Journal of Ethnopharmacology 125 (2009) 183–202 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm Review Phytochemistry and biological activities of Phlomis species Ilef Limem-Ben Amor a,b , Jihed Boubaker a,b , Mohamed Ben Sgaier a,b , Ines Skandrani a,b , Wissem Bhouri a,b , Aicha Neffati a,b , Soumaya Kilani a,b , Ines Bouhlel a,b , Kamel Ghedira a,b , Leila Chekir-Ghedira a,b,∗ a b Laboratory of Cellular and Molecular Biology, Faculty of Dental Medicine, Rue Avicenne, 5019 Monastir, Tunisia Unity of Pharmacognosy/Molecular Biology 99/UR/07-03, Faculty of Pharmacy, Rue Avicenne, 5000 Monastir, Tunisia a r t i c l e i n f o Article history: Received 1 December 2008 Received in revised form 17 June 2009 Accepted 20 June 2009 Available online 27 June 2009 Keywords: Phlomis Lamiaceae Secondary metabolites Ethnobotanical uses Pharmacological properties a b s t r a c t The genus Phlomis L. belongs to the Lamiaceae family and encompasses 100 species native to Turkey, North Africa, Europe and Asia. It is a popular herbal tea enjoyed for its taste and aroma. Phlomis species are used to treat various conditions such as diabetes, gastric ulcer, hemorrhoids, inflammation, and wounds. This review aims to summarize recent research on the phytochemistry and pharmacological properties of the genus Phlomis, with particular emphasis on its ethnobotanical uses. The essential oil of Phomis is composed of four chemotypes dominated by monoterpenes (␣-pinene, limonene and linalool), sesquiterpenes (germacrene D and ␤-caryophyllene), aliphalic compounds (9,12,15-octadecatrienoic acid methyl ester), fatty acids (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. The pharmacological activities of some Phlomis species have been investigated. They are described according to antidiabetic, antinociceptive, antiulcerogenic, protection of the vascular system, anti-inflammatory, antiallergic, anticancer, antimicrobial and antioxidant properties. © 2009 Elsevier Ireland Ltd. All rights reserved. Contents 1. 2. 3. 4. 5. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botanical description of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnobotanical use of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Uses recorded for Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Phlomis species with particular ethnobotanical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. The part of Phlomis used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Specific culinary use of some Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Secondary metabolites of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Essential oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Phenylethylalcohol glycosides structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Other secondary metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological properties of Phlomis species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Antidiabetic activity (in vivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antinociceptive activity (in vivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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, Tunisia. Tel.: +216 97 316 282; fax: +216 73 461 150. E-mail address: Leila.chekir@laposte.net (L. Chekir-Ghedira). 0378-8741/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2009.06.022 184 184 184 184 184 184 190 190 190 190 196 197 197 197 197 197 197 198 198 198 184 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 5.7. 6. Anti-infective testing in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.1. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.2. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.3. Antiparasitic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Antioxidant and antiradical activities (in vitro) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Plants are used worldwide for the treatment of diseases, and novel drugs continue to be developed through research from plants. There are more than 20,000 species of plants used in traditional medicines, and these are all potential reservoirs for new drugs (Hamamouchi, 2002). With the advance of modern medicine and drug research, chemical synthesis has replaced plants as the primary source of medicinal agents in industrialized countries. In developing countries, the majority of the world’s population cannot afford pharmaceutical drugs and use their own plant-based indigenous medicines. Traditional medicinal plants have received considerable attention because their bioactive components may lead to new drug discoveries. The Phlomis genus has been instrumental in the discovery of natural medicinal products (Kim, 2006). Phlomis is a large genus in the Lamiaceae family, with over 100 species distributed throughout Euro-Asia and North Africa continents. They have various uses that differ from one country to another. Their flowered parts are generally used as an herbal tea to treat gastrointestinal troubles and to promote good health by protecting the liver, kidney, bone and cardiovascular system. In addition, some Phlomis species have culinary uses. Over the last few years, there has been a rapid increase in the information available on the structures and pharmacological activities of new compounds isolated and identified from Phlomis species. In this review, we present recent Phlomis plant research in three sections: ethnobotanical uses, phytochemistry, biological and pharmacological activities of Phlomis plants. 2. Botanical description of Phlomis species The leaves of Phlomis are entire, opposite and decussate and rugose or reticulate veined. The bracts are similar or different from the lower leaves. All parts are frequently covered with hair. Bracteoles are ovate, lanceolate or linear. The flowers are arranged in whorls around the stems, which are usually square in section with rounded corners, although tomentum on stems can make them appear circular. The color of the flowers varies from yellow to pink, purple and white. The calyx is tubular or campanulate with 5 or 10 visible veins. It has five teeth, either all equal or with the outer two longer than the others. The upper lip is hood shaped and laterally compressed. The lower lip is trifid, the central lobe being larger than the lateral ones. There are four stamens ascending under the upper lip. The anther has a forked end, the upper fork being shorter than the lower. The fruits are four- or three-sided, nutlets, and sometimes topped with hair, and sometimes glabrous (Pottier-Alapetite, 1981). 3. 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 fact, there are many ethnobotanical sources that do not include any Phlomis species. In addition, some Phlomis species growing at high altitude (Phlomis olivieri (Sarkhail et al., 2006), Phlomis russeliana (Demirci et al., 2008), Phlomis viscosa (Karaman and Cömlekcioğolu, 198 198 198 200 200 200 201 2007), Phlomis integrifolia (Saracoglu et al., 2003)) and mountainous regions (Phlomis linearis (Demirci et al., 2008)) are not easy accessible resources and thus are not extensively used and studied. The details 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 the world have the same mode of use, namely as herbal tea (decoction or infusion) to treat gastric, abdominal and intestinal conditions (Phlomis bourgei . . .). Other species were described to protect the liver, the kidney, the heart, the veins and the bone from different pathologies (Table 1). Some Phlomis species were described to treat fever, cough and cold, such as Phlomis cephalotes and