Isoflavonoids in non-leguminous families: an update

R E V I E W

NPR www.rsc.org/npr

Isoflavonoids in non-leguminous families: an update

Jo¨el Reynaud,* David Guilet, Raphael Terreux, Monique Lussignol and Nadia Walchshofer Universit´e Claude Bernard Lyon 1, ISPB Facult´e de Pharmacie, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France. E-mail: reynaud@rockefeller.univ-lyon1.fr

Received (in Cambridge, UK) 3rd June 2005

First published as an Advance Article on the web 30th June 2005

Covering: the literature from the first reported isolation of isoflavonoids from non-leguminous families up to April 2005

This review provides a listing of isoflavonoids reported in non-leguminous families. Reviews published to date have principally focused on plants with the richest isoflavonoid contents, the family Leguminosae. After a brief recall of the structure of isoflavonoids, we present all isoflavonoid structures encountered in non-leguminous families which may, thereby, become new plant sources for these compounds. Articles reporting on their different functions in plants are pre- sented, as well as a brief summary discussing their potential benefits for human health. A list of 135 references is given.

1 Introduction

Over the past two decades, few plant secondary metabolism products have received as much attention from biochemists, plant pathologists, medical researchers, and dieticians as isoflavonoids.

At the beginning of plant chemistry, isoflavonoids were studied by phytochemists only and considered useful chemosys- tematic markers.

Later on, as they became known for their antifungal and insecticidal properties, they were considered as phytoalexins by phytophysiologists. Since their estrogen-like

Jo¨el Reynaud, PhD, Maˆıtre de Conf´erences (Assistant Professor), teaches botany to pharmacy students. His research interest is phytochemistry, and more precisely the study of flavonoids. He has been particularly involved in the study of flavonoids used as evolution indicators in the complex Lotus corniculatus (Fabaceae). His current research interests include the extraction and purification of natural plant products (flavonoids s. l.) with potential therapeutic properties.

David Guilet received his PhD from the University of Angers (France) where he studied natural compounds from Clusiaceae species under the supervision of Professor Pascal Richomme. He undertook a 2-year postdoctoral research position in Kurt Hosttetmann’s laboratory at the University of Lausanne (Switzerland). He is currently Maˆıtre de Conf´erences (Assistant Professor) at the Faculty of Pharmacy of Lyon University and teaches pharmacognosy. His research interests revolve around natural products: isolation, structure elucidation and bioactive potentialities.

Raphael Terreux, PhD, Maˆıtre de Conf´erences (Assistant Professor) and specialist in molecular modelling and Quantitative Structure–

Activity Relationships (QSAR), teaches physical chemistry. He undertook his PhD at the University of Nice-Sophia Antipolis (France), with a dissertation on drugs against the TAR RNA element of the HIV1 genome. He took a postdoctoral position at the Steacie Institute of The National Research Council of Canada (NRC), where he designed drugs from natural products for cancer therapy.

Monique Lussignol, Research Engineer, studies natural plant products: her current research interests revolve around flavonoids and saponins. She is also involved in the laboratory training of students preparing for research in plant chemistry.

Nadia Walchshofer obtained her PhD from Universit´e Claude Bernard-Lyon 1, where her work focused on the synthesis of heterocyclic compounds active against parasite organisms. She began her academic career at the faculty of Pharmacy of Lyon as an Assistant Professor of Medicinal Chemistry in 1984, then she was promoted to Professor of Organic Chemistry in 1998. Her research interests include medicinal chemistry, strategies for the synthesis of biologically active molecules, and the development of new synthetic methods.

Jo¨el Reynaud David Guilet Raphael Terreux Monique Lussignol Nadia Walchshofer

properties have been reported in humans, their interest as phy- toestrogens has grown considerably among human pathologists.

The presence of isoflavonoids is almost entirely restricted to the subfamily Fabaceae, of the family Leguminosae, but they are also occasionally found in some other angiosperm families.

Numerous papers have described the occurrence of isoflavonoids in the leguminous family. No review, to our knowledge, has specifically addressed the global distribution of isoflavonoids in families other than the Leguminosae, apart from two studies on Rutaceae

and Mysticaceae,

the chapter on isoflavonoids written by Dewick in the 1994 edition of “The Flavonoids”

:10.1039/b416248j

and a general review on isoflavonoids by Tahara and Ibrahim in 1995.

The purpose of this report is to update the non-leguminous sources of isoflavonoids. To that end, the isoflavonoids present in non-leguminous families reported in the literature are listed:

either by Wong (1975)

or Dewick (1982, 1988, 1994),

in the different issues of Harborne’s book “The Flavonoids”

(edn. 1975, 1982, 1988, 1994),

or by other authors,

as well as in “The Handbook of Natural Flavonoids” (1999) published by Harborne and Baxter.

Secondly, for studies subsequent to the completion of these books, we have re- viewed scientific databases such as SciFinder and PubMed (www.ncbi.nlm.nih.gov/entrez/query.fcgi). We were able to inventory over 160 types of isoflavonoids reported in 31 non- leguminous families.

