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Planta Med 2021; 87(14): 1128-1151
DOI: 10.1055/a-1527-4238
Biological and Pharmacological Activity
Reviews

Review of Studies on Phlomis and Eremostachys Species (Lamiaceae) with Emphasis on Iridoids, Phenylethanoid Glycosides, and Essential Oils[ # ]

İhsan Çalış 
Near East University, Faculty of Pharmacy, Department of Pharmacognosy, Lefkoşa (Nicosia), TRNC
,
K. Hüsnü Can Başer
Near East University, Faculty of Pharmacy, Department of Pharmacognosy, Lefkoşa (Nicosia), TRNC
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Abstract

As the sixth-largest Angiosperm family, Lamiaceae contains more than 245 genera and 7886 species that are distributed worldwide. It is also the third-largest family based on the number of taxa in Turkey where it is represented by 46 genera and 782 taxa with a high endemism ratio (44%). Besides, Lamiaceae are rich in plants with economic and medicinal value containing volatile and nonvolatile compounds. Many aromatic plants of Lamiaceae such as Salvia, Sideritis, Stachys, Phlomis, and Teucrium species are used in traditional herbal medicine throughout Turkey as well as in other Mediterranean countries. Salvia (Sage tea “Adaçayı”), Sideritis (Mountain tea “Dağçayı”), Stachys (Hairy Tea “Tüylü Çay”), and Phlomis (Turkish sage “Çalba or Şalba”) are the largest genera that are used as herbal teas. This review focuses on the volatile and nonvolatile compounds of Lamiaceae from the genera Phlomis and Eremostachys of the subfamily Lamioideae with emphasis on iridoids, phenylethanoid glycosides, and essential oils.


 

Key words

Phlomis - Eremostachys - Lamiaceae - Phlomideae - secondary metabolites - iridoids - phenylethanoids - essential oils

Abbreviations

5-HETE: 5-Hydroxyeicosatetraenoic acid
ACP: acyl carrier protein
cAMP: cyclic adenosine monophosphate
dRLh-88: rat hepatoma
FMPL: N-formyl-methionyl-leucyl-phenylalanine
GR: glutathione reductase
H460: human large cell carcinoma of the lung
HeLa: human epithelial carcinoma
HL-60: cells human promyelocytic leukemia cell line
L-DOPA: L-3,4-dihydroxyphenylalanine
MCF: 7 multidrug-resistant human breast cancer subline
NCI: (US) National Cancer Institute
P-388-D1: mouse lymphoid neoplasm
Ph. : Phlomis
PhEts: phenylethanoid glycosides
PMNs: polymorphonuclear neutrophils
ROS: reactive oxygen species
S-180: sarcoma cells
SF-268: central nervous system cancer cell lines
 

Introduction

As the sixth-largest Angiosperm family, Lamiaceae contains more than 245 genera and 7886 species distributed worldwide. It is also the third-largest family based on the number of taxa in Turkey. In Turkey, the family Lamiaceae comprises 46 genera and 782 taxa (603 species, 179 subspecies and varieties), of which 346 taxa (271 species, 75 subspecies and varieties) (ca. 44%) are endemic. There are 28 hybrid species, 24 of which are endemic. Stachys L. (118 taxa), Salvia L. (107 taxa), Sideritis L. (54 taxa), Phlomis L. (53 taxa), and Teucrium L. (49 taxa) are the largest 5 genera. Approximately 72% of the species are found in the largest 10 genera, while 15 genera are monotypic [1]. Lamiaceae are rich in plants with high economic and medicinal value due to essential oils and other active constituents. In the early 1990s, research focused mainly on the constituents of the essential oils including mono- and sesquiterpenes. With the advancement of spectroscopic techniques, a great variety of nonvolatile isoprenoids with di- and triterpenoid structures (free or glycosylated derivatives) and ecdysteroids were reported as constituents responsible for a wide range of biological activities. Iridoids and monoterpene lactones are nonvolatile glycosidic isoprenoids. The occurrence of iridoids in certain subfamilies has been of major taxonomic interest. Additionally, phenolic compounds, flavonoids (flavones, flavonols, flavanones, dihydroflavonols, chalcones), anthocyanins (cyanidin, delphinidin, malvidin, pelargonidin glycosides, and their acylated derivatives), and caffeoyl ester glycosides were attractive targets for many research groups because of their taxonomic significance and biological and pharmacological activities [2]. The high biological diversity in terms of the number of taxa, together with the large proportion of plants used traditionally, triggered phytochemical and pharmacognostical studies in drug discovery.


 

Initial Studies

The research interest in iridoids, as well as other chemical constituents of Lamiaceae plants, goes back to the year 1982 for one of the authors of this work (IC). Galeopsis pubescens was one of the species studied for iridoids by E. Rogenmoser at the Swiss Federal Institute of Technology (ETHZ) in the group of Prof. Sticher [3]. Iridoids such as daunoside, harpagide, acetylharpagide, and galiridoside had been reported from G. pubescens. A study performed on yet uncharacterized fractions of G. pubescens resulted in the isolation of 2 phenylethanoid glycosides (PhEts), martynoside and isomartynoside [4]. These 2 metabolites showed close similarity to the caffeic acid derivatives reported in higher plants by Harborne [5]. It was suggested that caffeic esters might be of considerable value in chemotaxonomic studies. The distribution of rosmarinic acid and orobanchin has been studied concerning their occurrence in some Tubiflorae. Orobanchin was described as a derivative of caffeic acid, 3,4-dihydroxyphenylethanol, glucose, and rhamnose, and had only been reported as a constituent of Orobanche minor (Orobanchaceae). In fact, the first studies on caffeoyl sugar esters go back to the 1950s. Echinacoside, a triglycosidic phenylethanoid isolated from Echinacea angustifolia (Asteraceae) in 1950 was structurally determined in 1983, while verbascoside first isolated in 1963 was structurally determined in 1968 [6].

The coexistence of iridoids and phenylethanoid glycosides in some plants of Tubiflorae led us to focus our research on randomly selected plants of Lamiaceae and Scrophulariaceae. Both compound groups have been suggested as being of considerable value in chemotaxonomic studies. Thus, studies have been initiated on plants such as Scrophularia scopolii (Scrophulariaceae) [7], [8], [9] , Betonica officinalis (Lamiaceae) [10], Stachys lavandulifolia (Lamiaceae) [11], Phlomis linearis (Lamiaceae) [12], [13], [14], P. bourgaei [15], [16], Pedicularis species (Scrophulariaceae) [17], Lagotis stolonifera (Scrophulariaceae) [18] Phlomis armeniaca, and Scutellaria salviiifolia [19], yielding iridoid and phenylethanoid glycosides. In contrast to the presence of a majority of aucubine-type iridoids in Scrophulariaceae, loganin-type iridoids were mostly detected and identified in Lamiaceae plants.

The Lamiaceae (Labiatae) Congress of 1991 at Royal Botanic Gardens, Kew, London has been a milestone for future studies. Ajugoideae, Chloanthoideae, Lamioideae, Nepetoideae, Pogostomonoideae, Scutellarioidea, Teucrioideae, and Viticoideae were declared as 8 subfamilies of Lamiaceae [20]. At this congress, the family Lamiaceae was discussed in the light of biogeography and phylogenetic relationships, systematic studies of selected characters and groups, biology, chromosome numbers and breeding system, chemical constituents, plant-insect interactions, and the economics of genera.

During the last 2 decades, the aspects and classification of various members of Lamiaceae have been investigated both chemotaxonomically and systematically. In 1999, 96 Lamiaceae taxa have been investigated for the presence of rosmarinic and caffeic acids [21]. Rosmarinic acid was found in all species of the subfamily Nepetoideae but was absent from those in the subfamily Lamioideae. However, Lamioideae species were rich in caffeic acid. In 2000, Pedersen studied 110 genera of Lamiaceae (Labiatae) for 2 chemical characters giving support to the subfamily division of the Lamiaceae [22]. Within the 2 large subfamilies, the genera of Lamioideae, rich in iridoids, were reported to contain phenylethanoid glycosides and to possess tricolpate pollen grains, while the genera of Nepetoidea that contain a higher amount of essential oils were reported to contain rosmarinic acid and were found to possess hexacolpate pollen grains. In 2017, 2 new subfamilies have been included in the Lamiaceae: Callicarpoideae (170 Callicarpa species) and Tectonoideae (3 Tectona species) [23]. According to recent studies, 12 subfamilies are recognized in Lamiaceae: Ajugoideae, Lamioideae, Nepetoideae, Prostantheroideae, Scutellarioideae, Symphorematoideae, Viticoideae. Cymarioideae, Peronematoideae, Premnoideae, Callicarpoideae, and Tectonoideae [1], [24], [25]. Thus, systematic studies strongly supported a rich diversity of Lamiaceae in many aspects including their chemical constituents. In the Flora of Turkey, Ajugoideae, Lamioideae, Nepetoideae, Scutellarioideae, and Viticoideae are the subfamilies of Lamiaceae that are represented by 48 genera and 782 taxa with a high degree of endemism (ca. 44%). Stachys (118 taxa), Salvia (107 taxa), Sideritis (54 taxa), Phlomis (53 taxa), and Teucrium (49 taxa) are the largest 5 genera that show high endemism ([Table 1]) [1], [26]. The members of this family are known as culinary, flavoring herbs or herbal teas, many of them native to Turkey as well as the Mediterranean area and many subtropical semi-arid zones worldwide.