Phlomis plukenettii (Table 1). Other Phlomis species such as Phlomis bovei subsp. bovei and Phlomis crinita are made into pastes and used as poultice or plaster to treat burns, lesions and skin infections and allergies (Table 1). For example, Phlomis crinita subsp. crinita and subsp. mauritanica, which grow in Spain and in Tunisia and Algeria, are used to heal lesions and burns by preparing a plaster from chopped leaves in Spain or as dried leaf powder in Tunisia and Algeria. However, the same species may have variable uses from one country to another: i.e., Phlomis fruticosa is used in Italy as an anticough agent and as a cicatrizant, whereas in Turkey and Greece, it is used to heal gastric ulcers. 3.2. Phlomis species with particular ethnobotanical uses Some species have particular uses in their respective countries. For example, the Syrian multi-component herbal tea called “Zahraa” is a complex mixture of leaves and/or flowers from 6 to 14 species, including Phlomis syriaca. Usually, these teas are consumed in households and in restaurants and cafes in Damascus (Carmona et al., 2005). Phlomis purpurea, also known as marioilas in Portugal has over 17 different medicinal uses in that country. It is directly ingested to treat gastric pains, and its olive oil decoction is used as an intestinal antispasmodic (Novais et al., 2004). In Spain, this plant is called “matagallos,” and its aerial infusion is frequently used to treat prostate and liver problems (González-Tejero et al., 1995). Phlomis lychnitis, named Candilera, is commonly used in Spain as an herbal tea, to treat gastric, intestinal and abdomen pains, as a tonic, sedative, carminative and astringent (Rivera Núñez and Obón De Castro, 1993; Fernández-Ocaña 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 rotata . . .), the seeds (Phlomis cephalotes) and the roots (Phlomis nepetaefolia). They are used as a decoction, an infusion or as a juice. The flowers of some Phlomis species are sweet and are consumed directly or sucked (Phlomis purpurea subsp. purpurea, Phlomis cephalotes). The leaves of Phlomis cephalotes are used to prepare an herb-pot. 185 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 1 Medicinal uses of selected Phlomis species. Phlomis species Regions Common names Uses recorded Formulation/Mode of usage References Phlomis angustissima Hub.-Mor. Phlomis aspera Willd Muğla (Turkey) Yaylaçayı NCa Herbal tea Ertuğ (2004) Bangladesh Choto halkusa, Dulfi, Kusa, Shetodrone Psoriasis, chronic skin eruptions, in chronic rheumatism, painful swellings, coughs and colds The juice of the leaves is used in psoriasis, chronic skin eruptions, in chronic rheumatism and applied to disperse painful swellings. The flowers are being warmed with a little honey and given orally for coughs and colds to children Khanam and Abul Hassan (2005) Throughout Indian sub-continent extending from Punjab to Assam and southward up to peninsular India Sinai (Egypt) Awarwar Antidiabetic NCa Isparta (Turkey) Algeria NCa Kayat El Adjarah Stomach ache Lesion and burns NCa NCa Khafagi and Dewedar (2000), Mohamed et al. (2000) Diğrak et al. (1999) Liolios et al. (2007) North Africa Farseouan, Tarseouan, Iniji, R’ilef and Azaref Gahand-Shang Stomach disorder Dry powder of the aerial part is mixed with the powder prepared from aerial parts of Mentha longifolia, Heracleum thomsonii, Thymus linearis and Angelica glauca in equal ratio and about one spoon is taken with a glass of warm water to cure gastric trouble Arial part Phlomis aurea Decne. Phlomis bourgei Boiss Phlomis bovei De Noé subsp. bovei Phlomis bracteosa Royle ex Benth. Lahaul valley (North-West Himalaya) Phlomis caucasica Rech. f. North west of Iran Gush barreh gafgazi Phlomis cephalotes Roth Bangladesh Barahal-kusa Throughout Indian