Phytochemistry and biological activities of Phlomis species

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Journal of Ethnopharmacology 125 (2009) 183–202

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Journal of Ethnopharmacology

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hytochemistry and biological activities of Phlomis species

lef Limem-Ben Amora,b, Jihed Boubakera,b, Mohamed Ben Sgaiera,b, Ines Skandrania,b,issem Bhouria,b, Aicha Neffati a,b, Soumaya Kilania,b, Ines Bouhlela,b, Kamel Ghediraa,b,

eila Chekir-Ghediraa,b,∗

Laboratory of Cellular and Molecular Biology, Faculty of Dental Medicine, Rue Avicenne, 5019 Monastir, TunisiaUnity of Pharmacognosy/Molecular Biology 99/UR/07-03, Faculty of Pharmacy, Rue Avicenne, 5000 Monastir, Tunisia

r t i c l e i n f o

rticle history:eceived 1 December 2008eceived in revised form 17 June 2009ccepted 20 June 2009vailable online 27 June 2009

a b s t r a c t

The genus Phlomis L. belongs to the Lamiaceae family and encompasses 100 species native to Turkey, NorthAfrica, Europe and Asia. It is a popular herbal tea enjoyed for its taste and aroma. Phlomis species are usedto treat various conditions such as diabetes, gastric ulcer, hemorrhoids, inflammation, and wounds. Thisreview aims to summarize recent research on the phytochemistry and pharmacological properties of thegenus Phlomis, with particular emphasis on its ethnobotanical uses. The essential oil of Phomis is composed

eywords:hlomisamiaceaeecondary metabolitesthnobotanical usesharmacological properties

of four chemotypes dominated by monoterpenes (�-pinene, limonene and linalool), sesquiterpenes (ger-macrene D and �-caryophyllene), aliphalic compounds (9,12,15-octadecatrienoic acid methyl ester), fattyacids (hexadecanoic acid) and other components (trans-phytol, 9,12,15-octadecatrien-1-ol). Flavonoids,iridoids and phenylethyl alcohol constitute the main compounds isolated from Phlomis extracts. Thepharmacological activities of some Phlomis species have been investigated. They are described accordingto antidiabetic, antinociceptive, antiulcerogenic, protection of the vascular system, anti-inflammatory,
antiallergic, anticancer, antimicrobial and antioxidant properties.
© 2009 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1842. Botanical description of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843. Ethnobotanical use of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

3.1. Uses recorded for Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843.2. Phlomis species with particular ethnobotanical uses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843.3. The part of Phlomis used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843.4. Specific culinary use of some Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

4. Secondary metabolites of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1904.1. Essential oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1904.2. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1904.3. Iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1964.4. Phenylethylalcohol glycosides structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1974.5. Other secondary metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

5. Pharmacological properties of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1975.1. Antidiabetic activity (in vivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1975.2. Antinociceptive activity (in vivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
5.3. Antiulcerogenic activity (in vivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.4. Protection of the vascular system (in vitro) . . . . . . . . . . . . . . . . . . . . . . . . .5.5. Anti-inflammatory and antiallergic activities (in vivo) . . . . . . . . . . . . .5.6. Anticancer activity (in vitro) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Faculty of Dental Medicine, Rue Avicenne, 5019 Monastir, TE-mail address: [email protected] (L. Chekir-Ghedira).

378-8741/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.jep.2009.06.022

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184 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202

5.7. Anti-infective testing in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985.7.1. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985.7.2. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985.7.3. Antiparasitic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

5.8. Antioxidant and antiradical activities (in vitro) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Plants are used worldwide for the treatment of diseases, andovel drugs continue to be developed through research from plants.here are more than 20,000 species of plants used in traditionaledicines, and these are all potential reservoirs for new drugs

Hamamouchi, 2002). With the advance of modern medicine andrug research, chemical synthesis has replaced plants as the pri-ary source of medicinal agents in industrialized countries. In

eveloping countries, the majority of the world’s population can-ot afford pharmaceutical drugs and use their own plant-based

ndigenous medicines. Traditional medicinal plants have receivedonsiderable attention because their bioactive components mayead to new drug discoveries. The Phlomis genus has been instru-

ental in the discovery of natural medicinal products (Kim, 2006).Phlomis is a large genus in the Lamiaceae family, with over 100

pecies distributed throughout Euro-Asia and North Africa con-inents. They have various uses that differ from one country tonother. Their flowered parts are generally used as an herbal teao treat gastrointestinal troubles and to promote good health byrotecting the liver, kidney, bone and cardiovascular system. Inddition, some Phlomis species have culinary uses.

Over the last few years, there has been a rapid increase in thenformation available on the structures and pharmacological activi-ies of new compounds isolated and identified from Phlomis species.n this review, we present recent Phlomis plant research in threeections: ethnobotanical uses, phytochemistry, biological and phar-acological activities of Phlomis plants.

. Botanical description of Phlomis species

The leaves of Phlomis are entire, opposite and decussate andugose or reticulate veined. The bracts are similar or different fromhe lower leaves. All parts are frequently covered with hair. Bracte-les are ovate, lanceolate or linear. The flowers are arranged inhorls around the stems, which are usually square in section with

ounded corners, although tomentum on stems can make themppear circular. The color of the flowers varies from yellow to pink,urple and white. The calyx is tubular or campanulate with 5 or 10isible veins. It has five teeth, either all equal or with the outer twoonger than the others. The upper lip is hood shaped and laterallyompressed. The lower lip is trifid, the central lobe being larger thanhe lateral ones. There are four stamens ascending under the upperip. The anther has a forked end, the upper fork being shorter thanhe lower. The fruits are four- or three-sided, nutlets, and some-imes topped with hair, and sometimes glabrous (Pottier-Alapetite,981).

. Ethnobotanical use of Phlomis species

A number of Phlomis species are used in folk medicine. In Table 1
we summarize the ethnobotanical use of 30 Phlomis species. In
act, there are many ethnobotanical sources that do not include anyhlomis species. In addition, some Phlomis species growing at highltitude (Phlomis olivieri (Sarkhail et al., 2006), Phlomis russelianaDemirci et al., 2008), Phlomis viscosa (Karaman and Cömlekciogolu,

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

2007), Phlomis integrifolia (Saracoglu et al., 2003)) and mountainousregions (Phlomis linearis (Demirci et al., 2008)) are not easy acces-sible resources and thus are not extensively used and studied. Thedetails on ethnobotanical uses are given below and in Table 1.

3.1. Uses recorded for Phlomis species

According to Table 1, a high number of Phlomis species over theworld have the same mode of use, namely as herbal tea (decoctionor infusion) to treat gastric, abdominal and intestinal conditions(Phlomis bourgei . . .). Other species were described to protect theliver, the kidney, the heart, the veins and the bone from differ-ent pathologies (Table 1). Some Phlomis species were described totreat fever, cough and cold, such as Phlomis cephalotes and Phlomisplukenettii (Table 1). Other Phlomis species such as Phlomis boveisubsp. bovei and Phlomis crinita are made into pastes and used aspoultice or plaster to treat burns, lesions and skin infections andallergies (Table 1). For example, Phlomis crinita subsp. crinita andsubsp. mauritanica, which grow in Spain and in Tunisia and Alge-ria, are used to heal lesions and burns by preparing a plaster fromchopped leaves in Spain or as dried leaf powder in Tunisia and Alge-ria. However, the same species may have variable uses from onecountry to another: i.e., Phlomis fruticosa is used in Italy as an anti-cough agent and as a cicatrizant, whereas in Turkey and Greece, itis used to heal gastric ulcers.

3.2. Phlomis species with particular ethnobotanical uses

Some species have particular uses in their respective coun-tries. For example, the Syrian multi-component herbal tea called“Zahraa” is a complex mixture of leaves and/or flowers from 6 to 14species, including Phlomis syriaca. Usually, these teas are consumedin households and in restaurants and cafes in Damascus (Carmonaet al., 2005). Phlomis purpurea, also known as marioilas in Portugalhas over 17 different medicinal uses in that country. It is directlyingested to treat gastric pains, and its olive oil decoction is usedas an intestinal antispasmodic (Novais et al., 2004). In Spain, thisplant is called “matagallos,” and its aerial infusion is frequently usedto treat prostate and liver problems (González-Tejero et al., 1995).Phlomis lychnitis, named Candilera, is commonly used in Spain as anherbal tea, to treat gastric, intestinal and abdomen pains, as a tonic,sedative, carminative and astringent (Rivera Núnez and Obón DeCastro, 1993; Fernández-Ocana et al., 1996; Vázquez et al., 1997;Tardio et al., 2006; Pardo de Santayana et al., 2005).

3.3. The part of Phlomis used

All parts of the Phlomis plants are used including the leaves(Phlomis aspera, Phlomis cephalotes . . .), the flowers (Phlomis aspera,

(Phlomis nepetaefolia). They are used as a decoction, an infusion oras a juice. The flowers of some Phlomis species are sweet and areconsumed directly or sucked (Phlomis purpurea subsp. purpurea,Phlomis cephalotes). The leaves of Phlomis cephalotes are used toprepare an herb-pot.

I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 185

Table 1Medicinal uses of selected Phlomis species.

Phlomis species Regions Common names Uses recorded Formulation/Mode ofusage

References

Phlomis angustissimaHub.-Mor.

Mugla (Turkey) Yaylacayı NCa Herbal tea Ertug (2004)

Phlomis aspera Willd Bangladesh Choto halkusa, Dulfi,Kusa, Shetodrone

Psoriasis, chronic skineruptions, in chronicrheumatism, painfulswellings, coughs andcolds

The juice of the leaves isused in psoriasis, chronicskin eruptions, in chronicrheumatism and appliedto disperse painfulswellings. The flowersare being warmed with alittle honey and givenorally for coughs andcolds to children

Khanam and AbulHassan (2005)

Throughout Indiansub-continentextending fromPunjab to Assam andsouthward up topeninsular India

Phlomis aurea Decne. Sinai (Egypt) Awarwar Antidiabetic NCa Khafagi and Dewedar(2000), Mohamed et al.(2000)

Phlomis bourgei Boiss Isparta (Turkey) NCa Stomach ache NCa Digrak et al. (1999)Phlomis bovei De Noé subsp.

boveiAlgeria Kayat El Adjarah Lesion and burns NCa Liolios et al. (2007)

North Africa Farseouan, Tarseouan,Iniji, R’ilef and Azaref

Phlomis bracteosa Royle exBenth.