Table 1 The subfamilies of Lamiaceae and the genera recorded in the Flora of Turkey.*

Subfamilies

Tribes

Genera

* Table has been prepared according to a tribal classification based on a plastome phylogenomic [26].

Lamioideae

Lamieae

Lamium

Marrubieae

Ballota, Marrubium, Pseudodictamnus Molucella

Leonureae

Leonurus, Chaiturus

Phlomideae

Phlomis, Eremostachys, Phlomoides

Stachydeae

Stachys, Sideritis, Prasium, Melittis

Galeopseae

Galeopsis

Scutellarioideae

Scutellaria

Ajugoideae

Ajugeae

Ajuga

Clerodendreae

Clerodendrum

Teucrieae

Teucrium

Viticoideae

Vitex

Nepetoidea

Mentheae

Mentha, Clinopodium, Melissa, Nepeta, Lophantus, Origanum, Thymus, Salvia, Hyssopus, Prunella, Lycopus, Dracocephalum, Glechoma, Thymbra, Satureja, Pentapleura, Ziziphora, Cyclotrichium, Micromeria, Hymenocrater, Lallemantia

Ocimeae

Ocimum, Hyptis, Lavandula

Elsholtzieae

Elsholtzia, Perilla

Our phytochemical and chemotaxonomic studies focused on the genus level of the members of tribes in Lamioideae (Lamieae: Lamium; Marrubieae: Marrubium, Molucella; Leonureae: Leonurus; Phlomideae: Phlomis, Eremostachys; Stachydeae: Stachys, Sideritis, Prasium; Galeopseae: Galeopsis), Scutellarioideae (Scutellaria), Ajugoideae (Ajugeae: Ajuga; Clerodenreae: Clerodendrum; Teucrieae: Teucrium) for iridoid and PhEts contents. The present review gives a detailed overview of the results from the studies performed on the species of genus Phlomis L. and Eremostachys Bunge from the Phlomideae tribe of the subfamily Lamioideae.


 

Phlomideae

Phlomis species

Unlike other genera, the genus Phlomis has been studied in detail for all of its species. In the frame of a project focused on the chemotaxonomy of the genus Phlomis, species recorded in the flora of Turkey were studied for their secondary metabolites with emphasis on iridoids and PhEts [27].

Phlomis species are perennial herbs or small shrubs, pilose or tomentose. Morphological characters are verticillasters few- to many-flowered, crowded or distant in the axil of floral leaves, bracteoles absent, few or numerous, subulate to ovate. Thirty-three Phlomis species recorded in the flora of Turkey have been divided into 3 groups. The species in Group A have a pink or purple corolla. Groups B and C have a yellow corolla, sometimes with brownish upper lip, the former being shrubs or herbs with numerous bracteoles, the latter being herbs having few or no bracteoles ([Fig. 1]) [25].

Zoom
Fig. 1 Classification of Phlomis species in the Flora of Turkey and the East Aegean Islands.

 

Iridoids

Throughout these studies, 21 iridoid glucosides (1–21) have been isolated ([Fig. 2]) [12], [13], [14], [19], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51]. Phlorogidosides A, B, and C (12, 19, and 20) have been reported from Ph. rigida [52]. Phlorogidoside C was also reported from Ph. tuberosa and named as 5-deoxysesamoside (12) in the same year [53]. Caryoptoside (21) was recently isolated from Ph. brevibracteata which is one of the 3 species growing in Cyprus [54]. This was the first record for caryoptoside in Phlomis species. Auroside (1), lamiide (3), and ipolamiide (4) were also isolated from Ph. floccosa collected from Libya [55].

Zoom
Fig. 2 Iridoids isolated from Phlomis species (1 – 21).

All of the iridoids isolated from Phlomis species have a monoglucosidic structure. Auroside (1), lamiide (3), and ipolamiide (4) have been encountered in most Phlomis species ([Table 2]). Brunneaogaleatoside (16) and lamiidoside (17) are p-coumaroyl ester derivatives. Among the iridoids isolated, 7-epi-lamalbide (6), ipolamiidic acid (13), lamiidic acid (14), 8-O-acetyl-shanzhizide (15), brunneogaleatoside (16), and chlorotuberoside (18) were described for the first time.

Table 2 Distribution of iridoid glucosides in Phlomis species (1 – 21) (see [Fig. 2]).

Iridoids 1 – 21

Phlomis species

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

Ref.

* Iridoids not detected; ** This species was collected from Cyprus; *** Collected from Libya; x = present; (1) auroside, (2) 8-epi-loganin, (3) lamiide, (4) ipolamiide, (5) lamalbide, (6) 7-epi-lamalbide, (7) 5-deoxypulchelloside I, (8) shanzhizide methyl ester, (9) phlomiol, (10) 7-epi-phlomiol, (11) sesamoside, (12) 5-deoxysesamoside, (13) ipolamiidic acid, (14) lamiidic acid, (15) 8-O-acetyl-shanzhizide, (16) brunneogaleatoside, (17) lamiidoside, (18) phlorigidoside A (19), phlorigidoside B, (20) chlorotuberoside, (21) caryoptoside

Ph. tuberosa

x

x

x

x

x

x

x

x

x

[29], [49]

Ph. samia

x

[35]

Ph. pungens

x

[52]

Ph. integrifolia

x

[38]

Ph. rigida

x

x

x

[54]

Ph. russeliana

x

[27]

Ph. fruticosa

x

x

[31]

Ph. lunariifolia

x

x

x

[42]

Ph. grandiflora

x

x

[31]

Ph. viscosa

x

x

x

[45]

Ph. bourgaei

x

[16]

Ph. leucophracta

x

x

x

[27]

Ph. longifolia

x

x

x

x

[28]

Ph. amanica

x

[51]

Ph. lycia

x

x

[33]

Ph. monocephala

x

x

[35]

Ph. chimerae

x

[32]

Ph. oppositiflora

x

[47]

Ph. bruguieri

x

x

x

[27]

Ph. armeniaca

x

[19]

Ph. physocalyx

x

[35]

Ph. angustissima

x

x

[48]

Ph. capitate

x

x

x

[41]

Ph. kotschyana

x

x

[44]

Ph. sieheana

x

[30]

Ph. sintenisii

x

x

x

[34]

Ph. lanceolata

x

[27]

Ph. linearis

x

x

x

[14]

Ph. brunneogaleata

x

x

[43]

Ph. nissolii

x

x

[41]

Ph. syriaca

x

[50]

Ph. kurdica

x

[27]

Ph. carica*

–

Ph. brevibracreata **

x

[55]

Ph. floccosa***

x

x

x

[56]

Structurally, iridoids isolated from Phlomis species can be classified into 4 groups, A, B, C, and D. Compounds 3 – 6, 8 – 10, 17 – 21 (A1), and 13 – 15 (A2) are mussaenoside derivatives. In subgroup A1, the COOH group located at C-4 is found as methyl ester. Sesamoside (11) and 5-deoxysesamoside (phlorogidoside C) (12) are oxygenated at C-8 as in groups A1 and A2 but form an epoxy functionality with C-7 building Group B. Compound 1, 2, and 7 are 8-epi-loganin derivatives with a secondary methyl group at C-8 (Group C). Group D is represented by only 1 compound, brunneogaleatoside (16), in which the double bond in the pyrane ring is located between C-4 and C-5, unlike in most iridoids. Further oxygenation patterns are observed at the C-5, C-6, and C-7 positions in groups A, B, and C ([Fig. 3]). Only 1 iridoid (18) is chlorinated.

Zoom
Fig. 3 Structural types of Phlomis Iridoids. R1, R2, and R3 = H, OH, Cl *Group A1, R4 = CH3; Group A2, R4 = H.

The distribution of the iridoids in the Phlomis species is given in [Table 2]. As seen in this table, Ph. tuberosa is the richest species and is completely different from the other species with regard to its iridoid content. 7-epi-Phlomiol (10), sesamoside (11), and 8-O-acetyl-shanzhizide (15) were only isolated from Ph. tuberosa. Furthermore, lamiide (3), ipolamiide (4), common iridoids for most of the Phlomis species, were not found in Ph. tuberosa. Lamiide (3) was identified in 20 species while ipolamiide (4) was found in 11 species. On the other hand, 3 and 4 were found together in 6 species. Eight iridoids–ipolamiidic acid (13), lamiidic acid (14), 8-O-acetyl-shanzhizide (15), brunneogaleatoside (16), lamiidoside (17), chlorotuberoside (18), and phlorigidosides A and B (19 and 20)–were reported only in 1 or 2 species.