2 Chemistry of isoflavonoids 2.1. Classification

Isoflavonoids (over 1000 structures) are a large subclass of flavonoids (approximately 5000 structures) with a 15-carbon (C6–C3–C6) backbone arranged as a 1,2-diphenylpropane skeleton.

In plants, isoflavonoids may be encountered as aglycones or as glycosides (with generally glucose, rhamnose or apiose as the sugar component), but glycosidic derivatives are less common than the free state. The number of isoflavonoid glycosides is thus extremely small compared with the very vast range of flavone and flavonol glycosides. This paper will only report on the aglycone skeletons, even if the compounds have been found as glycosides in the plants.

The number and complexity of possible substituents on the basic structural skeleton (methoxyl, aromatic or aliphatic acids, prenyl, methylenedioxy or isoprenyl. . .), the different oxidation levels and the frequent presence of extra heterocyclic rings account for the multiplicity of subgroups among isoflavonoids.

Some isoflavonoids are amino-substituted; these are called

“isoflavonoid alkaloids”,

whereas others may be chlorinated.

The presence of C-glycosylisoflavonoids has been reported in the Leguminosae

and in the Menispermaceae.

Isoflavonoids may also be found as dimers.

2.2. Isolation and identification

Techniques for the isolation and identification of isoflavonoids were previously described

and will not be discussed in this report. Of note, however, the combination of high-performance liquid chromatography (HPLC) with mass spectrometry (MS) has proved to be a useful tool, particularly when associated with atmospheric pressure chemical ionization (APCI). The use of capillary electrophoresis (CE) is also common, in particular in combination with electrospray ionization mass spectrom- etry (ESI-MS). Two-dimensional nuclear magnetic resonance (NMR) is frequently used for unambiguous identification of complex molecules. The increasing sensitivity of isolation and identification methods should make it possible to identify new occurrences of isoflavonoids in families where these molecules are currently considered rare or even non-existent.

Importantly, isoflavonoids, particularly aglycones, are more often present in rhizomes, roots, wood and bark than in leaves and flowers.

3 Isoflavonoids and phytochemists

Following the first reports and reviews by Harborne and Baxter in “The Handbook of Natural Flavonoids” published in 1999,

isoflavonoids are found primarily in Leguminosae, and more particularly in the sub-family Papilionaceae. According to Hegnauer and Grayer-Barkmeijer, 95% of isoflavonoid aglycone structures from the plant kingdom known in 1988 were reported in the only Leguminosae family: 89% of isoflavones, 95% of

rotenoids, and 100% of isoflavans, isoflavanones, coumestans and pterocarpans.

They were, then, widely used as taxonomic markers within this family. In 1995, Tahara and Ibrahim reported that some of these molecules had also been identified in 23 other angiosperm families.

According to Dewick, 465 structures were known in 1982, 630 in 1988 and 870 in 1993.

Of note, only 26 isoflavonoid aglycones were reported in the book by Geissman in 1962.

Many new isoflavonoid structures have been identified since the late nineties; their total number now exceeds a thousand.

Several additional families, outside the Leguminosae, have also been shown to synthesise these molecules. More than thirty families of flowering plants are known to produce isoflavonoids (mainly isoflavones). Yet, the family Leguminosae remains the most important family of plants involved in the synthesis of isoflavonoids (several hundreds of species for over a thousand different structures), all the more so as plants from other families often produce only 2 or 3 different molecules, or even only one in some cases.

Nine isoflavonoid subclasses have been mentioned in non- leguminous families (Table 1). As in the Leguminosae, the largest group consists of isoflavones.

3.1. Isoflavonoids in monocots

In monocots, few families (only 6 have been reported) seem able to produce isoflavonoids. The Iridaceae are the major source of isoflavonoids in this group, with more than 50 different compounds described (Table 3), mainly in the genus Iris where they are present in the rhizomes of approximately 20 species. As in the Leguminosae, it has been demonstrated that Iridaceae treated with cupric chloride are able to produce coumaronochromones in the leaves.

A study of green barley (Hordeum vulgare) published in 1992 mentioned the presence of a major “isoflavonoid” antioxidant identified as 2

-O-glucosylisovitexin

in the leaves of the plant.

Despite the use of the prefix “iso”, this compound is not an isoflavonoid but a C-glucosylflavone. Unfortunately, the error that had been made in the title has been duplicated on several occasions in further articles citing this paper.

A recent article by Markham and Mitchell makes it clear that this major “isoflavonoid antioxidant” corresponds in reality to a mixture of C-glucosylflavones.

Of note, however, several

Table 1 Subclasses of isoflavonoids in non-leguminous families

Subclasses Number of structures

A Isoflavones 124

B Isoflavanones 2

C Rotenoids 3

D Dehydrorotenoids 17

E 12a-Hydroxyrotenoids 6

F Pterocarpans 4

G Coumestans 5

H Isoflavanols 1

I Coumaronochromones 2

Table 2 Occurrence of isoflavonoids in non-leguminous families

A Isoflavone

Isoflavones Families Ref.