subcontinent Chepang (Nepal) Talang tolo Phlomis crinita Cav. subsp. crinita Phlomis crinita Cav. subsp. mauritanica Munby Danuwar (Nepal) Tharu (Nepal) Majhi (Punjab; Pakistan) Murcia, Almería (Spain) Tunisia, Algeria, Analgesic, anti-infection, digestive, throat infection Stimulant, diaphoretic, scabies, coughs and colds Shing and Lal (2008) Lotfipour et al. (2008), Delazar et al. (2008) The seeds yield medicinal oil. The fresh juice is used specifically as an external application in scabies. The flowers are administered in the form of syrup as a domestic remedy for coughs and colds. The leaves are eaten as a pot-herb Khanam and Abul Hassan (2005) Malarial fever, urinary complaints, nosebleed Four teaspoons of the decoction (flowers, leaves is boiled in water for 15 min, and filtered), three times a day, is given for malarial fever. A paste of the plant is boiled with mustard oil and applied to boils. Juice of the plant is given in the case of urinary complaints. Dried inflorescences are smoked and the smoke is expelled through the nose to treat nosebleed Manandhar (2002) Orejicas de fraile, Oreja de liebre Lesions and burns A cicatrizant plaster is prepared with the chopped leaves Khayatta, Khayatt el adjarah Lesions and burns The dried leaves are applied directly on fresh cuts and burns Rivera Núñez and Obón De Castro (1993), González-Tejero et al. (1995) Boukef (1986), Quezel and Santa (1963) Julpbi Gum Phoke jbar, tank jbar 186 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 1 (Continued ) Phlomis species Regions Common names Uses recorded Formulation/Mode of usage References Phlomis fruticosa L. Apulia, Calabria, Sicily and Sardinia (Italy) Sicily (Italy) NCa Anti-tussive NCa Guarrera and Lucia (2007) Sucu cu a sarvia sarvaggia Spices Lentini and Venza (2007) Italy NCa Wounds Muğla (Turkey) NCa Greece NCa Appetizer, stimulant, tonic, stomach pain, carminative, dyspeptic complaint Soothe sore muscles and joints Sauce for paste prepared by browning the leaves in bacon fat, butter or olive oil Leaves are used as a poultice on wounds Inflorescence and leaves are used to prepare a herbal tea A decoction leaves and seeds is used topically to soothe sore muscles and joints. Leaves are macerated in water with honey or wine and were taken orally Herbal tea Gürbüz et al. (2003) Only calyx are used Fernández-Ocaña et al. (1996) Demirci et al. (2003) Gastric ulcers Phlomis grandiflora H.S Thompson var. grandiflora Anatolya (Turkey) Ballikotu, Calba, çalba or şalba Phlomis herba-venti L. Jaén (Spain) Pujas, Matagallos central to east and southeast Anatolya (Turkey) Danuwar (Nepal) NCa Phlomis linearis Boiss & Bal Tonic, carminative, appetizer, stimulant, treatment of stomach disorders Veterinary antidiarrheic and soothe muscle pains Aromatic aroma, carminative, stimulant Julfi jbar Fresh cuts and wounds, malarial fever Bangladesh Dondocolos, Hal-Kusa, Sheto drone Appetizer, snakebite, headaches Phlomis lycia D. Don Muğla (Turkey) Deli salba Phlomis lychnitis L. Campo de Calatrava (Spain) Candilera, Ierba tolciera Appetizer, stimulant, tonic, stomach pain, carminative, dyspeptic complaint Vulnerary, antirheumatic, analgesic, lithoxitic, antihemorrhoidal, astringent, carminative, stomachic and abdomen pains (antidiarrheic appetizer, digestive) Jaén (Spain) Té, Matagallo, Torcida Phlomis linifolia Roth Té Amarillo Matagallo real Phlomis nepetaefolia L. Arrabida (Portugal) Salvinha India Bara guma, Thanail Astringent For haemorrhage For the nerves (tonic, sedative) For circulation, varicose vein Digestive, gastric, analgesic, intestinal, anti-inflammatory, analgesic, renal antispasmodic Scalds, eating skin diseases and ring worms. Breast (when it swells and milk does not pass throw the nipples) Herbal tea Juice of the plant, 3 teaspoons