 

Phenylethanoid glycosides

From Phlomis species, 35 PhEt glycosides were isolated (22–56) ([Figs. 4]–[6]) which can be classified under 11 main groups (A – K) according to the glycosidation patterns and include di-, tri-, and tetraglycosides ([Tables 3]–[6]). Diglycosides are classified into 3 groups (A, B, and C). Group A consists of verbascoside and its derivatives (22–28) with 3-O-(α-L-rhamnopyranosyl)-β-D-glucopyranoside as oligosaccharide moiety. Group B comprises only 1 compound, β-hydroxyacteoside (29), possessing the same oligosaccharide but a different aglycone, 3,4-dihydoxyphenyl-2-hydroxyethanol. Group C, which is rarely observed, has a different oligosaccharide moiety, 2-O-(β-D-apiofuranosyl)-β-D-glucopyranoside, 4-hydroxy-phenylethanol as aglycone and vanillic acid as ester moiety (31 – 32).

Zoom
Fig. 4 Phenylethanoid diglycosides.
Zoom
Fig. 5 Tri- and tetraglycosidic phenylethanoids.
Zoom
Fig. 6 Simple phenol glycoside (Group K).

Table 3 Phenylethanoid diglycosides (22–32) (see [Fig. 4]).

PhEts (Groups A – C)

R1

R2

R3

R4

R5

Group A

22

Decaffeoylacteoside

H

H

H

H

H

23

Verbascoside (= Acteoside)

E-Caffeoyl

H

H

H

H

24

cis-Acteoside

Z-Caffeoyl

H

H

H

H

25

iso-Acteoside

H

E-Caffeoyl

H

H

H

26

Leucosceptoside A

E-Caffeoyl

H

H

CH3

H

27

Martynoside

E-Feruloyl

H

H

CH3

H

28

iso-Martynoside

H

E-Feruloyl

H

CH3

H

29

4″-O-acetylmartynoside

E-Feruloyl

H

H

CH3

COCH3

Group B

30

β-hydroxyacteoside

E-Caffeoyl

H

OH

H

H

Group C

31

Hattuschoside

OCH3

32

Fimbrilloside (= Phlomisethanoside)

H

Five groups (D – H) are triglycosidic PhEts (33–53). Forsythoside B (33), samioside (37), myricoside (40), echinacoside (43), and phlinoside A (47) are representative compounds for each group that show different sites of attachment of the third sugar linked to the core 3-O-(α-L-rhamnopyranosyl)-β-D-glucopyranoside disaccharidic moiety.


 

Tri- and tetraglycosidic phenylethanoids (33–55)

[Table 4].

Table 4 Tri- and tetraglycosidic phenylethanoids (33–55) (see [Fig. 5]).

Phenethylalcohol

Acyl

Glucosyl

Rhamnosyl

R1

R2

R3

R4

R5

R6

R7

Triglycosidic PhEts

Group D

33

Forythoside B

H

H

H

Api

H

H

H

34

Alyssonoside

H

H

CH3

Api

H

H

H

35

Leucosceptoside B

CH3

H

CH3

Api

H

H

H

36

Lamiophlomoside A

H

CH3

CH3

Api

H

H

H

Group E

37

Samioside

H

H

H

H

H

H

Api

38

Integrifolioside A

H

H

CH3

H

H

H

Api

39

Integrifolioside B

CH3

H

CH3

H

H

H

Api

Group F

40

Myricoside

H

H

H

H

H

Api

H

41

Oppositifloroside

H

H

CH3

H

H

Api

H

42

Serratumoside

CH3

H

CH3

H

H

Api

H

Group G1

43

Echinacoside

H

H

H

Glc

H

H

H

44

Glucopyranosyl-(1→Gi − 6′)-martynoside

CH3

H

CH3

Glc

H

H

H

45

Wiedemannioside C

H

H

CH3

Glc

H

H

H

Group G2

46

Arenarioside

H

H

H

Xyl

H

H

H

Group H1

47

Phlinoside A

H

H

H

H

Glc

H

H

Group H2

48

Phlinoside B

H

H

H

Xyl

H

H

49

Phlinoside D

H

H

CH3

Xyl

H

H

50

Phlinoside F

CH3

H

CH3

Xyl

H

H

Group H3

51

Phlinoside C

H

H

H

Rha

H

H

52

Phlinoside E

CH3

H

H

Rha

H

H

Group H4

53

Teucrioside

H

H

H

Lyx

H

H

Tetraglycosidic PhEts

Group I

54

Physocalycoside

H

H

H

Glc

Rha

H

H

Group J

55

Lunarifolioside

H

H

H

Api

H

H

Api

 

Simple phenol glycoside (56)

Two tetraglycosidic PhEts, physocalycoside (54) and lunarifolioside (55), are representatives of 2 separate groups (I and J). Seguinoside K (56) is a simple phenol or hydroquinone glycoside, which is regarded as belonging to a further group (K) of PhEts since the aglycone and ester moieties are formed via the shikimate pathway as in other PhEts.

Phenylethanoid glycosides grouped according to glycosidation patterns are reported in [Table 5], and the distribution of PhEt groups (A – K) in Phlomis species is given in [Table 6].

Table 5 Phenylethanoid glycosides grouped according to glycosidation patterns (22–56).

Phenylethanoid Glycosides (Groups A – K)

  • Diglycosides

Group A

  • (22) Decaffeoylacteoside

  • (23) Verbascoside (= Acteoside)

  • (24) cis-Acteoside

  • (25) iso-Acteoside

  • (26) Leuceptoside A

  • (27) Martynoside

  • (28) iso-Martynoside

  • (29) 4″-O-acetyl-martynoside

Group B

  • (30) β-hydroxyacteoside

Group C

  • (31) Hattushoside

  • (32) Phlomisethanoside (= Fimbrilloside)

Triglycosides

Group D

  • (33) Forsythoside B

  • (34) Alyssonoside

  • (35) Leuceptoside B

  • (36) Lamiophlomoside A

Group E

  • (37) Samioside

  • (38) Integrifolioside A

  • (39) Integrifolioside B

Group F

  • (40) Myricoside

  • (41) Oppositifloroside

  • (42) Serratumoside

Group G1

  • (43) Echinacoside

  • (44) Glucopyranosyl-(1 → 6)-martynoside

  • (45) Videmannioside C

Group G2

  • (46) Arenarioside

Group H1

  • (47) Phlinoside A

Group H2

  • (48) Phlinoside B

  • (49) Phlinoside D

  • (50) Phlinoside F

Group H3

  • (51) Phlinoside C

  • (52) Phlinoside E

Group H4

  • (53) Teucrioside

Tetraglycosides

Group I

  • (54) Physocalycoside

Group J

  • (55) Lunarifolioside

Simple phenol glycoside = Hydroquinone glycoside

Group K

  • (56) Seguinoside K (= Phloviscoside)

Table 6 Distribution of phenylethanoid glycosides in Phlomis species.

Phenylethanoid Glycosides (Groups A – K)*

Phlomis species

A

B

C

D

E

F

G1

G2

H1

H2

H3

H4

I

J

K

Ref

* For Groups A – K, see [Table 3]; ** Collected from Cyprus; *** Collected from Libya; n. s.: not studied; x = present

Ph. tuberosa

x

x

[29]

Ph. samia

x

x

[35]

Ph. pungens

x

x

x

[52]

Ph. integrifolia

x

x

x

[38], [39]

Ph. rigida

n. s.

Ph. russeliana

x

x

x

[46]

Ph. fruticosa

x

x

[31]

Ph. lunariifolia

x

x

x

x

[42]

Ph. grandiflora

x

x

x

[31]

Ph. viscosa

x

x

x

x

[45]

Ph. bourgaei

x

x

x

[16]

Ph. leucophracta

x

x

[46]

Ph. longifolia

x

x

[28]

Ph. amanica

x

x

[51]

Ph. lycia

x

x

[33]

Ph. monocephala

x

x

[35]

Ph. chimerae

x

x

[32]

Ph. oppositiflora

x

x

x

[47]

Ph. bruguieri

x

[46]

Ph. armeniaca

x

x

x

x

x

[19]

Ph. physocalyx

x

x

x

x

[36]

Ph. angustissima

x

x

x

[48]

Ph. capitate

x

x

x

[41]

Ph. kotschyana

x

x

[44]

Ph. sieheana

x

x

x

[30]

Ph. sintenisii

x

x

[34]

Ph. lanceolate

x

[47]

Ph. linearis

x

x

x

x

[12], [13]

Ph. brunneogaleata

x

x

x

[43]

Ph. nissolii

x

x

x

x

x

[41], [46]

Ph. syriaca

x

x

x

[50]

Ph. kurdica

x

x

[46]

Ph. carica

x

[35]

Ph. brevibracteata**

x

x

[55]

Ph. floccosa***

x

x

[56]

Among the diglycosides (Group A), verbascoside (= acteoside) (23) was found in all Phlomis species. β-Hydroxyacteoside (Group B) was isolated from Ph. viscosa, Ph. siehana, and Ph. syriaca. Among the triglycosides, a member of Group D, forsythoside B (33), is the most common PhEt together with verbascoside (23) found in all the species. PhEts of Groups E, F, G, and H were observed in a very limited number of Phlomis species. In Groups E, F, and H, the third sugar is attached to the secondary hydroxyl groups, C-4(OH), C-3(OH), or C-2(OH) of the rhamnopyranose unit, respectively. In the subgroups of G1 and G2, the third sugar is glucose or xylose. The subgroups H1, H2, H3, and H4 differ from each other by the type of the third sugar, which is glucose, xylose, rhamnose, or lyxose, respectively. Phlinosides A – E (47 – 52) and teucrioside (53), classified in the subgroups of H1, H2, H3, and H4, were isolated from Ph. linearis [12], [13]. Teucrioside (53), bearing a very rare pentose, α-L-lyxose, and representing subgroup H4 was isolated only from Ph. armeniaca [19].