Daidzein (7,4-dihydroxy-) Rutaceae 2

Malvaceae 22

Menispermaceae 18

Formononetin (biochanin B) (7-hydroxy-4-methoxy-) Myristicaceae 23

Rutaceae 2

7,6-Dihydroxy-3-methoxy- Liliaceae 24

4Methylneobavaisoflavone (7-hydroxy-4-methoxy-3-prenyl-) Scrophulariaceae 15 2-Hydroxyformononetin (7,2-dihydroxy-4-methoxy-) Myristicaceae 15

2Methoxyformononetin (7-hydroxy-2,4-dimethoxy-) Papaveraceae 25

8-Methylretusin^a(7-hydroxy-8,4-dimethoxy-) Myristicaceae 3

Isoformononetin (4-hydroxy-7-methoxy-) Rutaceae 2

2,4-Dihydroxy-7-methoxy- Papaveraceae 25

2-Hydroxy-7,4-dimethoxy- Myristicaceae 23

6,7-Dihydroxy-3-methoxy-4,5-methylenedioxy- Vitaceae 26

6,8,3,5-Tetrahydroxy-7,4-dimethoxy- Iridaceae 27

Glycetein or glycitein (7,4-dihydroxy-6-methoxy-) Rutaceae 2

7,2-Dihydroxy-6-methoxy- Chenopodiaceae 15

7,8,5-Trihydroxy-6,3,4-trimethoxy- Iridaceae 27

Isocladrastin (3-hydroxy-6,7,4-trimethoxy-) Iridaceae 28

Kashmigenin (4-hydroxy-3,5-dimethoxy-6,7-methylenedioxy-) Iridaceae 28

2-Hydroxy-6,7-methylenedioxy- Chenopodiaceae 11

8,4-Dimethoxy-6,7-methylenedioxy- Ochnaceae 19

Ficusin B1 Moraceae 29

Genistein (5,7,4-trihydroxy-) Iridaceae 30

Moraceae 29

Rosaceae 12

Myristicaceae 3

Rutaceae 2

Biochanin A (5,7-dihydroxy-4-methoxy-) Myristicaceae 31

Rosaceae 32

Rutaceae 2

Malvaceae 22

Asteraceae 33

Orobol (5,7,3,4-tetrahydroxy-) Asteraceae 34

Poaceae 35

Moraceae 36

Scrophulariaceae 37

Asteraceae 33

Pratensein (5,7,3-trihydroxy-4-methoxy-) Iridaceae 15

Junipegenin A (5,7,3,5-tetrahydroxy-4-methoxy-) Iridaceae 11

3-O-Methylorobol (5,7,4-trihydroxy-3-methoxy-) Asteraceae 15

Moraceae 38

5,7-Dihydroxy-3,4-dimethoxy- Scrophulariaceae 37

2-Hydroxybiochanin A (5,7,2-trihydroxy-4-methoxy-) Myristicaceae 15 2-Methoxybiochanin A (5,7-dihydroxy-2,4-dimethoxy-) Myristicaceae 15

Nervosin^b(5,7,4-trihydroxy-2,3,6-trimethoxy-) Clusiaceae 39

Moraceae 40

Ficusin A2 Moraceae 29

5,7-Dihydroxy-8,4-dimethoxy- Polygalaceae 41

5,7,3,4-Tetrahydroxy-8-methoxy- Scrophulariaceae 37

5,7,3-Trihydroxy-8,4-dimethoxy- Iridaceae 42

5,7,3-Trihydroxy-8,4,5-trimethoxy- Iridaceae 43

Homotectorigenin (5,7,4-trihydroxy-8,3-dimethoxy-) Iridaceae 15

5,7,4-Trihydroxy-3-methoxy-8-prenyl- Asteraceae 15

Prunetin (5,4-dihydroxy-7-methoxy-) Rosaceae 15

Myristicaceae 31

Iridaceae 44

Ochnaceae 45

Rutaceae 2

5-Hydroxy-7,4-dimethoxy- Myristicaceae 31

Santal (7 methyl orobol) (5,3,4-trihydroxy-7-methoxy-) Asteraceae 15

Iridaceae 46

5,3-Dihydroxy-7,4-dimethoxy- Asteraceae 15

7,3-Methylorobol (5,4-dihydroxy-7,3-dimethoxy-) Asteraceae 15

Vavain (pentandrin) (5,5-dihydroxy-7,3,4-trimethoxy-) Bombacaceae 47 Eriocaulaceae 48

Table 2

Isoflavones Families Ref.