Lahaul valley(North-WestHimalaya)

Gahand-Shang Stomach disorder Dry powder of the aerialpart is mixed with thepowder prepared fromaerial parts of Menthalongifolia, Heracleumthomsonii, Thymuslinearis and Angelicaglauca in equal ratio andabout one spoon is takenwith a glass of warmwater to cure gastrictrouble

Shing and Lal (2008)

Phlomis caucasica Rech. f. North west of Iran Gush barreh gafgazi Analgesic, anti-infection,digestive, throatinfection

Arial part Lotfipour et al. (2008),Delazar et al. (2008)

Phlomis cephalotes Roth Bangladesh Barahal-kusa Stimulant, diaphoretic,scabies, coughs and colds

The seeds yieldmedicinal oil. The freshjuice is used specificallyas an externalapplication in scabies.The flowers areadministered in the formof syrup as a domesticremedy for coughs andcolds. The leaves areeaten as a pot-herb


Throughout IndiansubcontinentChepang (Nepal) Talang tolo Malarial fever, urinary

complaints, nosebleedFour teaspoons of thedecoction (flowers,leaves is boiled in waterfor 15 min, and filtered),three times a day, isgiven for malarial fever.A paste of the plant isboiled with mustard oiland applied to boils.Juice of the plant is givenin the case of urinarycomplaints. Driedinflorescences aresmoked and the smoke isexpelled through thenose to treat nosebleed

Manandhar (2002)

Danuwar (Nepal) JulpbiTharu (Nepal) GumMajhi (Punjab;Pakistan)

Phoke jbar, tank jbar

Phlomis crinita Cav. subsp.crinita

Murcia, Almería(Spain)

Orejicas de fraile, Orejade liebre

Lesions and burns A cicatrizant plaster isprepared with thechopped leaves

Rivera Núnez and ObónDe Castro (1993),González-Tejero et al.(1995)

Phlomis crinita Cav. subsp.mauritanica Munby

Tunisia, Algeria, Khayatta, Khayatt eladjarah

Lesions and burns The dried leaves areapplied directly on freshcuts and burns

Boukef (1986), Quezeland Santa (1963)


Table 1 (Continued )


References

Phlomis fruticosa L. Apulia, Calabria,Sicily and Sardinia(Italy)

NCa Anti-tussive NCa Guarrera and Lucia(2007)

Sicily (Italy) Sucu cu a sarviasarvaggia

Spices Sauce for paste preparedby browning the leavesin bacon fat, butter orolive oil

Lentini and Venza (2007)

Italy NCa Wounds Leaves are used as apoultice on wounds

Sokovic et al. (2002)

Mugla (Turkey) NCa Appetizer, stimulant,tonic, stomach pain,carminative, dyspepticcomplaint

Inflorescence and leavesare used to prepare aherbal tea

Brussel (2004), Sarac andUgur (2007)

Greece NCa Soothe sore muscles andjoints

A decoction leaves andseeds is used topically tosoothe sore muscles andjoints.

Gürbüz et al. (2003)

Gastric ulcers Leaves are macerated inwater with honey orwine and were takenorally

Phlomis grandiflora H.SThompson var. grandiflora

Anatolya (Turkey) Ballikotu, Calba, calba orsalba

Tonic, carminative,appetizer, stimulant,treatment of stomachdisorders

Herbal tea Demirci et al. (2008)

Phlomis herba-venti L. Jaén (Spain) Pujas, Matagallos Veterinary antidiarrheicand soothe muscle pains

Only calyx are used Fernández-Ocana et al.(1996)

Phlomis linearis Boiss & Bal central to east andsoutheast Anatolya(Turkey)

NCa Aromatic aroma,carminative, stimulant


Phlomis linifolia Roth Danuwar (Nepal) Julfi jbar Fresh cuts and wounds,malarial fever

Juice of the plant, 3teaspoons twice a day, isgiven in the case ofmalarial fever. A paste ofthe plant is applied tofresh cuts and wounds.

Manandhar (2002)

Bangladesh Dondocolos, Hal-Kusa,Sheto drone

Appetizer, snakebite,headaches

Leaves are roasted andeaten with salt for loss ofappetite and insnakebite. Juice of leavesis employed inheadaches


Phlomis lycia D. Don Mugla (Turkey) Deli salba Appetizer, stimulant,tonic, stomach pain,carminative, dyspepticcomplaint

Herbal tea (inflorescenceand leaves)

Sarac and Ugur (2007)

Phlomis lychnitis L. Campo de Calatrava(Spain)

Candilera, Ierba tolciera Vulnerary,antirheumatic, analgesic,lithoxitic,antihemorrhoidal,astringent, carminative,stomachic and abdomenpains (antidiarrheicappetizer, digestive)

Infusion or decoctionprepared using flowredaerial part, as herbal tea

Rivera Núnez and ObónDe Castro (1993), Tardioet al. (2006), Pardo deSantayana et al. (2005),Vázquez et al. (1997),Fernández-Ocana et al.(1996)

Jaén (Spain) Té, Matagallo, Torcida

Té Amarillo Astringent Flower suckedMatagallo real For haemorrhage Flower infusion

For the nerves (tonic,sedative)

Leaves decoction

For circulation, varicosevein

The infusion was appliedby friction

Arrabida (Portugal) Salvinha Digestive, gastric,analgesic, intestinal,anti-inflammatory,analgesic, renalantispasmodic

Infusion Novais et al. (2004)

Phlomis nepetaefolia L. India Bara guma, Thanail Scalds, eating skindiseases and ring worms.

Flower heads ashesemployed in scalds,burns and eating skindiseases and ring wormsby mixing the ashes offlower heads with curds.Roots crushed andrubbed on the breastwhen it swell s and milkdoes not pass throw thenipples

Vardhana (2008)

Breast (when it swellsand milk does not passthrow the nipples)




References

Phlomis ocymifolia Burm. f. South-eastern andeastern Africa,northwards toKenya. The Gaut-eng/Mpumalangaregion, the Easternand Western CapeProvince

Klipdagga, lion’s ear,Umcwili

Diabetes, hypertension,anaemia, eczema and otherskin irritations, purgativeand emmenagogue.

Used mainly as anaqueous infusion ordecoction, taken orallyor applied externally.

Habtemariam et al. (1994)

Phlomis orientalis Boiss Iran Cheseleh Mouth anti-inflammatory Mojab et al. (2003)Phlomis plukenetii Roth Nepal Gumpate Fever, cough and colds Juice of the plant Manandhar (2002)

Phlomis purpurea L.subsp. purpurea

Spain Matagallo For prostate and livercomplaints

The infusion of aerialpart

González-Tejero et al. (1995)

Sweets flowers whichare sucked

Tardio et al. (2006)

Arrabida (Portugal) Candeeiros, Marioila, Cardiotonic, antidiarrhoeic,for abdominal pain,digestive, gastric analgesic,intestinal anti-inflammatory,antihelmantic, emetic, forsea–sickness, for colds’prevention, renalantispasmodic, for bladderaliments, hepatic protector,for stomach ulcers, forgastritis

Infusion Novais et al. (2004)

Fever, cough and colds Olive oil decoction

Phlomis purpurea L. subsp.almeriensis (Pau) Losa andRivas Goday

Murcia (Spain) Oreja de liebre Diuretic, lithotritic NCa Rivera Núnez and Obón DeCastro (1993)

Phlomis rotata Benth. exHook. f.

Tibet Takpak Accumulation of serousfluids in the bone, skin andwound, headache, fever,cough, worm infections andswelling caused by cold.Promotes blood circulation.Eliminates blood stasis.Anti-inflammatory. Relievespains.

Leaf and flowerdecoctions are used forbone fracture, pain inligaments, and sinus

Pandey (2006), Zhang et al.(1991)

Phlomis russeliana (Sims.)Bentham

Bolu (Turkey) Ballıkotu, Calba, Calba orSalba

Tonic, carminative, appetizer,stimulant


Phlomis spinidens Nevski Japan Kuz kulok Antiallergic NCa Takeda et al. (2001)Phlomis syriaca Boiss Syria Zahraab Facilitate the digestion and

promotes good healthHerbal tea: Zahraa is acomplex mixture of sixto fourteen differentspecies like Rosadamascena Mill, Zeamays L, Phlomis syriacaBoiss. . .

Carmona et al. (2005)

Phlomis tuberosa L. Iran NCa Culinary use Leaves are grilled Naghibi et al. (2005)

Phlomis umbrosa Turcz.Bull

Korea Sok-dan Haemostatic, tineapedis,antihepatotoxic

NCa WHO Regional Publicationswestern Pacific Series NO 21(1998)

Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan(PJBH)b

Nourishes the kidney andconsolidates essencec, thusactivating brain function,promoting memory andlengthening life span.

PJBH is a decoction witheighteen dried herbsincluding the wholeplant of Dendrobiummoniliforme L., Phlomisumbrosa, fruits of Torilisjaponica Thunb,

Adams et al. (2007)

North China Cold The rhizome treat cold,been used to reduceswelling and staunchbleeding,anti-inflammatory anddetoxification properties

Liu et al. (2007)

Phlomis younghushandiiMukerjee

Tibet Lug mur Reproduction and sexualhealth, alleviates fever ofchest, common colds

Herbal tea Law and Salick (2007)

Phlomis zeylanica L Bangladesh Guma-guma Scabies, skin-diseases, inheadache and cold, snakebite

Juice of whole plant isused in scabies,skin-diseases, inheadache and cold. Thejuice of the leaves issniffed of as a remedy forsnakebite

Khanam and Abul Hassan(2005)

a NC: not cited.b The indicated name is not a common name of the plant but the name of the herbal mixture where they are included.c Essence or “jing”: means something specific of Korean traditional medicine.


Table 2Main essential oil constituents of Phlomis genus.

Species Monoterpene Sesquiterpene Fatty acids, aliphaticcompounds and alcohols

References

Chemotype that contains sesquiterpenePhlomis anisodonta Germacrene D (65.0%),

�-caryophyllene (11.0%)Sarkhail et al. (2005)

Phlomis bruguieri Germacrene D (60.5%),�-elemene (16.5%),germacrene B (7.1%),bicyclogermacrene (4.1%).