In groups D, G1, and G2, the glycosidation site of the third sugar is the primary hydroxyl function [(− 6[OH]) of the core sugar glucopyranose. Throughout these studies, only 2 tetraglycosidic phenylethanoid glycosides, physocalycoside (54) and lunarifolioside (55), were isolated from P. physocalyx [36] and P. lunariifolia [42]. In both compounds, the glycosidation sites of the third and fourth sugar units are on the primary hydroxyl group of the core sugar, glucose, and on one of the secondary hydroxyl groups of the rhamnose unit. The number of tetraglycosidic PhEts in nature is very limited.

During our studies, other types of compounds such as lignans and neolignans (57 – 69) ([Fig. 7], [Table 7]), monomeric phenylpropanoids (70 – 73) ([Fig. 8], [Table 8]), quinic acid, and shikimic acid esters (74 – 76) ([Fig. 9], [Table 9]), flavonoids (flavone and flavonol glycosides, methoxyflavones, flavanone) (77 – 90) ([Fig. 10], [Table 10]), terpenoids (mono-, di- and triterpenoids) (91 – 100) ([Fig. 11], [Table 11]), and miscellaneous metabolites (101 – 109) ([Fig. 12], [Table 12]) were also isolated.


 

Lignans and neolignans (57–69)

[Table 7].

Zoom
Fig. 7 Lignan and neolignans from Phlomis species.

Table 7 Lignans and neolignans from Phlomis species (57 – 69) (see [Fig. 7]).

Lignan and neolignans glycosides (57 – 69)

Phlomis species

Refs

57

Dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside
R1 = Glc; R2 = H; R3 = H

Ph. lycia Ph. viscosa

[33] [45]

58

Dihydrodehydrodiconiferyl alcohol 9-O-β-D-glucopyranoside
R1 = H; R2 = Glc; R3 = H

Ph. chimerae Ph. lunariifolia
Ph. viscosa

[33] [42] [45]

59

Dihydrodehydrodiconiferyl alcohol 9′-O-β-D-glucopyranoside
R1 = H; R2 = H; R3 = Glc

Ph. lunariifolia
Ph. viscosa

[42]

60

(−)-4-O-methyldihydrodehydrodiconiferyl alcohol 9′-O-β-D-glucopyranoside
R1 = CH3; R2 = H; R3 = Glc

Ph. chimerae Ph. viscosa

[32] [45]

61

(−)-4-O-methyldihydrodehydrodiconiferyl alcohol 9-O-β-D-glucopyranoside
R1 = CH3; R2 = Glc; R3 = H

Ph. viscosa

[45]

62

Dehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside
R1 = Glc; R2 = H; R3 = H

Ph. integrifolia

[38]

63

Dehydrodiconiferyl alcohol 9′-O-β-D-glucopyranoside
R1 = H; R2 = H; R3 = Glc

Ph. viscosa

[45]

64

(−)-4-O-methyldehydrodiconiferyl alcohol 9′-O-β-D-glucopyranoside
R1 = CH3; R2 = H; R3 = Glc

Ph. chimera

[32]

65

(7S,8R)-dehydroconiferyl alcohol-8-5′-dehydroconiferylaldehyde-4-O-β-D-glucopyranoside

Ph. oppositiflora

[47]

66

Syringaresinol-4′-O-β-D-glucopyranoside
R = H

Ph. grandiflora var. fimbrilligera
Ph. monocephala

[35]

67

Liriodendrin
R = β-D-glc

Ph. kotschyana
Ph. capitata
Ph. brunneogaleata

[44]

68

Lariciresinol 4-O-β-glucopyranoside

Ph. viscosa

[45]

69

8-O-4′ neolignan 4-O-β-glucopyranoside (= erythro-1-(4-O-β-glucopyranosyl-3-methoxyphenyl)-2-{2-methoxyl-4-[1-(E)-propen-3-ol]-phenoxyl}-
propan-1,3-diol)

Ph. viscosa

[45]


 

Monomeric phenylpropanoids (70–73)

[Table 8].

Zoom
Fig. 8 Monomeric phenylpropanoids from Phlomis species.

Table 8 Monomeric phenylpropanoids from Phlomis species (70 – 73) (see [Fig. 8]).

Monomeric phenylpropanoids

Phlomis species

Refs

70

Syringin, R1 = H, R2 = OCH3, R3 = β-glc

Ph. chimerae

[32]

Ph. carica

[35]

71

Coniferin, R1 = R2 = H, R3 = β-glc

Ph. carica

[35]

72

3,5-Dimethoxy-4-hydroxycinnamoyl alcohol 9-O-β-glucopyranoside
R1 = β-glc, R2 = OCH3, R3 = H

Ph. amanica

[51]

73

Dihydrosyringin

Ph. carica

[35]


 

Quinic acid and shikimic acid esters (74–76)

[Table 9].

Zoom
Fig. 9 Quinic acid and shikimic acid esters.

Table 9 Quinic acid and shikimic acid esters (74 – 76) (see [Fig. 9]).

Quinic acid and shikimic acid esters

Phlomis species

Refs

74

Chlorogenic acid, R = H

All Phlomis spp.

[27]

75

Caffeoylquinic acid methyl ester, R = CH3

Ph. brunneogaleata

[43]

76

5-O-Caffeoyl-shikimic acid

Ph. brunneogaleata

[43]


 

Flavonoids (77–90)

Luteolin and chrysoeriol glycosides (77 – 86) as flavone derivatives and kaempferol and quercetin glycosides (86 – 87) as 2 flavonol glycosides were isolated in addition to 2 methoxyflavonols (89 – 89) and a flavanone, naringenin (90) ([Fig. 10], [Table 10]).

Zoom
Fig. 10 Flavonoids.

Table 10 Flavonoids isolated from Phlomis species (77 – 90) (see [Fig. 10]).

Phlomis species

Ref

Flavone glycosides

77

Luteolin 7-O-β-D-glucopyranoside, R = H

Ph. brunneogaleata

[43]

Ph. lunariifolia

[42]

Ph. syriaca

[50]

78

Luteolin 7-O-β-D-glucuronopyranoside, R = H

Ph. floccosa

[55]

79

Luteolin 7-O-(6″-O-α-L-rhamnopyranosyl)- β-D- glucopyranoside, R = H

Ph. capitata

[41]

80

Luteolin 7-O-(6″-O-β-D-apiofuranosyl)-β-D-glucopyranoside, R = H

Ph. capitata

[41]

81

Luteolin 7-O-[4‴-O-acetyl-α-L-rhamnopyranosyl-(1 → 2)]-β-D-glucuronopyranoside**, R = H

Ph. lunariifolia

[42]

82

Chrysoeriol 7-O-β-D-glucopyranoside, R = CH3

Ph. brunneogaleata

[43]

Ph. integrifolia

[39]

Ph. oppositiflora

[47]

Ph. capitata

[41]

Ph. lunariifolia

[42]

Ph. syriaca

[50]

Ph. integrifolia

[38]

83

Chrysoeriol 7-O-(3″-O-p-coumaroyl)-β-D-glucopyranoside, R = CH3

Ph. integrifolia

[38]

84

Chrysoeriol 7-O-β-D-allopyranosyl-(1 → 2)-β-D-glucopyranoside,R = CH3

Ph. sintenisii

[34]

85

Chrysoeriol 7-O-[6‴-O-acetyl-β-D-allopyranosyl-(1 → 2)]-β-D-glucopyranoside (= stachyspinoside), R = CH3
Flavonol glycosides

Ph. sintenisii

[34]

86

Kaempferol 7-O-β-D-glucopyranoside, R = H

Ph. oppositiflora

[47]

87

Quercetin 3-O-β-D-glucopyranoside, R = OH

Ph. oppositiflora

[47]

Methoxyflavones

88

3-O-methyl-kaempferol, R = H

Ph. viscosa

[45]

89

3,3′-di-O-Methyl-quercetin, R = OCH3

Ph. viscosa

[45]

Flavanone

90

Naringenin

Ph. syriaca

[50]

Ph. angustissima

[48]


 

Terpenoids (91 – 100)

Terpenoids isolated from Phlomis spp are represented by 10 compounds (91 – 100), and include mono-, di- and triterpenoids ([Fig. 11]). The monoterpene glycosides betulalbuside A (91) and 1-hydroxylinaloyl 6-O-β-D-glucopyranoside (92) were isolated from few Phlomis species. Diterpenoids belong to pimarane-type and labdane-type (94–95). Amanicadol (93), a pimarane-type diterpene, was first reported from P. amanica [51]. Two labdane-type diterpenes, jhanol (94) and jhanol acetate (95), were isolated from P. bourgaei [15]. The most interesting result was the discovery in Ph. viscosa of a novel nortriterpene glycoside, norviscoside (96), that possesses a spirocyclic skeleton and was isolated together with 2 new oleanane-type triterpene glycosides, viscosides A and B (97, 98) [40]. Two structurally similar nortriterpenoids, (99 and 100) were also isolated from P. integrifolia [27].