5,8,3-Trihydroxy-7,2-dimethoxy- Chenopodiaceae 49

5,2-Dihydroxy-7,8-dimethoxy- Iridaceae 15

5,3-Dihydroxy-7,8,2-trimethoxy- Chenopodiaceae 50

6,8,3,5-Tetrachloro-5,4-dihydroxy-7-methoxy-3 Ochnaceae 17

6,8,3-Trichloro-5,4-dihydroxy-7-methoxy-4 Ochnaceae 17

(6-Hydroxy-biochanin A) 5,6,7-trihydroxy-4-methoxy- Asteraceae 33

5,6,7,3-Tetrahydroxy-4-methoxy- Iridaceae 51

5,6,7,4-Tetrahydroxy-3-methoxy- Iridaceae 15

5,6,7,4-Tetrahydroxy-8-methoxy- Iridaceae 44

Liliaceae 52

5,6,4-Trihydroxy-7-methoxy- Asteraceae 53

5,6,4-Trihydroxy-7,3-dimethoxy- Asteraceae 53

5,6,3-Trihydroxy-7,2-dimethoxy- Chenopodiaceae 49

Tectorigenin (5,7,4-trihydroxy-6-methoxy-) Iridaceae 54

Irisolidone (5,7-dihydroxy-6,4-dimethoxy-) Iridaceae 55

Myristicaceae 3

Irilin D (5,7,3,4-tetrahydroxy-6-methoxy-) Iridaceae 56

Iristectorigenin A (5,7,3-trihydroxy-6,4-dimethoxy-) Iridaceae 54

Irigenin (5,7,3-trihydroxy-6,4,5-trimethoxy-) Iridaceae 57

Clusiaceae 39

Iristectorigenin B (5,7,4-trihydroxy-6,3-dimethoxy-) Iridaceae 58

Junipegenin B (dalspinosin) (5,7-dihydroxy-6,3,4-trimethoxy-) Iridaceae 58

Liliaceae 59

Irilin B (5,7,2-trihydoxy-6-methoxy-) Chenopodiaceae 60

Iridaceae 56

5,7-Dihydroxy-6,2-dimethoxy- Iridaceae 61

Irisjaponin B (5,7-dihydroxy-6,2,3,4-tetramethoxy-) Iridaceae 46 Irisjaponin A (5,7-dihydroxy-6,2,3,4,5-pentamethoxy-) Iridaceae 46

5,7,4-Trihydroxy-6,8-dimethoxy- Polygalaceae 41

5,7-Dihydroxy-6,8,4-trimethoxy- Polygalaceae 41

7-Methyltectorigenin (5,4-dihydroxy-6,7-dimethoxy-) Euporbiaceae 62

Clusiaceae 39

7-Methylirisolidone (5-hydroxy-6,7,4-trimethoxy-) Iridaceae 58

6-Methoxyorobol-7-methylether (5,3,4-trihydroxy-6,7-dimethoxy-) Asteraceae 15

Belamcanidin (5-hydroxy-6,7,3,4-tetramethoxy-) Iridaceae 63

Asteraceae 64

Irilin A (5,2-dihydroxy-6,7-dimethoxy-) Chenopodiaceae 60

Iridaceae 56

5,3-Dihydroxy-6,7,2-trimethoxy- Chenopodiaceae 49

5,3-Dihydroxy-6,7,8,2-tetramethoxy- Chenopodiaceae 50

5,7,2,4-Tetrahydroxy-6,3-di(-3,3-dimethylallyl)5 Asteraceae 65

Laburnetin (5,7,4-trihydroxy-6-(2-hydroxy-3-methyl-3-butenyl-))6 Moraceae 66

Wighteone (erythrinine B) (5,7,4-trihydroxy-6-prenyl-) Moraceae 36

5,7,3,4-Tetrahydroxy-6-prenyl- Moraceae 36

Asteraceae 15

6,8 Diprenylorobol (5,7,3,4-tetrahydroxy-6,8-diprenyl-) Moraceae 67

Lupisoflavone (5,7,4-trihydroxy-3-methoxy-6-prenyl-) Asteraceae 34

6 Prenylisocaviunin (5,7-dihydroxy-8,2,4,5-tetramethoxy-6-prenyl-) Scrophulariaceae 15

Osajin7 Moraceae 66

Pomiferin^c8 Moraceae 15

9 Moraceae 66

Erythrinin C10 Moraceae 68

Warangalone (scandenone or scandenolone)11 Moraceae 68

Auriculasin12 Moraceae 66

Irilone (5,4-dihydroxy-6,7-methylenedioxy-) Iridaceae 57

Ochnaceae 45

4-O-Methylirilone (5-hydroxy-4-methoxy-6,7-methylenedioxy-) Iridaceae 43

Ochnaceae 69

Soforanarin A (5,3-dihydroxy-4-methoxy-6,7-methylenedioxy-) Iridaceae 70 Dichotomitin (5,3-dihydroxy-4,5-dimethoxy-6,7-methylenedioxy-) Iridaceae 55

Ochnaceae 71

Iriflogenin (3-methoxyirilone) (5,4-dihydroxy-3-methoxy-6,7-methylenedioxy-) Iridaceae 15

Ochnaceae 69

Squarrosin (5-hydroxy-3,4-dimethoxy-6,7-methylenedioxy-) Ochnaceae 15

Iridaceae 70

Noririsflorentin (5-hydroxy-3,4,5-trimethoxy-6,7-methylenedioxy-) Iridaceae 42

Irisone B (5,2-dihydroxy-6,7-methylenedioxy-) Iridaceae 61

Chenopodiaceae 15 Amaranthac´ees 72

Irisone A (5-hydroxy-2-methoxy-6,7-methylenedioxy-) Iridaceae 61

5,3-Dihydroxy-2-methoxy-6,7-methylenedioxy- Chenopodiaceae 50

5,8,3-Trihydroxy-2-methoxy-6,7-methylenedioxy- Chenopodiaceae 49

Garhwalin13 Celastraceae 15

Isoprunetin (5 methylgenisteine) (7,4-dihydroxy-5-methoxy-) Moraceae 36

Rosaceae 73

Table 2 (Cont.)