Sarkhail et al. (2005)

Phlomis cretica(verticillasters)

Germacrene D (34.0%),germacrene B (11.0%)

Basta et al. (2006)

Phlomis linearis (AP/H) �-Caryophyllene (24.2%),germacrene D (22.3%),caryophyllene oxide (9.2%)

Demirci et al. (2009)

Phlomis crinita ssp.mauritanica (leaves)(FAP/H)

trans-Caryophyllene(40.9%), germacrene D(39.1%)

Limem-Ben Amor et al.(2008)

Phlomis crinita ssp.mauritanica (flowers)(FAP/H)

�-Caryophyllene (58.2%),germacrene D (35.1%)

Limem-Ben Amor et al.(2008)

Phlomis russeliana(DAP/H)

�-Caryophyllene (22.6%),germacrene D (15.1%),caryophyllene oxide (8.1%)


Phlomis samia (FFAP/H) (E)-�-farnesene (20.7%),germacrene D (6.3%),�-caryophyllene (5.8%),caryophyllene oxide (3.2%),spathulenol (3.7%)

Aligiannis et al. (2004)

Phlomis grandiflora var.grandiflora (DAP/H)

�-Eudesmol (42.0%),�-eudesmol (16.1%)


Phlomis viscosa (DAP/H) Germacrene D (33.9%),bicyclogermacrene (15.3%)and (Z)-p-farnesene(10.7%)

Nese et al. (2006)

Phlomis olivieri (DAP/H) Germacrene D (26.4%) andbicyclogermacrene (12.7%).

Mohammad et al. (2005)

Chemotype that contains fatty acid, aliphatic compound and alcoholPhlomis szechuanensis(DAP/H)

trans-Phytol (50.8%),9,12,15-octadecatrienoicacid methyl ester (11.0%),hexadecanoic acid (7.1%),9,12-octadecadienoic acidmethyl ester (3.9%),hexadecanoic acid methylester (2.9%),9,12,15-octadecatrien-1-ol(2.2%), isophytol (1.6%)

Zhang and Wong (2008)

Phlomis umbrosa (DAP/H) Hexadecanoic acid (52.1%),9,12,15-octadecatrien-1-ol(24.8%), trans-phytol (5.7%),9,12-octadecadienoic acid(2.5%),9,12,15-octadecatrienoicacid methyl ester (1.8%),hexahydrofarnesyl acetone(1.8%)


Phlomis younghunsbandii Hexadecanoic acid,trans-phytol,9,12,15-octadecatrien-1-ol


Chemotype that contains monoterpene and sesquiterpenePhlomis bovei subsp.bovei (DAP/H)

Thymol (8.3%) Germacrene D (21.4%),�-caryophyllene (7%),�-bournonene (2.9%),hexahydrofarnesyl acetone(5.8%)

Liolios et al. (2007)

Phlomis chimerae(FDAP/H)

�-Pinene (5.5%), linalool(4.7%)

�-Caryophyllene (31.6%),germacrene D (6.1%),�-cadinene (5.0%),caryophyllene oxide (4.8%)

Celik et al. (2005)

Phlomis cretica (FFAP/H) �-Pinene (9.4%), linalool(7.5%), limonene (7.1%),cis-�-ocimene (5.4%)



Phlomis cretica (leaf) �-Pinene (11.2%) Germacrene D (47.9%) Basta et al. (2006)Phlomis fruticosa(DFAP/H) (sunny locality)

�-Pinene (38.9%),1,8-cineole (8.1%),limonene (2.1%), �-thujone(2%)

�-Caryophyllene (8.7%) Ristic et al. (2000)




References

Phlomis fruticosa(DFAP/H) (forest locality)

�-Pinene (56.6%),1,8-cineole (10.4%),limonene (2.2%), �-thujene(2.3%)

�-Caryophyllene (2%) Ristic et al. (2000)

Phlomis fruticosa(FFAP/H)

�-Pinene (12,6%), linalool(8%)

�-Caryophyllene (12.6%),germacrene D (21.4%),(Z)-�-bisabolene (7.1%)


Phlomis grandiflora var.grandiflora (DFAP/H)

�-Pinene (2.4%), limonene(2.7%)

Germacrene D (45.4%),�-caryophyllene (22.8%),bicyclogermacrene (4.9%)

Celik et al. (2005)

Phlomis lanata (FAP/H) �-Pinene (25.41%),limonene (15.67%)

trans-Caryophyllene(8.76%)

Couladis et al. (2000)

Phlomis lanceolata �-Pinene (8.7%) Germacrene D (47.0%),(E)-�-farnesene (10.5%),germacrene B (8.0%),bicyclogermacrene (5.9%)


Phlomis leucophracta(FDAP/H)

�-Pinene (19.2%), limonene(11.0%)


Celik et al. (2005)

Phlomis olivieri (ADAP/H) �-Pinene (11.7%) Germacrene D (28.1%),�-caryophyllene (16.1%),�-selinene (10.2%),bicyclogermacrene (7.4%),�-selinene (4.1%),�-cadinene (3.6%)�-elemene (3.5%),�-bourbonene (3.4%),�-humulene (2.7%)

Mirza and Baher Nik (2007)

Phlomis olivieri (FAP/H) �-Pinene (4.2%). Germacrene D (66.1%),�-selinene (5.1%),�-caryophyllene (4.2%)


Phlomis persica (DAP/H) �-Pinene (13.3%) Germacrene D (38.2%),bicyclogermacrene (16.3%)

Mohammad et al. (2005)

Chemotype that contains terpene, fatty acid, aliphatic compound and alcoholPhlomis megalantha(DAP/H)

�-Linalool (3.8%) Hexadecanoic acid (46.0%),9,12,15-octadecatrien-1-ol(24.8%), trans-phytol (5.7%),9,12-octadecadienoic acid(2.5%),9,12,15-octadecatrienoicacid methyl ester (1.8%),�-terpineol (1.5%)


Phlomis herba-venti L.(flower oil) (DAP/H)

Germacrene D (6.7%) Hexadecanoic acid (33.1%),6,10,14-trimethylpentadecan-2-one (16.2%),3-methyltetradecane (6.7%)

Morteza-Semnani et al.(2004)

Phlomis bruguieri Desf(DFAP)

�-Pinene (6.8%) Germacrene D (23.6%),�-caryophyllene (6.7%)

4-Hydroxy-4-methyl-2-pentanone(15.0%)

Morteza-Semnani, Saeedi(2005)

Phlomis herba-venti L.(leaf oil) (DAP/H)

�-Pinene (9.4%) Germacrene D (33.9%) Hexadecanoic acid (12.9%) Morteza-Semnani et al.(2004)

Phlomis viscosa Poiret(DFAP/H)

�-Caryophyllene (24.4%),germacrene D (4.7%),alloaromadendrene (11%),�-humulene (6,1%)

�-Monocyclofarnesylacetone(16.44%)

Karaman andCömlekciogolu (2007)

Phlomis lunariifolia �-Cubebene (2%),�-copaene (1,5%)

�-Caryophyllene (9%),(Z)-�-farnesene (6.5%),germacrene D (7.7%),bicyclogermacrene (2.6%),�-cadinene (1.7%),ar-curcumene (1.8%),caryophyllene oxide (1.2%)

Selina-4,11-diene((1/4)4,11-eudesmadiene)(2%), spathulenol (3.9%),�-cadinol (1.2%), 8 (14),15-isopimaradien-11-�-ol(5.5%), hexadecanoic acid(9.7%)


Phlomis amaniaca �-Pinene (2.1%) (Z)-�-Farnesene 8,3%,germacrene D (14.7%),bicyclogermacrene (10.7%)

Globulol (1.5%), Viridiflorol(1.1%), Spathulenol (6.3%),�-Cadinol (1.4%),15-Isopimaradien-11-�−ol(22.8%)


Phlomis monocephala �-Pinene (4.9%) Limonene (3.9%),�-caryophyllene (5.1%),(Z)-�-farnesene (3.1%),germacrene D (6%),bicyclogermacrene (1.5%),caryophyllene oxide (1.2%)

Selina-4,11-diene((1/4)4,11-eudesmadiene)(2.9%), spathulenol (3.8%),�-cadinol (1.2%),sandracopimaradiene(1.1%), manoyl oxide (6.1%),15-Isopimaradien-11�ol(12.7%), hexadecanoic acid(1.7%)





References

Phlomis sieheana �-Caryophyllene (1.1%),�-bourbonene (1.5%),�-elemene (1.4%),(Z)-�-farnesene (11.7%),(E)-�-farnesene (1.6%),germacrene D (16.6%),�-selinene (6.7%),�-selinene (1,5%),bicyclogermacrene (1.6%)

Hexahydrofarnesyl acetone(1.9%), spathulenol (3%),�-cadinol (1.4%), tricosane(1.1%), pentacosane (1.1%),dodecanoic acid (1.8%),heptacosane (1.2%),hexadecanoic acid (2.1%)


Phlomis armeniaca (Z)-�-Farnesene (6.2%),�-bourbonene (1.1%),(E)-�-farnesene (1.2%),germacrene D (23.4%),�-selinene (2.6%),bicyclogermacrene (2.3%)

Hexahydrofarnesyl acetone(2.3%), spathulenol (1.9%),�-cadinol (1.2%),4-methoxycarbonyl-7-methylcyclopenta[c]pyrane(1.4%), pentacosane (2.5%),dodecanoic acid (1.4%),heptacosane (2.3%),nonacosane (1.2%),hexadecanoic acid (4.9%)


Phlomis bruguieri (DAP) �-Pinene (6.8%) Germacrene D (23.6%),llene

4-Hydroxy-4-methyl-2- Morteza-Semnani and

F drodi

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4

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4

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�-caryophy

AP: fresh aerial part; DAP: dried aerial part, FDAP; flowered dried aerial part; H: hy

.4. Specific culinary use of some Phlomis species

Several Phlomis species have culinary uses. For example, theeaves of Phlomis fruticosa are browned in olive oil or butter or inacon fat and used to prepare a sauce for paste in Italy (Lentini andenza, 2007).

. Secondary metabolites of Phlomis species

Phytochemical investigations of Phlomis species were theubject of several studies, and, consequently, essential oils (summa-ized in Table 2), flavonoids, iridoids, phenylethylalcohol glycosidesnd other components were isolated (summarized in Table 3).