Zoom
Fig. 11 Mono-, di-, and triterpenoids from Phlomis species.

Table 11 Mono-, di-, and triterpenoids from Phlomis species (91–100) (see [Fig. 11]).

Phlomis species

Refs

Monoterpenes

91

Betulalbuside A

Ph. armeniaca

[19]

Ph. sieheana

[30]

Ph. carica

[37]

Ph. capitata

[41]

92

1-Hydroxylinaloyl 6-O-β-D-glucopyranoside

Ph. carica

[37]

Diterpenes

93

Amanicadol

Ph. amanica

[51]

94

Jhanol

Ph. bourgei

[15]

95

Jhanol acetate

Ph. borgei

[15]

Triterpenes and Nortriterpenes

96

Norviscoside: (17S)-2α,18β,23-trihydroxy-3,19-dioxo-19(18 → 17)-abeo-28-
norolean-12-en-25-oic acid 25-O-glucopyranosyl ester

Ph. viscosa

[40]

97

Viscoside A

Ph. viscosa

[40]

98

Viscoside B

Ph. viscosa

[40]

99

2α,3α,18β-Trihydroxy-19(18 → 17)-abeo-28-norolean-12-en-23-oic acid

Ph. integrifolia

[27]

100

2α,3α,18β,23-Tetrahydroxy-19(18 → 17)-abeo-28-norolean-12-en

Ph. integrifolia

[27]


 

Further compounds

Further compounds belonging to different chemical classes ([Fig. 12], [Table 12]) include a megastigmane glycoside (101), 2 acetophenone glycosides (105–106), and an octenol triglycoside (107).

Zoom
Fig. 12 Miscellaneous metabolites from Phlomis species.

Table 12 Miscellaneous metabolites from Phlomis species (101–109) (see [Fig. 12]).

Compounds

Phlomis species

Refs

101

Phlomuroside

Ph. samia

[37]

Ph. viscosa

[45]

Ph. carica

[37]

102

(2R,4S)-2-Carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrolidinium inner salt

Ph. brunneagaleata

[43]

103

Uridine

Ph. samia

[37]

104

2,6-Dimetoxy-4-hydroxyphenyl-1-O-β-D-glucopyranoside

Ph. samia

[37]

Ph. carica

[37]

105

4-Hydroxyacetophenon 4-O-(6′-O-β-D-apiofuranosyl)-β-D-glucopyranoside

Ph. brunneogaleata

[43]

Ph. kotschyana

[44]

106

Picein

Ph. carica

[37]

107

Lunaroside {1-octen-3yl O-β-apiofuranosyl-(1 → 6)-O-[β-glucopyranosyl-(1 → 2)]-β-glucopyranoside}

Ph. lunarifolia

[42]

108

1-O-Methyl-β-D-glucopyranoside

Ph. bourgaei

Ph. tuberosa

[49]

109

1-O-Ethyl-β-D-glucopyranoside

Ph. oppositiflora

[47]


 

 

Essential oils

Phlomis is represented in Turkey by 33 species and altogether 53 taxa. The rate of endemism on a species basis is 48% and on a taxon basis 57% [1]. The main components found in the essential oils of Phlomis species growing in Turkey and Northern Cyprus are summarized in [Table 13] [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75].

Table 13 Constituents of Phlomis spp. essential oils.

Species

Main Compounds (%)

References

*endemic; **endemic in Cyprus

Ph. amanica*

8(14),15-Isopimaradien-11α-ol (23%), germacrene-D (15%), bicyclo-germacrene (11%), (Z)-β-farnesene (8%)

[57], [58]

Ph. angustissima*

Hexadecanoic acid (19%)

[58]

Ph. armeniaca*

Germacrene D (23%), (Z)-β-farnesene (6%), hexadecanoic acid (5%)

[57], [58]

Germacrene D (27 – 23%), (E)-2-hexenal 10 – 12, β-caryophyllene (12 – 17%)

[59]

Germacrene D (24%), hexadecanoic acid (22%), hexahydrofarnesyl acetone (14%)

[60]

Germacrene D (36%), β-caryophyllene (18%), caryophyllene oxide (13%), (E)-β-farnesene (7%), hexahydrofarnesyl acetone (7%)

[61]

Ph. x bornmuelleri*

β-Caryophyllene (17%), germacrene D (17%)

[58]

Ph. bourgaei*

β-Caryophyllene (15 – 22%), α-cubebene (14 – 16%), germacrene-D (11 – 15%)

[59]

Germacrene D (11%), β-caryophyllene (11%), manoyl oxide (4%)

[62]

α-Cubebene (13 – 17%), β-caryophyllene (11 – 12%), germacrene D (11 – 13%)

[63]

β-Caryophyllene (37%), (Z)-β-farnesene (16%), germacrene D (11%)

[64]

Ph. brevibracteata**

leaf: Caryophyllene oxide (24%), β-caryophyllene (22%)
flower: β-Caryophyllene (265), caryophyllene oxide (7%)

[65]

Ph. bruguieri

Germacrene D (31%), hexadecanoic acid (22%), (Z)-β-farnesene (12%)

[58]

Ph. brunneogaleata*

β-Caryophyllene (25%), hexadecanoic acid (17%), germacrene D (16%)

[58]

Ph. capitata*

β-Caryophyllene (22%), germacrene D (12%)

[58]

Ph. chimerae*

β-Caryophyllene (32%), α-pinene (11%), limonene (6%)

[66]

β-Caryophyllene (35%), germacrene D (16%), caryophyllene oxide (6%)

[61]

Ph. cypria**

leaf: β-Caryophyllene (37%), germacrene D (21%)
flower: β-Caryophyllene (48%), germacrene D (17%)

[65]

Ph. grandiflora var. grandiflora*

β-Eudesmol (61 – 62%), β-curcumene (3 – 6%), ar-curcumene (2%)

[67]

β-Eudesmol (42%), α-eudesmol (16%), ar-curcumene (3%)

[68]

α-Pinene (19 – 26%), α-cedrene (19 – 28%), α-curcumene (12 – 14%)

[59]

α-Cedrene (26 – 31%), α-pinene (23 – 24%), α-curcumene (8 – 14%)

[63]

Ph. integrifolia*

Germacrene D (20%), (Z)-β-Farnesene (13%)

[58]

Ph. kotschyana

Hexadecanoic acid (17%), germacrene D (14%), β-caryophyllene (4%)

[58]

Ph. kurdica

β-Caryophyllene (31%), (Z)-β-farnesene (14%), germacrene D (2%)

[58]

Ph. leucophracta*

β-Caryophyllene (20 – 22%), limonene (11 – 15%), (E)-2-hexenal (8 – 9%)

[59]

β-Caryophyllene (23%), limonene (15%), (E)-2-hexenal (9 – 11%)

[63]

β-Caryophyllene (20%), α-pinene (20%), limonene (11%)

[66]

β-Caryophyllene (23%), germacrene D (10%)

[58]

Linalool (36%), β-caryophyllene (8%), caryophyllene oxide (8%), spathulenol (8%)

[75]

Ph. linearis

Germacrene D (17%), chrysanthenyl acetate (6%), trans-chrysanthenol (6%), 2-pentadecanone (5%)

[69]

β-Caryophyllene (24%), germacrene D (22%)

[70]

Ph. longifolia var. bailanica

β-Caryophyllene (19%), germacrene D (18%)

[58]

Ph. lunariifolia

Hexadecanoic acid (10%), β-caryophyllene (9%), germacrene-D (8%), 8(14),15-isopimaradien-11α-ol (6%)

[57]

Ph. lycia*

Germacrene-D (16%), β-caryophyllene (18%), limonene (14%)

[59]

Germacrene D (25 – 27%), β-caryophyllene (23 – 26%), limonene (6 – 11%)

[63]

β-Caryophyllene (21%), germacrene D (11%)

[58]

Ph. x melitenense

Germacrene D (27%), β-caryophyllene (2%)

[58]

Ph. monocephala*

8(14),15-Isopimaradien-11α-ol (13%), cermacrene D (6%), manoyl oxide (6%)

[57]

Germacrene D 19, (E)-β-farnesene (18%), α-pinene (16%)

[71]

Ph. nissolii*

Limonene (16 – 24%). β-caryophyllene (10 – 13%), germacrene-D (12 – 21%)

[59]

Germacrene D (34%), bicyclogermacrene (15%), (Z)-β-farnesene (11%), β-caryophyllene (9%)

[72]