Isoflavones Families Ref.

Gerontoisoflavone A (7,4-dihydroxy-5,3-dimethoxy-) Moraceae 36

7,5-Dihydroxy-5,4-dimethoxy-3-prenyl- Asteraceae 74

Genistein trimethyl ether (5,7,4-trimethoxy-) Ochnaceae 75

8,3-Dihydroxy-5,7,2-trimethoxy- Chenopodiaceae 49

5,7,8-Trimethoxy-3,4-methylenedioxy- Ochnaceae 71

6,7,3-Trihydroxy-5,2-dimethoxy- Chenopodiaceae 49

Muningin (6,4-dihydroxy-5,7-dimethoxy-) Iridaceae 58

6,3-Dihydroxy-5,7,2-trimethoxy- Chenopodiaceae 49

Soforanarin B (6,3,4-trihydroxy-5,7,5-trimethoxy-) Iridaceae 70

7-Hydroxy-5,6,6-trimethoxy-3,4-methylenedioxy Cucurbitaceae 76

7,3-Dihydroxy-5,6,2-trimethoxy- Chenopodiaceae 49

3-Hydroxy-5,6,7,2-tetramethoxy- Chenopodiaceae 49

Irisolone (nigricin) (4hydroxy-5-methoxy-6,7-methylenedioxy-) Iridaceae 57

Ochnaceae 71

Methylirisolone (5,4-dimethoxy-6,7-methylenedioxy-) Iridaceae 15

Ochnaceae 77

Isoiriskashmirianin (3-hydroxy-5,5-dimethoxy-6,7-methylenedioxy-) Iridaceae 78

Ochnaceae 71

Iriskumaonin (3-hydroxy-5,4-dimethoxy-6,7-methylenedioxy-) Iridaceae 15

Ochnaceae 71

Iriskashmirianin (nigricanin^d) (4-hydroxy-5,3-dimethoxy-6,7-methylenedioxy-) Iridaceae 78

Ochnaceae 71

Iriskumaonin methyl ether (5,3,4-trimethoxy-6,7-methylenedioxy-) Iridaceae 15

Ochnaceae 79

Irisflorentin (5,3,4,5-tetramethoxy-6,7-methylenedioxy-) Iridaceae 54 Betavulgarin (2-hydroxy-5-methoxy-6,7-methylenedioxy-) Chenopodiaceae 80 Caryophyllaceae 15 Amaranthaceae 81

Tlatlancuayin (5,2-dimethoxy-6,7-methylenedioxy-) Amaranthaceae 81

Iridaceae 56

Hemerocallone (5,2,5-trimethoxy-6,7-methylenedioxy-) Liliaceae 15

Torvanol14 Solanaceae 82

Table 2

B Isoflavanone

Isoflavanones Families Ref.

Padmakastein (5,4-dihydroxy-7-methoxy-) Rosaceae 6

2,3-Dihydroirigenin (5,7,3-trihydroxy-6,4,5-trimethoxy-) Iridaceae 51

C Rotenoid

Rotenoids Families Ref.

Rotenone15 Scrophulariaceae 51

Sumatrol16 Euphorbiaceae 62

Myriconol17 Myricaceae 15

D Dehydrorotenoid

Dehydrorotenoids Families Ref.

Mirabijalone C (5,2,3-trihydroxy-2-hydroxymethyl-7-methoxy-6-methyl isoflavone)18^e Nyctaginaceae 83

19 Euphorbiaceae 84

Stemonone (6-oxo-11-hydroxy-2,3,9-trimethoxy-) Stemonaceae 15

Stemonal (6,11-dihydroxy-2,3,9-trimethoxy-) Stemonaceae 15

Stemonacetal (11-hydroxy-2,3,9-trimethoxy-6-OCH2CH3) Stemonaceae 15

Coccineone B (6,9,11-trihydroxy-) Nyctaginaceae 85

Repenone (9,10,11-trihydroxy-6-OCOCH3) Nyctaginaceae 86

Repenol (3,9,10,11-tetrahydroxy-6-OCOCH3) Nyctaginaceae 86

Boeravinone A (9,11-dihydroxy-6-methoxy-10-methyl-) Nyctaginaceae 15

Boeravinone B (6,9,11-trihydroxy-10-methyl-) Nyctaginaceae 15

Boeravinone D (3,9,11-trihydroxy-10-methyl-) Nyctaginaceae 87

Boeravinone E (3,6,9,11-tetrahydroxy-10-methyl-) Nyctaginaceae 87

Boeravinone F (3,9,11-trihydroxy-6-oxo-10-methyl-) Nyctaginaceae 83

Diffusarotenoid (4,9-dihydroxy-10-methyl-6-pentanoate-) Nyctagynaceae 88

Mirabijalone B (4,6,9,11-tetrahydroxy-8,10-dimethyl-) Nyctaginaceae 83

Mirabijalone D (3,6,11-trihydroxy-9-methoxy-10-methyl-) Nyctaginaceae 83

9-O-Methyl-4-hydroxyboeravinone B (4,6,11-trihydroxy-9-methoxy-10-methyl-) Nyctaginaceae 83

Table 2 (Cont.)