.1. Essential oils

The essential oils from many Phlomis species has been studiedy means of gas chromatography coupled to mass spectrometryGC–MS) techniques. From the data reported in Table 2, we can seeariable oil compositions. Indeed, these differences often separatehlomis species into four chemotypes:

the first chemotype is rich in sesquiterpene: in this group, thetwo main components are redundant; germacrene D (1) and �-caryophyllene (2) (Fig. 1) (Sarkhail et al., 2005; Basta et al., 2006;Demirci et al., 2008; Limem-Ben Amor et al., 2008);the second is rich in monoterpene and sesquiterpene: the maincomponents of this class are �-pinene (3), limonene (4), linalool(5), germacrene D (1) and �-caryophyllene (2) (Fig. 1) (Ristic etal., 2000; Aligiannis et al., 2004; Celik et al., 2005; Liolios et al.,2007);fatty acids, aliphatic compounds and alcohol (diterpenoicalcohol, fatty acid alcohol, . . .) constitute the main compo-nents of the third chemotype: this group contains a highpercentage of hexadecanoic acid (6), trans-phytol (7) and 9,12,15-octadecatrien-1-ol (8) (Fig. 1) (Zhang and Wong, 2008);
the last chemotype is rich in terpene, fatty acids, aliphaticcompounds and alcohol (diterpenoic alcohol, fatty acid alco-hol, . . .) as its main constituents: this mixed group containshexadecanoic acid (6), �-pinene (3) and germacrene D (1)as major fatty acid, monoterpene and sesquiterpene, respec-
(6.7%). pentanone(15.0%)

Saeedi (2005)

stillation.

tively (Zhang and Wong, 2008; Morteza-Semnani et al.,2004).

It is possible that the chemical differentiation of essentialoils for Phlomis species is correlated to the existence of manychemotypes, provoked either by different climatic factors, or asa result of pollination caused by genetic differences (intraspecificor intrapopulation crosspollination). The considerable differencesamong Phlomis species may depend on the extraction procedure,the season, the stage of development and the distinct habitat inwhich the plant has been collected. It can be concluded that thecomposition of oils varies greatly with respect to the geographi-cal proximity (different species collected in the same region havesimilar compositions), mainly for the proportion of aliphatic com-pounds and terpenoids. All of these differences suggest furtherinvestigations on other Phlomis species may further confirm theirbiodiversity (Zhang and Wong, 2008).

4.2. Flavonoids

As can be seen in Table 3, flavonoids are the major phyto-constituents isolated from the Phlomis genus. These includeapigenin (9), luteolin (10), naringenin (11), eriodictyol (12), chryse-riol (13), kaempferol (14) and their glycosides (Fig. 1). The majorityof flavonoids identified in Phlomis genus are flavones, flavonolsand frequently 7- or 3-glycosylated. Luteolin-7-glucoside, luteolin-7-O-�-glucopyranoside, chrysoeriol-7-p-coumaroylglucosideand chrysoeriol-7-glucoside constitute the most commonlyglycosylated flavonoids founded in the Phlomis genus (El-Negoumy et al., 1986; Kyriakopoulou et al., 2001; Marin et al.,2007).

The flavone glycoside, tricin 7-O-glucoside, which is found inPhlomis fruticosa is rather unusual in the Lamiaceae family, buthas been reported previously from the Stachys subgenus Betonica(Marin et al., 2004). The flavonoid glycosides 7-O-glucosides, 7-O-glucuronides and 7-rutinoside, of apigenin (9), luteolin (10) and
chrysoeriol (13), the flavone C-glycoside vicenin-2 (15) and the fla-vanones, naringenin (11) and eriodictyol (12) (Fig. 1) (Hegnauer,1989; Tomas-Barberan et al., 1992) occur in the majority of Phlomisspecies (Azizian and Cutle, 1986; Barberan, 1986) and in the Lami-aceae family. Flavone p-coumaroylglycosides appears to be a unique


Table 3Compounds identified in Phlomis species.

Compounds Species References

FlavonoidsAcacetin-7-O-�-glucopyranoside Phlomis aurea Mohamed et al. (2000)

Apigenin Phlomis lychnitis Tomas et al. (1986)Phlomis samia Kyriakopoulou et al. (2001)

Apigenin-7-glucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccose El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)

Apigenin-7-rutinoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccose El-Negoumy et al. (1986)

Apigenin-7-p-coumaroylglucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccose El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)

Astragalin Phlomis spinidens Takeda et al. (2001)

Chryseriol Phlomis lychnitis Tomas et al. (1986)Phlomis samia Kyriakopoulou et al. (2001)Phlomis fruticosa Marin et al. (2007)

Chryseriol-7-glucuronide Phlomis fruticosa Marin et al. (2007)

Chrysoeriol-7-glucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)Phlomis fruticosa Marin et al. (2007)Phlomis caucasica Delazar et al. (2008)

Chrysoeriol-7-rutinoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis caucasica Delazar et al. (2008)

Chryseriol-7-rhamnosylglucoside Phlomis fruticosa Marin et al. (2007)

Chrysoeriol-7-p-coumaroylglucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)Phlomis purpurea Tomas-Barberan et al. (1992)Phlomis fruticosa Marin et al. (2007)Phlomis fruticosa Marin et al. (2007)Phlomis crinita Kabouche et al. (2005)

Chrysoeriol 7-O-(3′′-p-coumaroyl)-�-glucosideChrysoeriol-7-O(6′′-�-d-apiofuranosyl)-�-d-glucopyranoside Phlomis nisssoli Bucar et al. (1998)

Chrysoeriol-7-O-�-glucopyranoside Phlomis aurea Mohamed et al. (2000)Phlomis integrifolia Saracoglu et al. (2003)Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Eriodictyol Phlomis fruticosa Marin et al. (2007)Ermanin Phlomis samia Kyriakopoulou et al. (2001)Hesperetin Phlomis fruticosa Marin et al. (2007)Hispidulin-7-glucoside Phlomis aurea El-Negoumy et al. (1986)Isoquercitrin Phlomis spinidens Takeda et al. (2001)Isorhamnetin-3-p-coumaroylglucoside Phlomis purpurea Tomas-Barberan et al. (1992)

Kaempferol-3-glucosides Phlomis spectabilis Kumar et al. (1985)Phlomis caucasica Delazar et al. (2008)

Kaempferol-3-p-coumaroylglucoside Phlomis purpurea Tomas-Barberan et al. (1992)Kaempferol-3-(6′′-(E)-p-coumaroyl)glucosides Phlomis spectabilis Kumar et al. (1985)Kaempferol (7,4′dimethyl ether)-3-glucoside Phlomis spectabilis Kumar et al. (1985)Kaempferol (7,4′dimethyl ether)-3-(6′′-(E)-p-coumaroyl)glucosides Phlomis spectabilis Kumar et al. (1985)Kaempferol-3-O-�-d-glucopyranosyl-(1-6)-�-d-glucopyranoside Phlomis aurea Aboutabl et al. (2002)

Lucenin-2 Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)

Luteolin Phlomis lychnitis Tomas et al. (1986)Phlomis crinita Kabouche et al. (2005)

Luteolin-7-glucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)Phlomis purpurea Tomas-Barberan et al. (1992)Phlomis fruticosa Marin et al. (2007)

Luteolin-7-rutinoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccose El-Negoumy et al. (1986)




Luteolin-7-diglucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccose El-Negoumy et al. (1986)

Luteolin-7-p-coumaroylglucoside Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis lychnitis Tomas et al. (1986)Phlomis fruticosa Marin et al. (2007)

Luteolin-7-glucuronide Phlomis fruticosa Marin et al. (2007)Luteolin-7-rhamnosylglucoside Phlomis fruticosa Marin et al. (2007)Luteolin-7-O-[4-O-acetyl-�-rhamnopyranosyl-(1→2)]-�-glucuronopyranoside Phlomis lunariifolia Calis and Kirmizibekmez (2004)

Luteolin-7-O-�-glucopyranoside Phlomis aurea Mohamed et al. (2000)Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis brunneogaleata Kirmizibekmez et al. (2004)Phlomis crinita Kabouche et al. (2005)Phlomis tuberosa Calis et al. (2005)Phlomis younghusbandii Gao et al. (2007)

Luteolin-7-O-(6′′-�-d-apiofuranosyl)-�-d-glucopyranoside Phlomis nisssoli Bucar et al. (1998)

Naringenin Phlomis angustissima Yalcin et al. (2005)Phlomis fruticosa Marin et al. (2007)Phlomis caucasica Delazar et al. (2008)

Naringenin-7-glucoside Phlomis aurea El-Negoumy et al. (1986)Naringenin-7-p-coumaroylglucoside Phlomis aurea El-Negoumy et al. (1986)Phlomisflavosides A Phlomis spinidens Takeda et al. (2001)Phlomisflavosides B Phlomis spinidens Takeda et al. (2001)Quercetin-3-O-�-d-glucopyranoside Phlomis aurea Aboutabl et al. (2002)Rutin Phlomis caucasica Delazar et al. (2008)Tricin-7-glucoside Phlomis fruticosa Marin et al. (2007)

Vicenin-2 Phlomis aurea El-Negoumy et al. (1986)Phlomis floccosa El-Negoumy et al. (1986)Phlomis fruticosa Marin et al. (2007)

Iridoids8-O-Acetylshanzhiside Phlomis tuberose Ersöz et al. (2001b)

8-O-Acetylshanzhiside methyl ester Phlomis rigida Takeda et al. (2000)Phlomis spinidens Takeda et al. (2001)Phlomis medicinalis Yu et al. (2006)Phlomis umbrosa Liu et al. (2007)Phlomis younghusbandii Gao et al. (2007)

8-Acetylshanzhigenin methyl ester and 8-acetyl-1-epishanzhigenin methyl ester Phlomis umbrosa Guo and Cheng (2001)6-O-Acetyl-shanzhiside methyl ester Phlomis medicinalis Yu et al. (2006)

Auroside Phlomis linearis Calis et al. (1991)Phlomis aurea Mohamed et al. (2000), Aboutabl et

al. (2002)Phlomis angustissima Yalcin et al. (2005)

Barlerin 141 Phlomis rotata Zhang et al. (1991)Barlerin (8-O-acetylshanzhiside methyl ester) Phlomis younghusbandii Kasai et al. (1994)Brunneogaleatoside Phlomis brunneogaleata Kirmizibekmez et al. (2004)Chlorotuberoside Phlomis tuberosa Calis et al. (2005)

Dehydropentstemoside Phlomis rotata Zhang et al. (1991)Phlomis medicinalis Yu et al. (2006)

Deoxypulcheloside I Phlomis rigida Takeda et al. (2000)

5-Deoxypulchelloside I Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis lunariifolia Calis and Kirmizibekmez (2004)

5-Desoxysesamoside Phlomis tuberosa Alipieva et al. (2000), Calis et al.(2005)

3-Epiphlomurin Phlomis aurea Mohamed et al. (2000)8-Epiloganin Phlomis grandiflora var. grandiflora Takeda et al. (1999)

Phlomis aurea Mohamed et al. (2000), Aboutabl etal. (2002)

6-�-hydroxyipolamide Phlomis rigida Takeda et al. (2000)

Ipolamiide Phlomis linearis Calis et al. (1991)Phlomis armeniaca Saracoglu et al. (1995)Phlomis aurea Mohamed et al. (2000)Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Lamalbide Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis tuberosa Alipieva et al. (2000), Ersöz et al.