Limonene (15 – 21%), β-caryophyllene (14%), germacrene D (8%)

[63]

Germacrene D (15%), β-caryophyllene (13%), hexahydrofarnesyl acetone (12%), linalool (11%)

[75]

Germacrene D (25%), β-caryophyllene (8%)

[58]

Ph. oppositiflora*

Germacrene D (23%), germacrene B (15%), bicyclogermacrene (9%), camphor (6%), caryophyllene oxide (5%)

[69]

β-Caryophyllene (8%), germacrene D (6%), spathulenol (6%), γ-elemene (6%), bicyclogermacrene (5%), caryophyllene oxide (5%)

[58]

Ph. physocalyx*

(Z)-β-Farnesene (6%), germacrene D (5%), β-caryophyllene (4%)

[58]

Ph. pungens var. hirta

Germacrene D (15%)

[58]

Ph. pungens var. hispida

β-Caryophyllene (24%), cermacrene D (23%)

[58]

Ph. pungens var. pungens

(E)-2-Hexenal (13 – 18%), vinyl amyl carbinol (13 – 19%), germacrene-D (8 – 10%)

[59]

Vinyl amyl carbinol (13 – 19%), (E)-2-hexenal (17 – 18%), germacrene D (8%)

[59]

Hexadecanoic acid (68%), germacrene D (7%)

[60]

Ph. rigida*

β-Caryophyllene (31 – 39%), β-selinene (13 – 15%), caryophyllene oxide (4 – 5%)

[73]

β-Caryophyllene (60%), germacrene D (10%), (E)-2-hexenal (9%)

[71]

epi-Zonarene (14%), d-cadinene (11%), spathulenol (11%), α-copaene (8%)

[69]

Ph. russeliana*

β-Caryophyllene (22%), germacrene-D (15%), caryophyllene oxide (8%)

[68]

Ph. samia

Germacrene D (34%), β-caryophyllene (6%)

[73]

Germacrene-D (19 – 23%), β-caryophyllene (14 – 15%), α-copaene (10 – 11%)

[59]

Germacrene D (17%), α-copaene (8 – 15%), β-caryophyllene (9 – 14%)

[63]

Ph. sieheana*

Germacrene D (16%), β-caryophyllene (11%), α-pinene (8%)

[74]

Germacrene D (17%), (Z)-β-farnesene (12%), spathulenol (3%), hexahydrofarnesyl acetone (2%), hexadecanoic acid (2%)

[57], [58]

Ph. sintenisii*

spathulenol (7%)

[58]

Ph. syriaca

β-Bisabolol (42%), germacrene D (16%), β-caryophyllene (4%)

[58]

Ph. viscosa

8,13-Epoxy-15,16-dinorlabd-12-ene (22%), germacrene D (9%), β-caryophyllene (8%), germacrene B (6%), 8,13-epoxy-14-labdene (manoyl oxide) (1%), 8,13-epoxy-14-epi-
labdene (epi-manoyl oxide) (1%), sclareolide (3%), ambrox (1%), phytol (1%)

[58]

Ph. x vuralii

Caryophyllene oxide (17%), 8,12-epoxy-labd-14-en-13-ol (6%)

[61]

Phlomis species are oil-poor. Interestingly, this fact coincides with the occurrence of tricolpate pollen grains, and the essential oils comprise mainly sesquiterpenes, with germacrene D and β-caryophyllene being the most common constituents ([Fig. 13]) [76]. Indeed, within the 36 taxa studied for essential oils, 28 taxa (Ph. amanica, Ph. armeniaca, Ph. bornmuelleri, Ph. bourgaei, Ph. brevibracteata, Ph. bruguieri, Ph. bruneogaleata, Ph. capitata, Ph. chimerae, Ph. cypria, Ph. integrifolia, Ph. kotschyana, Ph. kurdica, Ph. leucophracta, Ph. linearis, Ph. longifolia var. bailanica, Ph. lunariifolia, Ph. lycia, Ph. melitenense, Ph. nissolii, Ph. oppositiflora, Ph. physocalyx, Ph. pungens var. hirta, Ph. pungens var. hispida, Ph. rigida, Ph. russeliana, Ph. samia, Ph. sieheana, Ph. viscosa) contain these 2 sesquiterpene hydrocarbons either singly or together as major constituents.

Zoom
Fig. 13 Major sesquiterpenes found in Phlomis essential oils.

Other major sesquiterpenes found in Phlomis oils are caryophyllene oxide (P. brevibracteata, P. vuralii), (Z)-β-farnesene (P. bruguieri, P. integrifolia, P. sieheana), spathulenol (P. sintenisii), α-cubebene (P. bourgeai), β-eudesmol (P. grandiflora var. grandiflora), and α-cedrene (P. grandiflora var. grandiflora) ([Fig. 13]).

P. viscosa is particularly rich in diterpenes. 8,13-Epoxy-15,16-dinorlabd-12-ene, 8,13-epoxy-14-labdene (Manoyl oxide), 8,13-epoxy-14-epilabdene (epi-Manoyl oxide), sclareolide, ambrox, and phytol were found in its oil. 8(14),15-Isopimaradien-11α-ol was found as a major constituent in the essential oils of P. amanica, P. monocephala, and P. lunariifolia ([Fig. 14]).

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Fig. 14 Diterpenes found in Phlomis essential oils.

Monoterpenes are rarely found in the essential oils of Phlomis taxa. Limonene (Ph. nissolii), linalool (Ph. leucophracta), and α-pinene (Ph. grandiflora var. grandiflora) were detected as the most common monoterpenes.

Among the nonterpenoid volatiles, hexadecanoic acid was found as the main constituent in the oils of Ph. angustissima, Ph. armeniaca, Ph. kotschyana, Ph. bruguieri, Ph. brunneogaleata, Ph. lunariifolia, and Ph. pungens var. pungens.

4-Methoxycarbonyl-7-methylcyclopenta[c]pyran was detected in the oils of Ph. armeniaca (0.2%) and Ph. sieheana (0.2%) and characterized using Wiley GC/MS Library peak matching. It was previously reported as a transformation product of ipolamiide (iridoid) after acid hydrolysis and was classified as fulvoiridoid (or pseudoazulene) ([Fig. 15]) [77]. 4-Methoxycarbonyl-7-methylcyclopenta[c]pyran was also isolated from Stachytarpheta glabra (Verbenaceae) [78].

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Fig. 15 Acid-catalyzed degradation of ipolamiide (4) to a fulvoiridoid (= pseudoazulene) (4a).

 

Phlomideae

Eremostachys Bunge

The genus Eremostachys is closely related to the genus Phlomis. The Irano-Turanian region is the richest zone for this genus with about 60 species [79]. In Turkey, the genus Eremostachys is represented by 3 species: E. moluccelloides, E. laciniata, and E. glabra [26].


 

Iridoids

The studies on E. moluccelloides and E. laciniata resulted in the isolation of 14 iridoid glucosides, of which 6 were common for both species. These were lamalbide (5), 5-deoxypulchelloside (7), shanzhizide methyl ester (8), sesamoside (11), 5-deoxysesamoside (phlorogidoside C) (12), and chlorotuberoside (18), [80], [81]. Additional iridoids were 6 β-hydroxy-7-epi-loganin (110), lamalbidic acid choline salt (111), 5-deoxy-sesamosidic acid (112), phloyosides I (113), II (114), and shanzhizide (115) ([Fig. 16]).

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Fig. 16 Iridoids from Eremostachys species (110 – 115).

These results suggest that the iridoids of Eremostachys species are structurally related to those of Phlomis with a close similarity of their oxidation pattern. A DNA sequence analysis confirmed the taxonomic relationship between both taxa [82].


 

Phenylethanoid glycosides

The studies on E. laciniata resulted in the isolation of di- and triglycosidic phenylethanoid glycosides, including verbascoside (23), leucosceptoside A (26), martynoside (27), and forsythoside B (33) [81].