E 12a-Hydroxyrotenoid

12a-Hydroxyrotenoids Families Ref.

Coccineone C^f(4,11-dihydroxy-9-methoxy-) Nyctaginaceae 89

Coccineone D^f(4,9,11-trihydroxy-) Nyctaginaceae 89

Coccineone E (11-hydroxy-9,10-dimethoxy-) Nyctaginaceae 90

Iridaceae 91

Boeravinone C (4,11-dihydroxy-9-methoxy-10-methyl-) Nyctaginaceae 83

Irispurinol (9,11-dihydroxy-10-methoxy-) Iridaceae 92

Mirabijalone A (4,11-dihydroxy-9-methoxy-8,10-dimethyl-) Nyctaginaceae 83

F Pterocarpan

Pterocarpans Families Ref.

Medicarpin (-3-hydroxy-9-methoxy-) Myricaceae 15

Myristicaceae 3

Maackiain (inermin) (-3-hydroxy-8,9-methylenedioxy-) Myristicaceae 3

Glyceollin II20 Zingiberaceae 11

Glyceollin III21 Zingiberaceae 11

G Coumestan

Coumestans Families Ref.

Coumestrol (3,9-dihydroxy-) Chenopodiaceae 15

Demethylwedelolactone (1,3,8,9-tetrahydroxy-) Asteraceae 15

Wedelolactone (1,8,9-trihydroxy-3-methoxy-) Asteraceae 15

Mutisifurocoumarin (8,9-dihydroxy-1-methyl-) Asteraceae 93

Norwedelic acid22 Asteraceae 15

Table 2

H Isoflavanol

Isoflavanol Families Ref.

Lapathinol (5-hydroxy-8-methoxy-6,7-methylenedioxy-) or (8-hydroxy-5-methoxy-6,7-methylenedioxy-) Polygonaceae 15

I Coumaronochromone

Coumaronochromones Families Ref.

Coccineone A (ayamenin) (-5,7,3-trihydroxy-) Nyctaginaceae 85

Wrightiadione23 Apocynaceae 94

aRetusin, also used for naming a methyl-3-flavonol isolated fromAriocarpus(Cactaceae).^bNervosin, also used for naming a diterpene.^cPomiferin, also used for naming a diterpene.^dNigricanin is also used for naming a phenol.^eThis isoflavone is placed here because this structure is a precursor of the dehydrorotenoids.^fTwo compounds isolated in 1986 and named in 1998 by A. S. Dos Santoset al.⁹⁰

Table 3 Summary of the occurrence of isoflavonoids in non-leguminous families In monocots:

Families Structure number Families Structure number

Eriocaulaceae 1 Iridaceae 52

Liliaceae s. l. 4 Poaceae 1^a

Stemonaceae 3 Zingiberaceae 2

In dicots:

Families Structure number Families Structure number

Amaranthaceae 3 Apocynaceae 1

Asteraceae 21 Bombacaceae 1

Caryophyllaceae 1 Celastraceae 1

Chenopodiaceae 19 Clusiaceae 3

Cucurbitaceae 1 Euphorbiaceae 3

Malvaceae 2 Menispermaceae 1^b

Moraceae 18 Myricaceae 2

Myristicaceae 13 Nyctaginaceae 19

Ochnaceae 17 Papaveraceae 2

Polygalaceae 3 Polygonaceae 1

Rosaceae 5 Rutaceae 7

Scrophulariaceae 6 Solanaceae 1

Vitaceae 1

a+3 structures mentioned in bourbon and in beer?^bAs 8-C-glucoside.¹⁸

gas chromatograhy/mass spectrometry (GC/MS) analyses per- formed in 1987 have evidenced the presence of isoflavonoids in bourbon

and in beer.

This finding was confirmed in 2004 in two analyses of beer samples using micellar electrokinetic capil- lary chromatography (MEKC) with diode-array detection.

Although both beer and bourbon are prepared from barley, the isoflavonoids they contain must originate from another source.

3.2. Isoflavonoids in dicots

Among the dicots, five non-leguminous families are particularly outstanding because of their relative abundance in isoflavonoids:

the Asteraceae (21 molecules), the Chenopodiaceae and the Nyc-

taginaceae (19 molecules each), the Moraceae (18 molecules),

the Ochnaceae (17 molecules) (Table 3). However, this presence

of isoflavonoids has been reported in only few species among these five families.

The estrogenic activity of black cohosh extracts (Cimicifuga racemosa, syn. Actaea racemosa, Ranunculaceae) regularly re- ported in the literature is generally credited to the presence of formononetin.