(2001b), Calis et al. (2005)




Lamiide Phlomis linearis Calis et al. (1991)Phlomis aurea Mohamed et al. (2000), Aboutabl et

al. (2002)Phlomis herba-ventis ssp. pungens Alipieva et al. (2000)Phlomis pungens var. pungens Ismailoglu et aL. (2002)Phlomis physocalycoside Ersöz et al. (2003)Phlomis angustissima Yalcin et al. (2005)

Lamiridoside Phlomis rigida Takeda et al.(2000)Phlomis spinidens Takeda et al. (2001)

Penstemoside Phlomis younghusbandii Kasai et al. (1994)

Phlomiol Phlomis longifolia var. longifoliaPhlomis younghusbandii

Ersöz et al. (2001a)

Gao et al. (2007)

Phlomiside (=gentiobioside) Phlomis aurea Aboutabl et al. (2002)Phlomurin Phlomis aurea Mohamed et al. (2000)Phlorigidoside A (2-O-acetyllamiridoside) Phlomis rigida Takeda et al. (2000)Phlorigidoside B (8-O-acetyl-6-�-hydroxyipolamide) Phlomis rigida Takeda et al. (2000)

Phlorigidoside C (5-deoxysesamoside) Phlomis rigida Takeda et al. (2000)Phlomis spinidens Takeda et al. (2001)

Phloyosides I (7-epiphlomiol) Phlomis rotata Zhang et al. (1991)Phlomis younghusbandii Kasai et al. (1994)Phlomis mongolica Li and Zhang (2000)Phlomis tuberosa Calis et al. (2005)Phlomis medicinalis Yu et al. (2006)Phlomis umbrosa Liu et al. (2007)

Phloyosides II Phlomis younghusbandii Kasai et al. (1994)Phloyosides II Phlomis mongolica Li and Zhang (2000)Pulchelloside-I Phlomis younghusbandii Gao et al. (2007)

Sesamoside Phlomis tuberosa Alipieva et al. (2000), Calis et al.(2005)

Phlomis younghusbandii Kasai et al. (1994), Gao et al. (2007)Phlomis medicinalis Yu et al. (2006)

Shanzhigenin methyl ester and 1-epishanzhigenin methyl ester Phlomis umbrosa Guo and Cheng (2001)

Shanzhiside methyl ester Phlomis rotata Zhang et al. (1991)Phlomis younghusbandii Kasai et al. (1994), Gao et al. (2007)Phlomis rigida Takeda et al. (2000)Phlomis spinidens Takeda et al. (2001)Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis tuberosa Ersöz et al. (2001b), Alipieva et al.

(2000), Calis et al. (2005)Calis and Kirmizibekmez (2004)

Phlomis lunariifolia Yu et al. (2006)Phlomis medicinalis Liu et al. (2007)Phlomis umbrosa

6′′-Syringyl-sesamoside Phlomis umbrosa Liu et al. (2007)Phenylethyalcohol glycosides

Acteoside = verbascoside Phlomis armeniaca Saracoglu et al. (1995)Phlomis grandiflora var. grandiflora Takeda et al. (1999)Phlomis aurea Mohamed et al. (2000)Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis tuberosa Ersöz et al. (2001b), Calis et al.

(2005)Phlomis samia Kyriakopoulou et al. (2001)Phlomis phsocalys Ersöz et al. (2003)Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis brunneogaleata Kirmizibekmez et al. (2004)Phlomis crinita Kabouche et al. (2005)Phlomis umbrosa Liu et al. (2007)Phlomis caucasica Delazar et al. (2008)Phlomis lanceolata Nazemiyeh et al. (2008)

Decaffeoylacteoside Phlomis tuberosa Calis et al. (2005)Phlomis umbrosa Liu et al. (2007)

Dimethylether myricoside Phlomis oppostiflora Calis et al. (2005)Echinacoside Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Forsythoside B Phlomis armeniaca Saracoglu et al. (1995)Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis tuberosa Ersöz et al. (2001b), Calis et al.

(2005)




Phlomis spinidens Takeda et al. (2001)Phlomis aurea Aboutabl et al. (2002)Phlomis pungens var. pengens Ismailoglu et al. (2002)Phlomis phsocalys Ersöz et al. (2003)Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis brunneogaleata Kirmizibekmez et al. (2004)Phlomis caucasica Delazar et al. (2008)Phlomis lanceolata Nazemiyeh et al. (2008)

Glucopyranosyl-(1→G (i)-6)-martynoside Phlomis brunneogaleata Kirmizibekmez et al. (2004)3-Hydroxy-4-methoxy-�-phenylethoxy-O-[2,3-diacetyl-�-l-rhamnopyranosyl-(1→3)]-4-O-feruloyl-[�-d-apio-furapiofuranosyl-(1→6)]-�-d-glucopyranoside(2′′ ′ ,3′′ ′-diacetyl-O-detonyosideD)

Phlomis umbrosa Liu et al. (2007)

3-Hydroxy-4-methoxy-�-phenyle thoxy-O-[3,4-diacetyl-�-l-rhamnopyranosyl-(1→3)]-4-O-feruloyl-[�-d-apiofuranosy-(1→6)]-�-d-glucopyranoside(3′′ ′ ,4′′ ′-diacetyl-O-betonyosideD)

Phlomis umbrosa Liu et al. (2007)

Isoverbascoside Phlomis brunneogaleata Kirmizibekmez et al. (2004)Phlomis umbrosa Liu et al. (2007)

Integrifoliosides A (3,4-dihydroxy-�-phenylethoxy-O-�-d-apiofuranosyl-(1→4)-�-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-�-d-glucopyranoside)

Phlomis integrifolia Saracoglu et al. (2003)

Integrifoliosides B (3-hydroxy-4-methoxy-�-phenylethoxy-O-�-d-apiofuranosyl-(1→4)-�-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-�-d-glucopyranoside)

Phlomis integrifolia Saracoglu et al. (2003)Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Leucosceptoside A Phlomis armeniaca Saracoglu et al. (1995)Phlomis longifolia var. longifolia Ersöz et al. (2001a)Phlomis physocalyx Ersöz et al. (2003)Phlomis tuberosa Calis et al. (2005)

Martynoside Phlomis physocalyx Ersöz et al. (2003)Myricoside Phlomis oppostiflora Calis et al. (2005)Myricoside-3′′-O-methylether{3,4-dihydroxy-�-phenylethoxy-O-�-d-apiofuranosyl-(1→>3)-�-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-�-d-glucopyranoside}

Phlomis oppostiflora Calis et al. (2005)

2-Phenylethyl-O-�-Xylopyranosyl-(1→2)-�-glucopyranoside Phlomis aurea Mohamed et al. (2000)Phlomisethanoside Phlomis grandiflora var. grandiflora Takeda et al. (1999)Physocalycoside (3-hydroxy-4-methoxy-�-phenylethoxy-O-[�-l-rhamnopyranosyl-(1→2)-�-l-rhamnopyranosyl-(1→3)]-4-O-feruloyl-[�-d-glucopyranosyl-(1→6)]-�-d-glucopyranoside)

Phlomis physocalycoside Ersöz et al. (2003)

Samioside Phlomis angustissima Yalcin et al. (2005)

Samioside (1-O-3.4-(dihydroxyphenyl)ethyl �-d-apiofuranosyl-(1→4)-�-l-rhamnopyranosyl-(1→3)-4-O-caffeoyl-�-d-glucopyranoside)

Phlomis samia Kyriakopoulou et al. (2001)Phlomis umbrosa Liu et al. (2007)

Serratumoside A {3-hydroxy,4-methoxy-�-phenylethoxy-O-�-d-apiofuranosyl-(1→3)-�-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-�-d-glucopyranoside}


Wiedemannioside C Phlomis physocalyx Ersöz et al. (2003)

Alyssonoside Phlomis pungens var. pengens Ismailoglu et al. (2002)Phlomis integrifolia Saracoglu et al. (2003)Phlomis angustissima Yalcin et al. (2005)Phlomis umbrosa Liu et al. (2007)

Cistanoside B Phlomis mongolica Li and Zhang (2000)Phlinoside A (3,4-dihydroxy-�-phenylethoxy-O-�-d-glucopyranosyl-(1→2)-�-l-rhamnopyranosyl-(1→3)-4-O-caffeoyl-�-d-glucopyranoside)

Phlomis linearis Calis et al. (1990)

Phlinoside B (3,4 dihydroxy-�-phenylethoxy-0-�-d-xylopyranosyl-(1→2)-�-l-rhamnopyranosyl-(1→3)-4-O-caffeoyl-�-d-glucopyranoside)

Phlomis linearis Calis et al. (1990)Phlomis armeniaca Saracoglu et al. (1995)

Phlinoside C (3,4-dihydroxy-�-phenylethoxy-O-�-l-rhamnopyranosyl-(1→2)-�-l-rhamnopyranosyl-(1→3)-4-0-caffeoyl-�-d-glucopyranoside)

Phlomis linearis Calis et al. (1990)Phlomis armeniaca Saracoglu et al. (1995)Phlomis lanceolata Nazemiyeh et al. (2008)

Phlinoside D (3,4-dihydroxy-�-phenylethoxy-O-�-d-xylopyranosyl-(1→2)-�-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-�-d-glucopyranoside)


Phlinoside E (3,4-dihydroxy-�-phenylethoxy-O-�-l-rhamnopyranosyl (l→2)-�-l-rhamnopyranosyl-(l→3)-4-O-feruloyl-�-d-glucopyranoside)


Phlinoside F (�-(3-hydroxy,4-methoxyphenyl)ethyl-O-[�-xylopyranosyl(1→2)-�-rhamnopyranosyl-(1→3)]-O-4-O-feruloyl-�-glucopyranoside

Phlomis angustissima Yalcin et al. (2005)

Teucrioside Phlomis armeniaca Saracoglu et al. (1995)

Acetophenone glycosides4-Hydroxyacetophenone 4-O-(6′-O-�-d-apiofuranosyl)-�-d-glucopyranosideAcridone alkaloidDaucosterol Phlomis younghusbandii Gao et al. (2007)Aliphatic alcohol glycosideLunaroside-1-octen-3-yl-O-�-apiofuranosyl-(1→6)-O-[�-glucopyranosyl-(1→2)]-�-glucopyranoside

Phlomis lunariifolia Calis and Kirmizibekmez (2004)




Benzyl alcohol glycosidesBenzyl alcohol-O-�-xylopyranosyl-(1→2)-�-glucopyranoside Phlomis aurea Mohamed et al. (2000)Caffeic acid esters

Chlorogenic acid Phlomis brunneogaleata Kirmizibekmez et al. (2004)Phlomis longifolia var. Longifolia Ersöz et al. (2001a)

3-O-Caffeoylquinic acid methyl ester Phlomis brunneogaleata Kirmizibekmez et al. (2004)5-O-Caffeoylshikimic acid Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Diterpenoid glycosyl estersBaiyunoside Phlomis medicinulis Katagari et al. (1991)Phlomisoside I Phlomis younghusbandii Katagari et al. (1991), Kasai et al.