 

 

Bioactivity Studies

Bioactivity studies were mostly performed with isolated compounds. Earlier studies focused on phenylethanoid glycosides. In 1994, the structures of more than 150 phenylethanoid glycosides and their biological activities were discussed in detail [83]. This review summarized the methods for isolation, purification, structure elucidation and biological activities, biogenesis, and taxonomy of the PhEts. Acteoside (= verbascoside) is one of the major PhEts isolated from medicinal plants, and many further PhEts have been widely investigated for their inhibitory activities on enzymes such as aldose reductase, 5-lipoxygenase, protein kinase C, and cAMP-phosphodiesterase and on 5-HETE (5-hydroxyeicosatetraenoic acid) formation. In addition, antibacterial, cytotoxic, antioxidant, antihepatotoxic, antihypertensive, analgesic, sedative, anti-tremor L-DOPA, and immunosuppressant activities, as well as protective activity against a decrease of libido and learning behaviors in mice, have been described. In 1995, acteoside (23), leucosceptoside A (26), martynoside (27), forsythoside B (33), phlinosides B (48) and C (51), and teucrioside (53) as well as an iridoid glucoside, ipolamiide (4), isolated from Ph. armeniaca have been investigated for cytotoxic and cytostatic activities by the MTT method against dRLh-88 (rat hepatoma), HeLa, P-388-D1 (mouse lymphoid neoplasm), and S-180 (sarcoma) cell lines [19]. PhEts with a caffeoyl moiety as ester functionality were reported to show activity against several types of cancer cells. Structure-activity relationships revealed the importance of the presence of ortho-dihydroxy aryl units in PhEts. Thus, 23, 33, and 53 were reported to show stronger activity compared to methoxylated PhEts such as 26 and 27. As a continuation of these studies, 4 more PhEts, angorosides A, B, and C isolated from Scrophularia scopolii [7], [8] and poliumoside from Teucrium polium and a lignan, (+)-syringaresinol O-β-D-glucopyranoside (66), from Scutellaria albida subsp. colchica were investigated for cytotoxic and cytostatic activities [84]. No activity was observed for methylated derivatives such as angorosides B and C. The caffeic acid-containing PhEts angoroside A and poliumoside, as well as (+)-syringaresinol O-β-D-glucopyranoside (66), were found to exhibit significant cytotoxic activity against dRLh-84, HeLa, S-180, and P388/D1 cells. No cytotoxic effects against primary-cultured rat hepatocytes were observed for PhEts [84]. In 2000, a series of 21 PhEts were tested for radical scavenging activity by quantifying their effects on the production of reactive oxygen species (ROS) in a luminol-enhanced chemiluminescence assay with formyl-methionine-leucyl-phenylalanine (FMPL)-stimulated human polymorphonuclear neutrophils (PMNs) [19]. The compounds used in this study were isolated from Lamiaceae (Phlomis, Galeopsis, Marrubium, Scutellaria species), Globulariaceae (Globularia sp.), and Scrophulariaceae (Pedicularis and Digitalis sp.). They possessed mono-, di- and triglycosidic structures and include some deacyl derivatives. PhEts acylated with phenolic acids were found to show stronger activity whereas the deacyl derivatives were more than 30-fold less active. The potency of the antioxidant activity was mainly depending on the number of phenolic hydroxyl or methoxyl groups. The sugar type and the position of the glycosidic bonds, as well as the sugar sequence, seemed to have no effect on the activity [85]. Forty-eight PhEts isolated not only from Lamiaceae plants but also from Scrophulariaceae, Globulariaceae, and Oleaceae plants were reviewed concerning their structural diversity and biological activities studied in house or in collaborative settings [86]. Regardless of the plant from which it was isolated, acteoside (22) has been the most studied compound among the PhEts. Acteoside-induced apoptosis in HL-60 cells [87]. Moreover, these studies suggest that acteoside possesses a selectivity in its cytotoxic activity between normal cells and cancer cells. It was proposed that the activity of acteoside depends mainly on the redox state in cells. Moreover, antimetastatic activity examined on lung metastasis using a mouse model with B16 melanoma cells has shown a suppressive effect of acteoside (23) [88]. Four PhEts glycosides–lavandulifolioside, acteoside (23), leucosceptoside A (26), and martynoside (27)–isolated from aerial parts of Sideritis lycia (Lamiaceae) have been investigated for their anti-inflammatory activity together with flavonoid glycosides isolated from the same plant [89]. Lavandulifolioside is a triglycosidic phenylethanoid glycoside, which can be classified in the group H and was first isolated from Stachys lavandulifolia [11]. In this study, the flavonoid glycosides showed higher activity than PhEts. However, the gastric ulceration effect of PhEts was found to be less than that of flavonoid glycosides [89]. Acteoside and an iridoid, 1,5,9-epi-deoxyloganic acid, isolated from Nepeta ucrainica (Subfamily: Nepetoideae) have been investigated for immunomodulatory activity [90]. Acteoside showed a positive chemotactic activity at all doses, and the intracellular killing activity of neutrophils did not change significantly. On the other hand, the decreasing values observed with higher doses point to possible immunosuppresive and antioxidant effects.

In vitro effects of acteoside (23) and forsythoside B (33) together with isoorientin have been investigated on purified bovine kidney cortex GR. Both compounds inhibited bovine kidney cortex GR in a concentration-dependent manner. Forsythoside B and acteoside were found to act as an uncompetitive inhibitor of GR, which causes accumulation of reactive oxygen species and depletion of the glutathione pool. It has been assumed that the inhibition of GR might be significant in drug resistance [91].

Due to the high number of constituents and the richest chemical diversity of the structures isolated, metabolites from P. brunneogaleata and P. viscosa were submitted to an activity screening panel [43], [45].

Inhibitory activities of 16 compounds belonging to different chemical groups isolated from P. brunneogaleata were tested against parasitic protozoa (Plasmodium falciparum, Trypanosoma cruzi, T. brucei, Leishmania donovani) and plasmodial enoyl-ACP reductase [43]. These compounds include 2 iridoids, ipolamiid (4) and brunneogaleatoside (16); 6 PhEts, verbascoside (23), isoverbascoside (24), forsythoside B (33), echinacoside (43), integrifolioside B (39), glucopyranosyl-(1→Gi − 6)-martynoside (44); a lignan, liriodendrin (67); 3 caffeic acid esters, chlorogenic acid (74), 3-O-caffeoyl-quinic acid (75), and 5-O-caffeoyl-shikimic acid (76); 2 flavone glycosides, luteolin 7-O-β-D-glucopyranoside (77) and chrysoeriol 7-O-β-D-glucopyranoside (82); an acetophenone glycoside, 4-hydroxyacetophenone 4-O-(6′-O-β-D-apiofuranosyl)-β-D-glucopyranoside (105); and (2R,4S)-2-carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrolidinium inner salt (102). Flavone derivatives 77 and 82 were found to possess the highest antimalarial activity among the tested metabolites. Both compounds also exhibited substantial leishmanicidal activity, and 77 displayed strong enzyme inhibitory potential toward plasmodial Fabl enzyme [43].

The studies on P. viscosa resulted in the isolation of a total 27 compounds, comprising 2 oleanan-type triterpene saponins, 1 nortriterpene [40], 3 iridoids, 10 PhETs, 1 megastigmane glycoside, 2 lignans, 7 neolignans, and 1 hydroquinone glycoside [45]. The isolated compounds included the iridoids: ipolamiide (3), lamiide (4) and lamiidoside (17); the PhEts: decaffeoyl-acteoside (22), verbascoside (23), isoacteoside (25), leucosceptoside A (26), martynoside (27), β-hydroxyacteoside (30), forsythoside B (33), alyssonoside (34), leucosceptoside B (35), and myricoside (40); a hydroquinone glycoside: seguinoside K (56); the neolignan glucosides: dihydrodehydrodiconiferylalcohol 4-O-β-glucopyranoside (57), a mixture of dihydrodehydro-diconiferylalcohol 9-O-β-glucopyranoside (58) and dihydrodehydrodiconiferylalcohol 9′-O-β-glucopyranoside (59); (−)-4-O-methyl-dihydrodehydrodiconiferyl alcohol 9′-O-β-D-glucopyranoside (60); (−)-4-O-methyl-dihydrodehydrodiconiferyl alcohol 9-O-β-D-glucopyranoside (61); dehydrodiconiferyl-alcohol 9'-O-β-glucopyranoside (63); 8-O-4′ neolignan 4-O-β-glucopyranoside (= erythro-1-(4-O-β-glucopyranosyl-3-methoxyphenyl)-2-{2-methoxyl-4-[1-(E)-propen-3-ol]-phenoxyl}-propan-1,3-diol) (69); the lignan glucosides: syringaresinol 4′-O-β-glucopyranoside (66) and lariciresinol 4-O-β-glucopyranoside (68) and a megastigmane glycoside: phlomuroside (101). Samioside (37) isolated from P. samia [35] was also added to the activity screenings.

The metabolites from P. viscosa were tested for radical scavenging, antibacterial and antifungal activities, and cell growth inhibition. All the compounds were also evaluated for cell growth inhibition versus 3 cell lines (MCF 7, NCI-H460, and SF-268) in the NCI cancer prescreen panel. Iridoids were not active. In contrast, PhEts 23, 25, 33, 34, 37, and 40 were found to reduce the growth of at least 1 cell line to < 32% of the control (dl-a-tocopherol) and were further subjected to the full 60-cell line panel. However, the concentrations required to inhibit cell growth at the GI-50 level were greater than 47 µM in all cases, with minimal differential inhibition among the cell lines. Thus, these compounds were not investigated further as inhibitors of cancer cell growth. Compounds 23, 25, 33, 37, and 40 were found to be free radical scavengers with activity comparable to dl-α-tocopherol. Compounds 23, 25, 33, and 37 exhibited weak activity against Gram (+) bacteria [45]. The antioxidative activity of the PhEts was in line with an earlier study [84]. In one of the ongoing studies on Phlomis species, the protective effect of the PhEts from P. pungens against free radical-induced functional endothelial injury was found to correlate with the free radical scavenging activity arising from the phenolic hydroxyl groups [91].

