B 376
represents the rst naturally occurring 2-arylbenzofuran dimer
with a C-3–C-3 linkage.
Twelve heterodimers, hirtellanones A–L 377–388, composed
of 2-an arylbenzofuran unit joined to either an isoavan, iso-
avone or isoavanone unit, were isolated from the EtOH
extract of Campylotropis hirtella (Fabaceae).205 The natural
occurrence of 2-arylbenzofurans attached to isoavonoids has
rarely been reported, with only eight such compounds previ-
ously extracted from Lespedeza cyrtobotrya Miq. and L.
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Review
oribunda.206,207 Each dimer is linked via a carbonyl bridge,
which is vital in initiating the phenol oxidative coupling reac-
tion the at C-30 of the isoavanone or isoavan to the C-8 of the
2-arylbenzofuran. Most of the compounds displayed immuno-
suppressive effects on Con A and LPS-induced splenocyte
proliferation in vitro. The heterodimer 384, an isoavone linked
to 2-arylbenzofuran, showed the highest activity with IC50 values
of 3.68 mM for T lymphocyte and 1.79 mM for B lymphocyte
suppression. These results revealed that the occurrence of a 2,3-
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double bond in the isoavonoid (isoavone) moiety may be
essential for immunosuppressive activity. Further examination
of the extract of C. hirtella led to the isolation and identication
of the rst isoavan-coumaronochromone dimer reported to
date, 389, together with an unusual isoavone 23.48 The
proposed biosynthetic pathway suggested that the unusual
dimer 389 was derived from hirtellanone C 381 reported from
the same plant via a sequence Michael addition-type reaction,
as depicted in Scheme 3.48
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Scheme 3 Proposed biosynthetic pathway for dimer 389.
Phytochemical investigation of the antibacterial and anti-
fungal active MeOH extract of Chlorophytum tuberosum Roxb
roots (Asparagales), used by indigenous people of India to
cure various ailments, led to the isolation of a bis-
isoavonoid glycoside characterized as bis(8-methyl-
40 methoxy-7-O-a-L-rhamnopyranoside)-C-5–C-500 -bisiso-
avone 390.208 This symmetrical dimer is derived from the
Nat. Prod. Rep.
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Review
rare C-8 methylated formononetin 7-O-a-L-rhamnopyrano-
side. Gynandrinone 391, another new isoavone dimer, iso-
lated from the MeOH extract of Gynandriris sisyrinchium
(Iridaceae) displayed signicant antioxidant activity with an
IC50 value of 41.8 mM.42 The isoavone dimer is derived from
20 ,30 -dimethyl tenuifone and irisolidone linked by the C-5–O–
C-7 ether bridge.
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Scheme 4 Suggested biosynthetic pathway for compounds 392–394.
Phytochemical study of the twigs and leaves of Belamcanda
chinensis (Iridaceae), Chinese traditional medicine for the
treatment of throat ailments, resulted in the identication of
three unprecedented spiroiridals attached to isoavones at the
C-8 position named belamcandanins A–C 392–394.209 The rela-
tive congurations of the spiroiridals were determined by ana-
lysing their 1H–1H coupling and their NOE and ROESY data. The
anti-relationship of H-80 /H-90 and H-90 /H-100 was conrmed by
their 10.8 Hz coupling constants. The biosynthetic pathway for
the unusual compounds was suggested starting from the
biogenic belamcanda 395, as depicted in Scheme 4. The latter
may undergo deacetylation and hydrogenation followed by
oxidation to produce the intermediate i, which was subjected to
nucleophilic attack by the isoavone to offer intermediate ii.
Dehydration followed by hydrogenation would produce
compounds 392–394.
13. Conclusions
391 novel isoavonoids were isolated and characterised during
the review period, including 237 isoavonoids from 74 Legu-
minosae species, 74 from 14 the Moraceae species, 18 from six
Iridaceae species and 56 isoavonoids from 28 different plant
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families. In the search for biologically active compounds,
Campylotropis hirtella (Franch) Schindl. (Leg.) afforded the
highest number of isoavonoids (36 new isoavonoids), fol-
lowed by Maclura tricuspidata with 24 isoavonoids and Morus
alba with 17 new isoavonoids during the review period.
Bioactivity-guided fractionation of plant extracts resulted in the
isolation of several very potent bioactive isoavonoids that can
be potential lead drug candidates. The isoavone dimers 372–
374 extracted from Sphenostylis marginata subsp. erecta (Baker
f.) Verdc showed effective hydroxyl radical scavenging activity
with ED50 values ranging from 0.71–0.91 mM, as well as very
potent inhibitory activity on NF-kB p65 with IC50 values ranging
from 0.006–1.5 mM, of which sphenostylisin A 372 was found to
be the most effective NF-kB p65 inhibitor with an IC50 value of
6 nM, which was >10 times more powerful than the positive
control, rocaglamide.126 The C-benzylated complex isoavone
165 extracted from Maclura tricuspidata displayed neuro-
protective activity with 6-OHDA induced cell death in neuro-
blastoma cells (IC50 ¼ 0.5 mM).130 The pterocarpan,
pruinosanone D 200, isolated from Caragana pruinosa displayed
high inhibitory activity against NO production with an IC50
value of 0.62 mM, which was found to be superior to that of the
positive control (aminoguanidine 20.13 mM).51 The rotenoid,
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caeruleanone A 288, isolated from Millettia caerulea fruits
(Graham) Baker displayed strong mitochondrial trans-
membrane inhibition (IC50 ¼ 0.07 mM).175 Coumar-
onochromone 301 isolated from Campylotropis hirtella (Leg.)
showed strong inhibitory inuence on B lymphocyte activity
with the IC50 value of 0.28 mM.112 Thus, further investigations on
pharmacology and chemistry, as well as toxicological research,
should be carried out for better validation of the therapeutic
potential of complex isoavonoids, especially isoavonoid
dimers, and coumaronochromones.
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14. Species checklist
See ESI.†
15. Conflicts of interest
The author declares no conicts of interest.
16. Acknowledgements
The Author thanks Miss Ahlam Awawdeh for valuable advice on
IT.
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