Yet, HPLC analyses conducted in 2002 by Kennelly et al.

and by Li et al.

on rhizomes from various populations of Cimicifuga racemosa and on commercial extracts of the plant have failed to provide evidence of the presence of isoflavonoids in these samples. A more recent study

has suggested that the methods used in the two studies previously described (HPLC with in-line photodiode array and evaporative light scattering detection) for the determination of formononetin were not sen- sitive enough compared to the use of the fluorescent properties of formononetin. Complementary experiments confirming the possible presence of isoflavonoid in this species are thus required.

Hop (Humulus lupulus L., Cannabaceae), a plant with known estrogenic activity, is sometimes reported to contain isoflavonoids. This estrogenic activity of hop (and of beer) has, in fact, recently been assigned to prenylated derivatives of naringenin (a flavanone).

Isoflavonoid compounds present in non-leguminous families are generally the same as those of leguminous plants, apart from some rare types that have only been reported in non-leguminous families.

If we take into account the phylogenetic tree of the An- giosperm Phylogeny Group (APG II 2003),

we see that isoflavonoids of non-leguminous families are present in system- atic groups with no close phylogenetic relations. In monocots, the compounds are specially abundant in the Asparagales (particularly in the family Iridaceae, 52 structures). In dicots, they are abundant in the Caryophyllales (19 molecules in the Nyctaginaceae, and in the Chenopodiaceae), in the Malpighiales (17 molecules in the Ochnaceae), in the Rosales (18 molecules in the Moraceae) and in the Asterales (21 molecules in the Asteraceae). Of note, there are more than 1000 different molecules present in the Fabales, whereas plants of the family Nyctaginaceae seem to have specialised in the synthesis of dehydrorotenoids (10 in 16 structures) and hydroxyrotenoids (5 in 16 structures).

The Polygonaceae are known to possess only one isoflavonoid but of a very rare type (lapathinol, see structure in 3.5).

Isoflavonoids have also been mentioned in various commercial teas and coffees

but no study has documented their occurrence in the plants themselves.

Also of interest is the presence of isoflavonoids in the Gymnosperms: Cupressaceae (Juniperus, 8 structures), Podocarpaceae (5 structures) and Araucariaceae (2 structures) as well as in the Bryophytes (3 structures reported).

3.3. Isoflavones

A common trait between leguminous and non-leguminous fam- ilies is the prominent presence of isoflavones. These constitute

more than 120 different molecules identified. Non-leguminous isoflavones are frequently methylated or prenylated (8 of the 18 molecules described in the Moraceae are prenylated

). The presence of a methylenedioxy group is also often reported.

Rotenoids are generally subdivided into three major types, depending on their oxidation level: rotenoids sensu stricto, 12a- hydroxyrotenoids and dehydrorotenoids. In non-leguminous families, 27 different rotenoids sensu lato have been identified, mostly in the Nyctaginaceae (18 types).

3.5. Miscellaneous structures

Other rare isoflavonoid structures may be encountered in non- leguminous families: pterocarpans, coumestans, coumarono- chromones, isoflavanones and isoflavanols.

Isoflavonoids with a methylenedioxy group in the A ring are rare,

and unevenly distributed: 19 of the 52 structures identified in the family Iridaceae and 12 of the 17 structures identified in the Ochnaceae possess such a methylenedioxy group.

Another striking feature is the chemical kinship between the two families (although one belongs to the monocots and the other one to the dicots): they have 11 identical structures, all with a methylenedioxy group:

Irilone: R

R

OH; R

R

H

4

-Methylirilone: R

OH; R

OMe; R

R

H Iriflogenin: R

R

OH; R

OMe; R

H Squarrosin: R

OH; R

R

OMe; R

H Dichotomitin: R

R

OH; R

R

OMe Irisolone: R

OMe; R

OH; R

R

H 4

-Methylirisolone: R

R

OMe; R

R

H Isoiriskashmirianin: R

R

OMe; R

OH; R

H Iriskumaonin: R

R

OMe; R

OH; R

H

Iriskashmirianin (Nigricanin): R

R

OMe; R

OH;

R

H

Iriskumaonin methyl ether: R

R

R

OMe; R

H Concerning isoflavonols, only 2 natural structures have been described to date: the first one was found in the Legumi- nosae (ambanol),

and the second one in the Polygonaceae (lapathinol).

Recent studies have made it possible to isolate new

isoflavonoid structures from manipulated plant cell cultures. For

instance three new compounds have been described in manipu-

and especially one isoflavone (2 -O-methylabronisoflavone: 5,7- dihydroxy-2

-methoxy-6-methylisoflavone).

No isoflavone had been reported before in this family.

4 Isoflavonoids and plant physiologists

Isoflavonoids were first identified as part of the broader group of anti-microbial phytoalexin compounds which are synthesised by plants in response to attacks by pathogens. As with other phytoalexins, isoflavonoids may be either synthesised de novo after the plant tissue has been exposed to microbial infection or is pre-existent in the plant in the absence of any microbial or fungal infection. However, for some authors, the term “phytoalexins” is too restrictive because this single term corresponds to molecules with two different functional levels. Vanetten et al.

define

“phytoalexins” sensu stricto for compounds (among them some isoflavonoids) synthesised in direct response to microbial attack or other stressors (such as abiotic inducers including heavy metals, UV light, herbicides) and the name “phytoanticipins”

for compounds (among them some isoflavonoids) present in vivo before any microbial or other attack. An isoflavonoid would thus serve as both a phytoalexin and a phytoanticipin within the same plant by these definitions.