(1994)Phlomisoside II Phlomis medicinalis Katagari et al. (1991)

Phlomisoside III (�-d-xylopyranosyl(l→2)-�-d-glucopyranosylester-15,16-epoxy-8,13 (16),14-labdatrien-19-oic acid)

Phlomis younghusbandii Katagari et al. (1991), Kasai et al.(1994)

Phlomis medicinalis

Phlomisoside IV (�-l-rhamnopyranosyh (1→2)-�-d-glucopyranosylester-15,16-epoxy-8,13 (16),14-labdatrien-19-oic acid)

Phlomis younghusbandii Katagari et al. (1991), Kasai et al.(1994)

LignansLariciresinol-4′-O-�-d-glucoside Phlomis spinidens Takeda et al. (2001)

Liriodendrin Phlomis aurea Mohamed et al. (2000)Phlomis brunneogaleata Kirmizibekmez et al. (2004)

Megastigmane glucosidesCitroside Phlomis grandiflora var. grandiflora Takeda et al. (1999)

Phlomis spinidens Takeda et al (2001)

Phlomuroside Phlomis aurea Mohamed et al. (2000)Phlomis lunariifolia Calis and Kirmizibekmez (2004)

Monoterpen glycosidesBetulalbuside A Phlomis armeniaca Saracoglu et al. (1995)


8-Hydroxylinaloyl 3-O-�-d-glucopyranoside Phlomis armeniaca Saracoglu et al. (1995)

Neolignan glucosidesDehydrodiconiferylalcohol 9′-O-�-d-glucopyranoside Phlomis lunariifolia Calis and Kirmizibekmez (2004)

Phlomis tuberosa Calis et al. (2005)

(7S, 8R)-Dehydroconiferyl alcohol-8-5′-dehydroconiferyl aldehyde4-O-�-d-glucopyranoside


Dihydrodehydrodiconiferyl alcohol-9-O-�-d-glucopyranoside Phlomis chimerae Ersöz et al. (2002)Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis tuberosa Calis et al. (2005)

Dihydrodehydrodiconiferyl alcohol 9′-O-�-d-glucopyranoside Phlomis lunariifolia Calis and Kirmizibekmez (2004)Phlomis tuberosa Calis et al. (2005)

Longifloroside A ((−)-4-O-methyldehydrodiconiferylalcohol-9′-O-�-d-glucopyranoside)

Phlomis chimerae Ersöz et al. (2002)

(−)-4-O-Methyldihydrodehydrodiconiferyl alcohol-9′-O-�-d-glucopyranoside Phlomis chimerae Ersöz et al. (2002)

Nortriterpens28-Noroleana-16,21-diene-3�,19 �,23,29-tetrol Phlomis spectabilis Kumar et al. (1992)28-Noroleana-l6,21-diene-3 �,19 �,29-triol-23-al. Phlomis spectabilis Kumar et al. (1992)(17S)-2�,18 �,23-Trihydroxy-3,19-dioxo-19(18→17)-abeo-28-norolean-12-en-25-oicacid �-d-glucopyranosyl ester

Phlomis viscosa Calis et al. (2004)

Oleanane-type triterpen glycosides29-(�-d-glucopyranosyloxy)-2�,3 �,23-trihydroxyolean-12-en-28-oic acid Phlomis viscosa Calis et al. (2004)30-(�-d-glucopyranosyloxy)-2�,3 �,23-trihydroxyolean-12-en-28-oic acid Phlomis viscosa Calis et al. (2004)

Phenolic glycosidesSyringin Phlomis aurea Mohamed et al. (2000)


Pyrrolidinium derivatives(2S,4R)-2-Carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt[(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline inner salt

Phlomis brunneogaleata Kirmizibekmez et al. (2004)

�-Sitosterol 3-O-�-d-glucopyranoside and 1-methyl-O- �-d-glucopyranoside Phlomis tuberosa Calis et al. (2005)Syringaresinol-4-O-�-d-Glucopyranoside Phlomis angustissima Yalcin et al. (2005)


ts pre

corTdetmae7aaSce

Fig. 1. Main componen

haracteristic of the Lamioideae subfamily, as indicated by reportsf their presence in the genus Anisomeles, Ballota, Galeopsis, Leonu-us, Marrubium, Phlomis, Sideritis and Stachys (Marin et al., 2004;omas-Barberan et al., 1992; Gil Munoz, 1993). They have not beenetected in the subfamily Nepetoideae of the Lamiaceae, and arencountered infrequently in other plant families. This is in contrasto flavonol 3-O-p-coumaroylglycosides, which are relatively com-

on. Within the Lamioideae, the 7-O-p-coumaroylglycosides ofpigenin (9) are more widespread than the corresponding chryso-riol derivatives. However, the (E)- and the (Z)-forms of chrysoeriol-O-(3′′-p-coumaroyl) glucoside, as reported in Phlomis fruticosa,
lso occur in Phlomis lychnitys L. (Tomas et al., 1986) and Ballotacetabulosa (Sahpaz et al., 2002), and the (E)-form is known fromtachys chrysantha, Stachys candida (Skaltsa et al., 2000), Marrubiumylleneum (Michelis et al., 2002), Phlomis integrifolia (Saracoglut al., 2003) and Phlomis crinita (Kabouche et al., 2005). Chryso-
sent in Phlomis species.

eriol 7-O-(3′′,6′′-di-(E)-p-coumaroyl)glucoside was reported fromMarrubium velutinum (Karioti et al., 2003) and chrysoeriol 7-O-p-coumaroylglucosides, in which the linkage of the acid to the sugarwas not determined, were detected in the leaves or trichomes ofPhlomis aurea, Phlomis floccosa (El-Negoumy et al., 1986), Ballotaacetabulosa (Mericli et al., 1988), Phlomis purpurea and Ballota hir-sute (Gil Munoz, 1993). Therefore, p-coumaroyl esters of chrysoeriol7-O-glucoside are characteristic of the Lamioideae genus Phlomis,Ballota and Marrubium, and to some extent Stachys, although thecorresponding apigenin (9) glycoside is more common (Marin etal., 2004).

4.3. Iridoids

A number of iridoid glycosides have been isolated from thePhlomis species. The most frequent iridoids are shanzhiside methyl

nopha

eFi1P2tl2tp(l2Paalr

4

ewsiLlfSo(raaslCpfafnh2pec1

4

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pP

I.L.-B. Amor et al. / Journal of Eth

ster (16), 8-O-acetylshanzhiside methyl ester (17) and lamiide (18).or example shanzhiside methyl ester (16) (Fig. 1) was reportedn nine Phlomis species including Phlomis rotate (Zhang et al.,991), Phlomis younghusbandii (Kasai et al., 1994; Gao et al., 2007),hlomis rigida (Takeda et al., 2000), Phlomis spinidens (Takeda et al.,001), Phlomis longifolia var. longifolia (Ersöz et al., 2001a), Phlomisubrosa (Ersöz et al., 2001b; Alipieva et al., 2000), Phlomis lunariifo-ia (Calis and Kirmizibekmez, 2004), Phlomis medicinalis (Yu et al.,006), Phlomis umbrosa (Liu et al., 2007). Several new iridoid struc-ures have been isolated from Phlomis species. 3-epiphlomurin,hlomurin and phlomiside were characterized from Phlomis aureaMohamed et al., 2000). In addition, in Phlomis longifolia var. longifo-ia, a new iridoid structure was identified as phlomiol (Ersöz et al.,001a). Ersöz et al. (2001b) purified 8-O-acetylshanzhiside, fromhlomis tuberosa. Phloyosides I and II (from Phlomis younghusbandii)nd III (from Phlomis mongolica) were purified by Kasai et al. (1994)nd Li and Zhang (2000), respectively. Takeda et al. (2000) iso-ated three new iridoids; phlorigidosides A, B and C from Phlomisigida.

.4. Phenylethylalcohol glycosides structures

The genus Phlomis is rich in phenylethylalcohol glycosides,.g., verbascoside (acteoside) (19) and forsythoside B (20) (Fig. 1),hich have been reported, respectively, from 13 and 11 Phlomis

pecies as seen in Table 3. However, within the Lamiaceae fam-ly, verbascoside (19) was reported previously from Faradaya,amium, Leonurus, Marrubium, Phlomis, Prostanthera, Oxera, Scutel-aria, Sideritis, and Stachy. However, forsythoside B (20) was onlyound in the genera Ballota, Phlomis, Marrubium, Scutellaria andtachy. Caffeic acid conjugates are considered to be chemotax-nomically important characters within the Lamiaceae familyHegnauer, 1989; Grayer and Kok, 1998). Verbascoside (19) andelated compounds that contain a caffeic acid moiety, sugars andphenylethyl group occur characteristically in the ajugoid Lami-

ceae (Grayer and Kok, 1998). Several new phenylethylalcoholtructures have been identified from Phlomis genus. In Phlomisinearis, five new structures were identified as Phlinoside A, B,, D and E (Calis et al., 1990, 1991). Indeed, the same com-ounds were isolated from Phlomis armeniaca (phlinoside B) androm Phlomis armeniaca and Phlomis lanceolata (phlinoside C) inddition to their identification in Phlomis linearis. In Phlomis longi-olia var. longifolia, another structure has been elucidated andamed phlomisethanoside (Takeda et al., 1999), and samiosideas been characterized from Phlomis samia (Kyriakopoulou et al.,001). Alyssonoside was characterized from Phlomis pungens var.ungens (Ismailoglu et al., 2002), Phlomis integrifolia (Saracoglut al., 2003) and Phlomis umbrosa (Liu et al., 2007) and teu-rioside was isolated from Phlomis armeniaca (Saracoglu et al.,995).