The potential inhibitory effect of verbascoside (= acteoside) (23) on neurotoxicity has been studied, and the compound has been suggested to be useful in the treatment of neurological diseases such as parkinsonism [92]. The recent studies have focused on the chemistry, pharmacological activity, and pharmacokinetics of PhEts [93], [94], [95]. Verbascoside (= acteoside) (23), as a widely distributed PhEt in the plant kingdom, has been discussed in many perspectives, including biosynthesis, production using biotechnological methods and pharmacological activities, molecular features, and principal photoprotective activities in human keratinocytes [93]. The presence of PhETs in many medicinal plants and the diversity in their structure and biological activity have been a point of attraction for scientists. In 2016, Xue and Yang reviewed the biological activities such as neuroprotective, anti-inflammatory, antioxidant, antibacterial and antiviral, cytotoxic, immunomodulatory properties, and enzyme inhibitory effects, as well as pharmacokinetic properties of the new PhEts isolated between 2005 and 2015 [94]. A recent review reported the structures of 375 PhEts including 57 mono-, 143 di-, 161 tri-, and 14 tetraglycosidic structures, their plant sources, biosynthesis, and chemical synthesis together with their pharmacological activities in a wider perspective [95].

Finally, some Phlomis oils have been tested for various biological activities. The following activities were detected: Antibacterial: Ph. grandiflora [68], Ph. russeliana [68]; anticandidal (Ph. amanica [58], Ph. armeniaca [58], Ph. lunariifolia [58], Ph. monocephala [58], Ph. sieheana [58]); antimicrobial (Ph. sieheana [74]); antioxidant (Ph. armeniaca [59], Ph. bourgaei [64], Ph. leucophracta [75], Ph. nissolii [75], Ph. pungens [60]); and enzyme-inhibitory (Ph. armeniaca [60], Ph. nissolii [75], Ph. pungens [60]).


 

Concluding Remarks

Our studies on Phlomis species resulted in the isolation of many iridoids (1 – 21) and PhEts (22 – 56) as glycosidic compounds. Iridoids are highly oxygenated ([Fig. 2]). They are biogenetically derived from either 8-epi-loganin without 8-O-substitution or mussaenoside with 8-O-substitution involving further hydroxylation at positions 5, 6, and 7 and esterification or formation of iridoids with a 7,8-epoxy group as reported by Alipieva et al. [96]. Chlorotuberoside (18) and phloyosides II (114) are 2 chloro-substituted iridoids isolated from P. tuberosa [49] and E. laciniata [81]. Iridoids isolated from Eremostachys species were closely related to those iridoids isolated from Phlomis species, indicating a close relationship within the same tribe of Phlomideae.

PhEts from Phlomis and Eremostachys species include di-, tri-, and tetraglycosides (22–56) ([Figs. 4]–[6]). Deacylverbascoside (22) or verbascoside (23), which have 3-O-(α-L-rhamnopyranosyl)-β-D-glucopyranoside as oligosaccharide moiety, build the core structure for all tri- and tetraglycosidic compounds. The third and fourth sugars are apiose, arabinose, xylose, lyxose, rhamnose, or glucose whereas apiose is the most abundant.

During our studies on Phlomis species, priority has been given to iridoids and phenylethanoids. Therefore, it would not be correct to generalize with the structures and numbers of compounds other than iridoids and phenylethanoids. Other compounds have been presented here to show the structural diversity of the chemical constituents of Phlomis species.

Neo-, oxy-, and lignan glycosides are the third major group of metabolites isolated. Neolignans are mostly diconiferyl alcohol derivatives (57–65). Lignans are furofuran-type (66–67) or tetrahydrofuran-type lignans (68). Flavonoids are mostly flavone glycosides of luteolin and chrysoeriol (77–85). Few flavonols are kaempferol and quercetin derivatives (86–89). A flavanone, naringenin (90), was only isolated from 2 Phlomis species.

Terpenoids are another metabolite group, represented by 10 compounds (91–100), which are mono-, di-, and triterpenoids. Particularly interesting are the 28-noroleanane-derived spirocyclic triterpenoids (96, and 99–100). Similar triterpenoids that display this rare type of spirocyclic skeleton have also been isolated from the rhizomes of the Chinese medicinal plant P. umbrosa, which is used to treat colds, reduce swelling, and staunch bleeding [97], [98], [99]. Metabolites belonging to further chemical classes include a megastigmane glycoside (101), 2 acetophenone glycosides (105–106), and an octenol triglycoside (107).

Almost all Phlomis species of Turkey and 2 species from Northern Cyprus have been analyzed for essential oils. Phlomis essential oils are characterized by low yields and by the occurrence of sesquiterpenes as main constituents. Germacrene D and β-caryophyllene are the typical sesquiterpenes found in 75% of the oils. Some Phlomis oils like the oil from P. viscosa are rich in diterpenes. 8(14),15-Isopimaradien-11α-ol, a recently described diterpene, was found in 3 Phlomis species. Some Phlomis oils have been tested for antimicrobial, antioxidant, and enzyme-inhibitory activities.

Our studies focused on the iridoids and PhEts and were performed on Phlomis and Eremostachys species. They have resulted in the isolation of more than 100 metabolites including a wide range of chemical classes as summarized above. These results indicate not only the chemical diversity of the metabolites isolated but also the potential biological and pharmacological activities of plants of the family Lamiaceae for drug discovery studies. In this context, a recent review article on the antimalarial active compounds from the plants of Lamiaceae underlines their potential in the search for lead compounds [100]. The potential of Lamiaceae is also emphasized by a recent review focusing on flavonoids, fatty acid derivatives, and sterols and their wide range of biological activities [101].

Taken together, these observations show that the members of this family are still a highly interesting group of plants for further taxonomic, phytochemical, biological, and pharmacological studies.


 

Funding

The studies performed on the Phlomis L. species were supported by The Scientific and Technological Research Council of Turkey (TUBITAK-SBAG-2304).


 

Contributorsʼ Statement

Conception and design of the work: İ. Çalış; data collection: İ. Çalış, K. H. C. Başer; drafting the manuscript: İ. Çalış; critical revision of the manuscript: İ. Çalış, K. H. C. Başer.


 

 

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors kindly thank Ali A Dönmez (Hacettepe University, Department of Biology, Ankara, Turkey), MY Dadandı (Erciyes University, Faculty of Science and Letters, Department of Biology, Erciyes, Turkey), İ Saracoğlu, T Ersöz, H Kırmızbekmez, FN Yalçın, US Harput (Hacettepe University, Faculty of Pharmacy Department of Pharmacognosy, Ankara, Turkey), Randa Aldaba and Azmi Hanoğlu (Near East University, Faculty of Pharmacy Department of Pharmacognosy, Lefkoşa, TRNC), Mehmet Koyuncu and Ayşegül Köroğlu (Ankara University, Faculty of Pharmacy, Ankara, Turkey), Betül Demirci and Fatih Demirci (Anadolu University Faculty of Pharmacy, Department of Pharmacognosy, Eskişehir, Turkey) and other co-authors for their participation in the studies performed on the Phlomis and Eremostachys species. Our thanks also go to F Celep (Department of Biology, Faculty of Arts and Sciences, Kırıkkale University, Kırıkkale, Turkey) for his kind help in the taxonomy of Lamiaceae and its subfamilies and tribes based on his recent phylogenomic studies.

# Dedicated to Prof. Dr. Otto Sticher on the occasion of his 85th birthday.



Correspondence

Prof. Dr. İhsan Çalış
Near East University
Faculty of Pharmacy
Department of Pharmacognosy
Near East Boulevard
99138 Lefkoşa (Nicosia) TRNC Mersin 10
Turkey   
Phone: + 90 (5 33) 8 75 69 86   
Fax: 90 (3 92) 6 80 20 38   

Publication History

Received: 12 March 2021

Accepted after revision: 09 June 2021

Article published online:
20 August 2021

© 2021. Thieme. All rights reserved.

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Fig. 1 Classification of Phlomis species in the Flora of Turkey and the East Aegean Islands.
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Fig. 2 Iridoids isolated from Phlomis species (1 – 21).
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Fig. 3 Structural types of Phlomis Iridoids. R1, R2, and R3 = H, OH, Cl *Group A1, R4 = CH3; Group A2, R4 = H.
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Fig. 4 Phenylethanoid diglycosides.
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Fig. 5 Tri- and tetraglycosidic phenylethanoids.
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Fig. 6 Simple phenol glycoside (Group K).
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Fig. 7 Lignan and neolignans from Phlomis species.
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Fig. 8 Monomeric phenylpropanoids from Phlomis species.
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Fig. 9 Quinic acid and shikimic acid esters.
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Fig. 10 Flavonoids.
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Fig. 11 Mono-, di-, and triterpenoids from Phlomis species.
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Fig. 12 Miscellaneous metabolites from Phlomis species.
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Fig. 13 Major sesquiterpenes found in Phlomis essential oils.
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Fig. 14 Diterpenes found in Phlomis essential oils.
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Fig. 15 Acid-catalyzed degradation of ipolamiide (4) to a fulvoiridoid (= pseudoazulene) (4a).
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Fig. 16 Iridoids from Eremostachys species (110 – 115).