To complicate the traditional definition of isoflavonoids, nu- merous findings have pointed out that, beside their phytoalexin function, isoflavonoids are involved in important biological plant processes.

They seem to be directly involved in mutu- alistic symbioses between leguminous plants and soil micro- organisms: the root exudation of isoflavonoids might act as a chemoattractant and be associated with Rhizobium invasion and nodule formation through promoting microbial growth and inducing nodulation genes.

The role of isoflavonoids present in non-leguminous plants which do not establish such mutualistic symbioses remains to be defined. Are they simply phytoalexins, sensu stricto, as demonstrated in Iris pseudacorus, a plant which produces fungitoxic metabolites when treated with cupric chloride?

The role of rotenoids in plants seems easier to understand.

These natural products are widely known for their insecticidal activity and some of them are actually used as insecticides (the most famous being rotenone). Some isoflavonoids have shown some activity as insect-feeding deterrents. They have also been used as fish poisons.

A study conducted on the soils of areas cultivated with the perennial weed Pluchea lanceolata (Asteraceae) has shown the occurrence of a glucoside of formononetin, a compound which has been shown to inhibit significantly root and shoot growth of mustard for instance.

The presence of formononetin in the whole plant has not been assessed.

5 Isoflavonoids and human pathologists

In 1954, 53 plants were known to possess an estrogenic activity, a number expanded to over 300 in 1975.

Isoflavones and coumestans (both from the group of isoflavonoids) have been identified as the most common estrogenic compounds in these plants and named “phytoestrogens”. Phytoestrogens (or sometimes “phyto-oestrogens”) are naturally occurring non- steroidal compounds of plants which promote estrogenic activity in mammals. The designation “phytoestrogens” was further extended to other plant compounds including, for instance, lignans, anthraquinones, chalcones, prenylflavonoids.

Among these compounds of plant origin, isoflavonoids are currently considered of utmost value in human therapeutics.

Despite inconsistent data, numerous studies have shown an association between isoflavone-rich dietary consumption and reduced cancer risk (particularly as regards breast and prostate cancers).

For instance, Asian populations who have low rates of breast and prostate cancer consume 20–80 mg per day of genistein, almost entirely derived from soybean, whereas the dietary intake of genistein in the United States has been estimated at 1–3 mg per day.

It has been shown that some isoflavonoids can act as inhibitors of the multidrug resistance transporter MRP1 through influenc- ing the biophysical properties of membranes.

The preventive role of isoflavonoids in cancer, either breast, prostate or colon cancers, cardiovascular diseases, osteoporosis, and menopausal symptoms has been largely documented.

Some authors go as far as considering them “a gold mine for metabolic engineering”.

At the beginning of this year, a well-documented review published by the French Health Products Safety Agency (AFSSAPS)

reported on the safety and potential benefits of phytoestrogens (including isoflavonoids) in human food.

Although the AFSSAPS examined a considerable amount of bibliographical information, no conclusive data could be obtained. Little unquestionably reliable information is available at present and further clinical studies are needed to confirm the benefits that are generally expected from these molecules.

On the other hand, a recent study

assessing the increased incidence of prostate cancers in several Asian countries over the period 1978–1997, demonstrated that this increase was higher in some of these countries (principally in urban populations) than in western countries, with no less than a 118% increase in Singapore, for instance. This phenomenon is suspected to be due to changes towards a western lifestyle, principally western food that would be a significant contributing factor.

Beside the Leguminosae, many non-leguminous plants con- taining isoflavonoids are used in traditional medicines around the world. For example, Iris potanini has long been used in Mongolian folk medicine for the treatment of various diseases such as bacterial infections, inflammation and even cancer.

Rhizome and root decoctions of Iris germanica, a well-known ornamental plant particularly rich in isoflavonoids (a dozen molecules identified), are used in Pakistan folk medicine under the name “Irsa”.

Cudrania cochinchinensis (Moraceae) is used in China for treating hepatitis.

Boerhaavia coccinea (Nyctagi- naceae) is used in north-east Brazil against venereal disease and for removing renal, liver and vesical calculus,

whereas another Boheraavia species, Boheraavia repens, is used in Bangladesh for hydrops.

6 Conclusion

Following the advances of isolation and identification tech- niques, isoflavonoid structures have regularly been described in new non-leguminous families. Whereas the Leguminosae remain the main source of isoflavonoids, some other flowering families also show a noticeable diversity in their isoflavonoid content:

the Asteraceae, the Chenopodiaceae, the Nyctagynaceae, the

Moraceae and the Ochnaceae for the dicots and especially the

Iridaceae for the monocots.

7 Acknowledgements

Special thanks to Marie-Dominique Reynaud for her expert assistance in the English translation of this review.

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