.5. Other secondary metabolites

In the Phlomis genus, many other secondary metabolites arencountered such as acetophenone glycoside, acridone alkaloid,
liphatic alcohol glycoside, benzyl alcohol glycoside, caffeic acidsters, diterpenoid glycosyl ester, lignan, megastigmane gluco-ide, monoterpene glycosides, neolignan glucoside, nortriterpenes,leanane-type triterpene glycoside, phenolic glycosides and pyrro-idinium derivatives.
Katagiri et al. (1991) purified and characterized four new diter-ene glycosyl ester structures (Phlomisoside I, II, III and IV) fromhlomis younghusbandi and Phlomis medicinalis.

rmacology 125 (2009) 183–202 197

5. Pharmacological properties of Phlomis species

5.1. Antidiabetic activity (in vivo)

Several Phlomis species are recognized for their antidiabeticproperties, i.e., Phlomis aurea, Phlomis ocymifolia (Table 1). Theiractivity may be due essentially to their ability to protect liver andpancreas integrity by reducing the oxidative stress in diabetes orby stimulating the production of enzymes implicated in glucosemetabolism.

Sarkhail et al. (2007) evaluated the antihyperglycemic activityof Phlomis anisodonta methanolic extract (PAME) in a streptozocin(STZ)-induced model of diabetes in rats. Streptozocin provokesan irreversible destruction of pancreatic �-cells, causing degran-ulation and reduced secretion of insulin. STZ-induced diabetes ischaracterized by severe loss in body weight, and the presence ofdiabetic complications such as, myocardial, cardiovascular, gas-trointestinal, nervous, kidney and urinary bladder dysfunction dueto oxidative stress. The administration of PAME (400 mg kg−1) for10 days showed a significant reduction in blood glucose, an increasein plasma insulin levels and a decrease in body weight loss in STZ-treated rats. The observed antihyperglycemic effect was the resultof the ability of PAME to improve plasma ferric reducing antioxidantpower, reduce liver lipid peroxidation and combat oxidative stressthrough the activation of hepatic antioxidant enzymes. PAME-treated diabetic rats indicated a significant increase in hepaticsuperoxide dismutase, catalase, and glutathione peroxidase activi-ties (Sarkhail et al., 2007).

5.2. Antinociceptive activity (in vivo)

Analgesic properties have been reported for some Phlomisspecies like Phlomis caucasica, Phlomis fruticosa, Phlomis herba-venti,Phlomis lychnitis (Table 1). Sarkhail et al. (2003) confirmed the anal-gesic properties of three Phlomis species and proved their painreliving activity.

Total extract of Phlomis olivieri and Phlomis anisodonta at a doseof 150 mg kg−1 and Phlomis persica at a dose of 100 mg kg−1 reducesignificantly the number of acetic acid-induced writhes in mice,revealing antinociceptive properties comparable to indomethacin(Sarkhail et al., 2003). Mohajer et al. (2005) reported analgesicproperties of Phlomis lanceolata total extract and four fractions(diethyl ether, ethyl acetate, n-butanol and water extracts). In fact,100 mg kg−1 of these extracts exhibited an inhibitory effect on bothformalin tests and in an acetic acid-induced writhes test.

5.3. Antiulcerogenic activity (in vivo)

In Turkey, Spain, Iran, Syria, Greece and Portugal, herbal tea(decoction, infusion) prepared with Phlomis species is commonlyused as digestive aid and to treat gastric ulcers and aches. Thus, it isnot surprising to find that extracts of Phlomis species are antiulcero-genic. Two different studies have confirmed the gastroprotectiveactivity of Phlomis grandiflora and Phlomis crinita subsp. mauritan-ica aqueous extract (Gürbüz et al., 2003, Limem-Ben Amor et al.,2009).

Aqueous extracts of P. grandiflora were shown to possess a highprotective effect (100% inhibition) against EtOH-induced ulcero-genesis in rats. Ethanol induces longitudinal ulcer lesions in theglandular part of the stomach and stimulates leukotrienes, the 5-lipoxygenase pathway, mast cell secretion, and the breakdown of
reactive oxygen species resulting in damage to the gastric mucosa.Stomachs in four out of six rats treated with the methanol extractof P. grandiflora were completely protected from any visible dam-age (Gürbüz et al., 2003). Upon histopathological examinationthe aqueous (2.67 g/kg) and methanol extracts (2.41 g/kg) of P.

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randiflora exhibited high inhibitory activity of the ethanol effectn stomach sections. Gastric protection provided by these plantxtracts was better than the reference drug misoprostol (400 �g/kg)Gürbüz et al., 2003). The study of Gürbüz et al. (2003) supportshe ethnopharmacological use of P. grandiflora. It demonstrates thathese species possess high gastroprotective activity.

Limem-Ben Amor et al. (2009) demonstrated that the aqueousxtract (300 mg kg−1) of Phlomis crinita subsp. mauritanica reducedlcerogenesis induced with alcohol 50◦, in mice. It reduces ulcero-enesis by 91% in comparison to cimetidine (the positive control),hich itself inhibits ulcerogenesis by 71%. Phlomis crinita subsp.auritanica is used in folk medicine to treat lesions and burns,

ut, in the work realized by Limem-Ben Amor et al. (2009), it wassed to protect the stomach epithelia against lesions induced byhe alcohol. These finding supports the ethnopharmacological usesf Phlomis species as gastroprotective plants.

.4. Protection of the vascular system (in vitro)

Aortic rings, isolated from rats, can be induced to contractpon treatment with phenylephrine. Conversely, acetylcholine can

nduce relaxation. Electrolysis of a physiological solution has beenhown to generate free radicals such as superoxide radical (O2−),ydrogen peroxide (H2O2) and hydroxyl radical (•OH). Interest-

ngly, the incubation of aortic rings with the aqueous extract200 �g/ml), phenylethylalcohol fraction (100 �g/ml) and iridoidraction (150 �g/ml), prepared from Phlomis pungens var. pungens,revented the inhibition of acetylcholine response induced bylectrolysis. However, the protection afforded by these fractionsas partial, as acetylcholine-induced relaxation was still reduced

s compared to the control response obtained before electrolysisIsmailoglu et al., 2002).

Major components of the phenylethylalcohol fraction includingorsythoside B and alyssonoside provided partial protection at aoncentration of 10−4 M against the electrolysis-induced inhibitionf the acetylcholine response in aortic rings. The major compo-ent of the iridoid fraction, lamiide, was also tested and was found

neffective at a concentration of 10−4 M in preventing electrolysis-nduced impairment of the acetylcholine response (Ismailoglu etl., 2002).

The protective activity of different extracts and compoundssolated from Phlomis pungens var. pungens against free radical-nduced impairment of endothelium-dependent relaxation may beelated to their free radical scavenging property (Ismailoglu et al.,002).

It is true that Phlomis pungens var. pungens is not reportedn folk medicine (Table 1) but found that some Phlomis speciesike Phlomis lychnitis or Phlomis rotate, Phlomis purpurea pos-ess antihemorrhoidal and cardiotonic activities, and promoteslood circulation and eliminates blood stasis. Although detailedtudies are lacking, future work will likely produce interestingesults.

.5. Anti-inflammatory and antiallergic activities (in vivo)

Phlomis umbrosa is used in folk medicine to treat kidney andrain problems and it has been shown to have hemostatic proper-ies. Shin et al. evaluated the anti-inflammatory properties of thispecie. To assess the contribution of the aqueous extract of Phlomismbrosa, Turcz root (PUAE) anaphylaxis, an in vivo model of sys-emic anaphylaxis, was used. Compound 48/80 (0.008 g/kg BW) was
sed as a fatal systemic anaphylaxis inducer. PUAE (0.01–1 g/kg)
nhibited both the systemic allergic reaction (Shin et al., 2008) andystemic anaphylaxis (Shin and Lee, 2003) induced by 48/80. PUAEnhibited mastocyte dependent allergic reactions and reducednflammatory cytokine and histamine secretion, suggesting that

rmacology 125 (2009) 183–202

PUAE may be beneficial in the treatment of allergic diseases (Shinet al., 2008).

Passive cutaneous anaphylaxis is one of the most important invivo models of anaphylaxis for local allergic reactions. The localextravasations can be induced by a skin injection of the anti-body anti-dinitrophenyl (anti-DNP IgE) followed by an antigenicchallenge. Both oral and intraperitoneal administrations of PUAE(0.001–1 g/kg) dose dependently inhibit passive cutaneous anaphy-laxis and histamine release from rat peritoneal mast cells activatedby 48/80 or anti-DNP IgE (Shin et al., 2008; Shin and Lee, 2003).

The level of cyclic AMP (cAMP) in human mast cells (HMC-1cells) when PUAE (1 mg/mL) was added, transiently and signif-icantly increased compared with that of basal cells. In HMC-1cells induced with the calcium ionophore A23187 and phorbol12-myristate 13-acetate, PUAE (0.1 and 1 mg/mL) inhibited thesecretion of tumor necrosis factor-� (TNF-�), interleukin (IL)-6 andinterleukin (IL)-1� (Shin et al., 2008; Shin and Lee, 2003).

5.6. Anticancer activity (in vitro)

Phenyl propanoid caffeic acid, phenylethyl alcohol andphenylethylalcohol glycosides isolated from Phlomis armeniacawere found to show cytotoxic activity against several kinds of can-cer cells. However they did not affect the growth and viability ofprimary cultured rat hepatocytes (Saracoglu et al., 1995).

Verbascoside, isoverbascoside, forsythoside B and 3-O-caffeoylquinic acid methyl ester isolated from Phlomisbrunneogaleata showed cytotoxic activity against L6 cell lines(Kirmizibekmez et al., 2004).

5.7. Anti-infective testing in vitro

Many Phlomis species are known to possess anti-infective activi-ties. They reduce fever, attenuate cough, treat throat infections andeliminate worm infections (Table 1). They are rich in essential oilsas recognized by their antimicrobial activity. Consequently, manystudies have evaluated the antimicrobial activities of essential oilsextracted from Phlomis species.

5.7.1. Antibacterial activityEssential oils extracted from different Phlomis species show

important antibacterial effects against a wide range of pathogenicbacteria. Escherichia coli, Klebsiella pneumonia, Staphylococcusaureus and Pseudomonas aeruginosa seem to be the most sen-sitive bacteria to Phlomis essential oils (Table 4). In addition toessential oils, methanol extracts of some Phlomis species (Phlomisbruguieri, Phlomis herba-venti, Phlomis olivieri) possess antibacterialeffects against Escherichia coli, Klebsiella pneumonia, Staphylococ-cus aureus, Staphylococcus sanguis and Pseudomonas aeruginosa(Morteza-Semnani et al., 2006).

5.7.2. Antifungal activityAs can be seen in Table 4, methanol extracts, ethanol extracts and

essential oils extracted from the majority of Phlomis species exhibitantifungal activity toward different Candida species (Candida albi-cans, Candida glabrata, Candida tropicalis). The methanol extractsof Phlomis bruguieri, Phlomis herba-venti and Phlomis olivieri inhibitthe growth of Aspergillus niger (Morteza-Semnani et al., 2006). Theethanol extract of Phlomis fruticosa has antifungal activity againstAspergillus ochraceus, Cladosporium caladosporioides and Phomopsishelianthi whereas the essential oil of this Phlomis species inhibits
only the growth of the two last fungi (Ristic et al., 2000). In addi-tion to its anti-Candida activity, the essential oil of Phlomis lanatainhibits the growth of Torulopis glabrata (Couladis et al., 2000).
Demirci et al. (2008) reported the antifungal activity of Phlomisrusseliana and Phlomis grandiflora var. grandiflora essential oils


Table 4Antimicrobial activity of Phlomis species.

Microbes Phlomis species (extracts and compounds) withantimicrobial activity

References

BacteriaBacillus subtilis Phlomis fruticosa (essential oil, ethanol extract) Ristic et al. (2000)Enterococcus cloacae Phlomis samia (Samoside) Kyriakopoulou et al. (2001)Enterococcus feacalis Phlomis crinita ssp. mauritanica Limem-Ben Amor et al. (2008)

Escherichia coli Phlomis fruticosa (essential oil) Ristic et al. (2000)Phlomis lanata (essential oil) Couladis et al. (2000)Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001)Phlomis fruticosa (essential oil) Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis russeliana (essential oil) Demirci et al. (2008)Phlomis grandiflora var. grandiflora (essential oil) Demirci et al. (2008)

Klebsiella pneumonia Phlomis lanata (essential oil) Couladis et al. (2000)Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004)Phlomis fruticosa (essential oil) Ristic et al. (2000), Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)

Micrococcus luteus Phlomis fruticosa (essential oil) Ristic et al. (2000)

Staphylococcus aureus Phlomis fruticosa (essential oil) Ristic et al. (2000)Phlomis samia (Samoside) Kyriakopoulou et al. (2001)Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis crinita ssp. mauritanica Limem-Ben Amor et al. (2008)

Staphylococcus aureus(multi-drug resistant strains)

Phlomis lanceolata (forsythoside B, verbascoside) Nazemiyeh et al. (2008)

Staphylococcus epidermidis Phlomis samia (Samoside) Kyriakopoulou et al. (2001)

Staphylococcus sanguis Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)

Salmonella typhimurium Phlomis crinita ssp. mauritanica Limem-Ben Amor et al. (2008)

Pseudomonas aeruginosa Phlomis lanata (essential oil) Couladis et al. (2000)Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004)Phlomis fruticosa (essential oil) Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)

Yersinia enterocolitica Phlomis russeliana (essential oil) Demirci et al. (2008)Phlomis grandiflora var. Grandiflora (essential oil) Demirci et al. (2008)

FungiAspergillus niger Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)

Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)

Aspergillus ochraceus Phlomis fruticosa (ethanol extract) Ristic et al. (2000)Cladsporium cladosporioides Phlomis fruticosa (essential oil, ethanol extract) Ristic et al. (2000)

Candida albicans Phlomis lanata (essential oil) Couladis et al. (2000)Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004)Phlomis fruticosa (essential oil) Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)Phlomis bruguieri (methanol extract) Morteza-Semnani et al. (2006)Phlomis herba-venti (methanol extract) Morteza-Semnani et al. (2006)Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006)

Candida glabrata Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004)Phlomis fruticosa (essential oil) Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)

Candida tropicalis Phlomis lanata (essential oil) Couladis et al. (2000)Phlomis samia (Samoside, essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004)Phlomis fruticosa (essential oil) Aligiannis et al. (2004)Phlomis cretica (essential oil) Aligiannis et al. (2004)



Microbes Phlomis species (extracts and compounds) withantimicrobial activity

References

Clostridium perfringens Phlomis russeliana (essential oil) Demirci et al. (2008)Phlomis grandiflora var. Grandiflora (essential oil) Demirci et al. (2008)

Phomopsis helianti Phlomis fruticosa (essential oil, ethanol extract) Ristic et al. (2000)Rhizopus Phlomis lychinitis (non polar extracts) Lopez et al. (2007)Torulopis glabrata Phlomis lanata (essential oil) Couladis et al. (2000)

ParasitesLeishmania donovani Phlomis brunneogaleata (brunneogaleatoside, (2S,4R)-2-

carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidiniuminner salt[(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline innersalt], verbascoside, isoverbascoside, forsythoside B,echinacoside, glucopyranosyl-(1→G (i)-6)-martynoside,integrifolioside B, luteolin 7-O-�-d-glucopyranoside,chrysoeriol 7-O-�-d-glucopyranoside, liriodendrin,glycoside 4-hydroxyacetophenone4-O-(6′-O-�-d-apiofuranosyl)-�-d-glucopyranoside,chlorogenic acid, 3-O-caffeoylquinic acid methyl ester,5-O-caffeoylshikimic acid)

Kirmizibekmez et al. (2004)

Phlomis kurdica (CHCl3-soluble portion)Tasdemir et al. (2005)

Plasmodium falciparum Phlomis brunneogaleata (brunneogaleatoside,3-O-caffeoylquinic acid methyl ester, luteolin7-O-�-d-glucopyranoside, chrysoeriol7-O-�-d-glucopyranoside, isoverbascoside)


Phlomis kurdica (CHCl3-soluble portion)Phlomis leucophracta (CHCl3-soluble portion) Tasdemir et al. (2005)

Tasdemir et al. (2005)

Trypanosoma brucei rhodesiense Phlomis brunneogaleata (brunneogaleatoside, (2S,4R)-2-carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidiniuminner salt[(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline innersalt], verbascoside, isoverbascoside, forsythoside B,echinacoside, glucopyranosyl-(1→G (i)-6)-martynoside,luteolin 7-O-�-d-glucopyranoside, chrysoeriol7-O-�-d-glucopyranoside, liriodendrin, chlorogenic acid,

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gainst Clostridium perfringens. Lopez et al. (2007) described thenti-Rhizopus activity of nonpolar extracts of Phlomis lychinitis.

.7.3. Antiparasitic activitySeveral compounds purified from Phlomis brunneogaleata show

nti-parasite activities against Leishmania donovani, Plasmodiumalciparum and Trypanosoma brucei rhodesiense (Kirmizibekmez etl., 2004).

The soluble portion of the Phlomis kurdica chloroform extractossesses anti-Leishmania, anti-Plasmodium and anti-Trypanosomactivity whereas the same type of extract prepared from Phlomiseucophrata inhibits only Trypanosoma growth (Tasdemir et al.,005).

The cited antiplasmodial activities are due to the inhibition abil-ty of the purified eonyl-ACP reductase (FabI), a crucial enzyme inhe fatty acid biosynthesis of Phlomis falciparum (Kirmizibekmez etl., 2004; Tasdemir et al., 2005).

.8. Antioxidant and antiradical activities (in vitro)

Phlomis fruticosa and Phlomis lanata methanol extract have
ntioxidant activity. They prevent bleomycin-Fe (II) catalyzedrachidonic acid superoxidation (Couladis et al., 2003).
Forsythoside B, acteoside (the two major phenylethylalco-ol glycoside in Phlomis genus) purified from Phlomis caucasicand samioside prepared from Phlomis samia were found to be

yl ester, 5-O-caffeoylshikimic

le portion)Tasdemir et al. (2005)

potent scavengers of 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical(Kyriakopoulou et al., 2001; Delazar et al., 2008).

6. Conclusions

The growing significance of natural products in drug discoveryand development is obvious. Phlomis is a very valuable genus to thediscovery and utilization of natural medicinal products. As futureinvestigations continue, this genus may prove to be a rich source ofnew compounds for the development of new therapeutic agents.

Throughout our literature review we observed that the speciesof the genus Phlomis is recognizable by variable contents of essentialoils. Thus, the main components of Phlomis permitted us to dividethis genus into four chemotypes; sesquiterpene-containing chemo-types (germacrene D (1) and �-caryophyllene (2)), monoterpeneand sesquiterpene-containing chemotype (�-pinene (3), limonene(4), linalool (5), germacrene D (1) and �-caryophyllene (2)), fattyacid, aliphatic compound and alcohol containing chemotype (hex-adecanoic acid (6), trans-phytol (7) and 9,12,15-octadecatrien-1-ol(8)) and terpene, fatty acid, aliphatic compound and alcoholcontaining chemotype (hexadecanoic acid (6), �-pinene (3) and
germacrene D (1)).
Apigenin (9), luteolin (10), naringenin (11), eriodictyol (12) andchryseriol (13) are the most commonly occurring flavonoids in thePhlomis species. They are generally 7- or 3-glycosylated. Phlomis isrich in iridoids like 8-O-acetylshanzhiside methyl ester (17), lami-

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de (18) and shanzhiside methyl ester (16), and phenylethylalcohollycosides. In this last group, we found acteoside and forsythoside Bs compounds that occur frequently in this species. The remaininghemical compounds (monoterpene, sesquiterpene, nortriterpene,ignan, neolignan and caffeic acid derivatives) are not well studied

ith the exception of their essential oils.Studies regarding the pharmacological activity of these species

ave focused on the antimicrobial effects of essential oils orther extracts. The antidiabetic, the antinociceptive, antiulcero-enic, anti-inflammatory, antiallergic and antioxidant activitiesf some Phlomis species extracts have been also reported. Mostf the mentioned studies were conducted using crude prepara-ions of Phlomis species, and the chemical profiles were not welletailed. With the availability of primary information, other studiesuch as phyto-pharmacology of Phlomis extracts, standardization ofxtracts, identification and isolation of active principles and phar-acological studies of isolated compounds can be conducted. Theseay be followed by the development of lead molecules for drug

iscovery as well as provide information for herbal formulations.n addition, despite the large number of identified compounds inhe Phlomis genus, there is a scarcity of detailed examinations ofheir pharmacological activities.

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Phytochemistry and biological activities of Phlomis species

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