twice a day, is given in the case of malarial fever. A paste of the plant is applied to fresh cuts and wounds. Leaves are roasted and eaten with salt for loss of appetite and in snakebite. Juice of leaves is employed in headaches Herbal tea (inflorescence and leaves) Infusion or decoction prepared using flowred aerial part, as herbal tea Soković et al. (2002) Brussel (2004), Sarac and Ugur (2007) Demirci et al. (2008) Manandhar (2002) Khanam and Abul Hassan (2005) Sarac and Ugur (2007) Rivera Núñez and Obón De Castro (1993), Tardio et al. (2006), Pardo de Santayana et al. (2005), Vázquez et al. (1997), Fernández-Ocaña et al. (1996) Flower sucked Flower infusion Leaves decoction The infusion was applied by friction Infusion Flower heads ashes employed in scalds, burns and eating skin diseases and ring worms by mixing the ashes of flower heads with curds. Roots crushed and rubbed on the breast when it swell s and milk does not pass throw the nipples Novais et al. (2004) Vardhana (2008) 187 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 1 (Continued ) Phlomis species Regions Common names Uses recorded Formulation/Mode of usage References Phlomis ocymifolia Burm. f. South-eastern and eastern Africa, northwards to Kenya. The Gauteng/Mpumalanga region, the Eastern and Western Cape Province Iran Nepal Klipdagga, lion’s ear, Umcwili Diabetes, hypertension, anaemia, eczema and other skin irritations, purgative and emmenagogue. Used mainly as an aqueous infusion or decoction, taken orally or applied externally. Habtemariam et al. (1994) Cheseleh Gumpate Mouth anti-inflammatory Fever, cough and colds Juice of the plant Spain Matagallo For prostate and liver complaints Phlomis orientalis Boiss Phlomis plukenetii Roth Phlomis purpurea L. subsp. purpurea Phlomis purpurea L. subsp. almeriensis (Pau) Losa and Rivas Goday Phlomis rotata Benth. ex Hook. f. The infusion of aerial part Sweets flowers which are sucked Infusion Novais et al. (2004) Cardiotonic, antidiarrhoeic, for abdominal pain, digestive, gastric analgesic, intestinal anti-inflammatory, antihelmantic, emetic, for sea–sickness, for colds’ prevention, renal antispasmodic, for bladder aliments, hepatic protector, for stomach ulcers, for gastritis Fever, cough and colds Murcia (Spain) Oreja de liebre Diuretic, lithotritic NCa Rivera Núñez and Obón De Castro (1993) Tibet Takpak Leaf and flower decoctions are used for bone fracture, pain in ligaments, and sinus Pandey (2006), Zhang et al. (1991) Bolu (Turkey) Accumulation of serous fluids in the bone, skin and wound, headache, fever, cough, worm infections and swelling caused by cold. Promotes blood circulation. Eliminates blood stasis. Anti-inflammatory. Relieves pains. Tonic, carminative, appetizer, stimulant Antiallergic Facilitate the digestion and promotes good health Herbal tea Demirci et al. (2008) NCa Takeda et al. (2001) Carmona et al. (2005) Olive oil decoction Japan Syria Phlomis tuberosa L. Iran NCa Culinary use Phlomis umbrosa Turcz. Bull Korea Sok-dan Haemostatic, tineapedis, antihepatotoxic NCa Paeng-Jo-Yeon-NyeonBaek-Ja-In-Hwan (PJBH)b Nourishes the kidney and consolidates essencec , thus activating brain function, promoting memory and lengthening life span. PJBH is a decoction with eighteen dried herbs including the whole plant of Dendrobium moniliforme L., Phlomis umbrosa, fruits of Torilis japonica Thunb, The rhizome treat cold, been used to reduce swelling and staunch bleeding, anti-inflammatory and detoxification properties Herbal tea North China Cold Phlomis younghushandii Mukerjee Tibet Lug mur Phlomis zeylanica L Bangladesh Guma-guma c Tardio et al. (2006) Candeeiros, Marioila, Ballıkotu, Calba, Calba or Salba Kuz kulok Zahraab a González-Tejero et al. (1995) Arrabida (Portugal) Phlomis russeliana (Sims.) Bentham Phlomis spinidens Nevski Phlomis syriaca Boiss b Mojab et al. (2003) Manandhar (2002) Reproduction and sexual health, alleviates fever of chest, common colds Scabies, skin-diseases, in headache and cold, snakebite Herbal tea: Zahraa is a complex mixture of six to fourteen different species like Rosa damascena Mill, Zea mays L, Phlomis syriaca Boiss. . . Leaves are grilled Juice of whole plant is used in scabies, skin-diseases, in headache and cold. The juice of the leaves is sniffed of as a remedy for snakebite NC: not cited. The indicated name is not a common name of the plant but the name of the herbal mixture where they are included. Essence or “jing”: means something specific of Korean traditional medicine. Naghibi et al. (2005) WHO Regional Publications western Pacific Series NO 21 (1998) Adams et al. (2007) Liu et al. (2007) Law and Salick (2007) Khanam and Abul Hassan (2005) 188 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 2 Main essential oil constituents of Phlomis genus. Species Monoterpene Chemotype that contains sesquiterpene Phlomis anisodonta Phlomis bruguieri Phlomis cretica (verticillasters) Phlomis linearis (AP/H) Phlomis crinita ssp. mauritanica (leaves) (FAP/H) Phlomis crinita ssp. mauritanica (flowers) (FAP/H) Phlomis russeliana (DAP/H) Phlomis samia (FFAP/H) Phlomis grandiflora var. grandiflora (DAP/H) Phlomis viscosa (DAP/H) Phlomis olivieri (DAP/H) Sesquiterpene Sarkhail et al. (2005) ␤-Caryophyllene (22.6%), germacrene D (15.1%), caryophyllene oxide (8.1%) (E)-␤-farnesene (20.7%), germacrene D (6.3%), ␤-caryophyllene (5.8%), caryophyllene oxide (3.2%), spathulenol (3.7%) ␤-Eudesmol (42.0%), ␣-eudesmol (16.1%) Germacrene D (33.9%), bicyclogermacrene (15.3%) and (Z)-p-farnesene (10.7%) Germacrene D (26.4%) and bicyclogermacrene (12.7%). Demirci et al. (2008) Phlomis younghunsbandii ␣-Pinene (5.5%), linalool (4.7%) Phlomis cretica (FFAP/H) ␣-Pinene (9.4%), linalool (7.5%), limonene (7.1%), cis-␤-ocimene (5.4%) ␣-Pinene (11.2%) ␣-Pinene (38.9%), 1,8-cineole (8.1%), limonene (2.1%), ␣-thujone (2%) Phlomis cretica (leaf) Phlomis fruticosa (DFAP/H) (sunny locality) Sarkhail et al. (2005) Basta et al. (2006) Demirci et al. (2009) Limem-Ben Amor et al. (2008) Limem-Ben Amor et al. (2008) Aligiannis et al. (2004) Demirci et al. (2008) Nese et al. (2006) Mohammad et al. (2005) trans-Phytol (50.8%), 9,12,15-octadecatrienoic acid methyl ester (11.0%), hexadecanoic acid (7.1%), 9,12-octadecadienoic acid methyl ester (3.9%), hexadecanoic acid methyl ester (2.9%), 9,12,15-octadecatrien-1-ol (2.2%), isophytol (1.6%) 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-octadecatrienoic acid methyl ester (1.8%), hexahydrofarnesyl acetone (1.8%) Hexadecanoic acid, trans-phytol, 9,12,15-octadecatrien-1-ol Phlomis umbrosa (DAP/H) Phlomis chimerae (FDAP/H) References Germacrene D (65.0%), ␤-caryophyllene (11.0%) Germacrene D (60.5%), ␥-elemene (16.5%), germacrene B (7.1%), bicyclogermacrene (4.1%). Germacrene D (34.0%), germacrene B (11.0%) ␤-Caryophyllene (24.2%), germacrene D (22.3%), caryophyllene oxide (9.2%) trans-Caryophyllene (40.9%), germacrene D (39.1%) ␤-Caryophyllene (58.2%), germacrene D (35.1%) Chemotype that contains fatty acid, aliphatic compound and alcohol Phlomis szechuanensis (DAP/H) Chemotype that contains monoterpene and sesquiterpene Thymol (8.3%) Phlomis bovei subsp. bovei (DAP/H) Fatty acids, aliphatic compounds and alcohols Zhang and Wong (2008) Zhang and Wong (2008) Zhang and Wong (2008) Germacrene D (21.4%), ␤-caryophyllene (7%), ␤-bournonene (2.9%), hexahydrofarnesyl acetone (5.8%) ␤-Caryophyllene (31.6%), germacrene D (6.1%), ␦-cadinene (5.0%), caryophyllene oxide (4.8%) ␤-Caryophyllene (17.5%), germacrene D (20.1%) Liolios et al. (2007) Germacrene D (47.9%) ␤-Caryophyllene (8.7%) Basta et al. (2006) Ristic et al. (2000) Celik et al. (2005) Aligiannis et al. (2004) 189 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 2 (Continued ) Species Phlomis fruticosa (DFAP/H) (forest locality) Monoterpene Sesquiterpene ␣-Pinene (56.6%), 1,8-cineole (10.4%), limonene (2.2%), ␣-thujene (2.3%) ␣-Pinene (12,6%), linalool (8%) ␤-Caryophyllene (2%) ␤-Caryophyllene (12.6%), germacrene D (21.4%), (Z)- -bisabolene (7.1%) Phlomis grandiflora var. ␣-Pinene (2.4%), limonene Germacrene D (45.4%), grandiflora (DFAP/H) (2.7%) ␤-caryophyllene (22.8%), bicyclogermacrene (4.9%) Phlomis lanata (FAP/H) ␣-Pinene (25.41%), trans-Caryophyllene limonene (15.67%) (8.76%) Phlomis lanceolata ␣-Pinene (8.7%) Germacrene D (47.0%), (E)-␤-farnesene (10.5%), germacrene B (8.0%), bicyclogermacrene (5.9%) Phlomis leucophracta ␣-Pinene (19.2%), limonene ␤-Caryophyllene (20.2%), (FDAP/H) (11.0%) germacrene D (4.5%) 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%) 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%) Chemotype that contains terpene, fatty acid, aliphatic compound and alcohol Phlomis megalantha ␤-Linalool (3.8%) (DAP/H) Phlomis fruticosa (FFAP/H) Phlomis herba-venti L. (flower oil) (DAP/H) Germacrene D (6.7%) Phlomis bruguieri Desf (DFAP) ␣-Pinene (6.8%) Germacrene D (23.6%), ␤-caryophyllene (6.7%) Phlomis herba-venti L. (leaf oil) (DAP/H) Phlomis viscosa Poiret (DFAP/H) ␣-Pinene (9.4%) Germacrene D (33.9%) Phlomis lunariifolia ␣-Cubebene (2%), ␣-copaene (1,5%) Phlomis amaniaca ␣-Pinene (2.1%) Phlomis monocephala ␣-Pinene (4.9%) ␤-Caryophyllene (24.4%), germacrene D (4.7%), alloaromadendrene (11%), ␣-humulene (6,1%) ␤-Caryophyllene (9%), (Z)-␤-farnesene (6.5%), germacrene D (7.7%), bicyclogermacrene (2.6%), ␦-cadinene (1.7%), ar-curcumene (1.8%), caryophyllene oxide (1.2%) (Z)-␤-Farnesene 8,3%, germacrene D (14.7%), bicyclogermacrene (10.7%) Limonene (3.9%), ␤-caryophyllene (5.1%), (Z)-␤-farnesene (3.1%), germacrene D (6%), bicyclogermacrene (1.5%), caryophyllene oxide (1.2%) Fatty acids, aliphatic compounds and alcohols References Ristic et al. (2000) Aligiannis et al. (2004) Celik et al. (2005) Couladis et al. (2000) Sarkhail et al. (2005) Celik et al. (2005) Mirza and Baher Nik (2007) Sarkhail et al. (2003) Mohammad et al. (2005) 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-octadecatrienoic acid methyl ester (1.8%), ␣-terpineol (1.5%) Hexadecanoic acid (33.1%), 6,10,14trimethylpentadecan-2one (16.2%), 3-methyltetradecane (6.7%) 4-Hydroxy-4-methyl-2pentanone (15.0%) Hexadecanoic acid (12.9%) ␣Monocyclofarnesylacetone (16.44%) Selina-4,11-diene ((1/4)4,11-eudesmadiene) (2%), spathulenol (3.9%), ␣-cadinol (1.2%), 8 (14),15isopimaradien-11-␣-ol (5.5%), hexadecanoic acid (9.7%) Globulol (1.5%), Viridiflorol (1.1%), Spathulenol (6.3%), ␣-Cadinol (1.4%), 15-Isopimaradien-11-␣−ol (22.8%) 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%) Zhang and Wong (2008) Morteza-Semnani et al. (2004) Morteza-Semnani, Saeedi (2005) Morteza-Semnani et al. (2004) Karaman and Cömlekçioğolu (2007) Demirci et al. (2008) Demirci et al. (2008) Demirci et al. (2008) 190 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 2 (Continued ) Species Monoterpene Phlomis sieheana Phlomis armeniaca Phlomis bruguieri (DAP) ␣-Pinene (6.8%) Sesquiterpene Fatty acids, aliphatic compounds and alcohols References ␤-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%) (Z)-␤-Farnesene (6.2%), ␤-bourbonene (1.1%), (E)-␤-farnesene (1.2%), germacrene D (23.4%), ␤-selinene (2.6%), bicyclogermacrene (2.3%) 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%) Demirci et al. (2008) Hexahydrofarnesyl acetone (2.3%), spathulenol (1.9%), ␣-cadinol (1.2%), 4-methoxycarbonyl-7methylcyclopenta[c]pyrane (1.4%), pentacosane (2.5%), dodecanoic acid (1.4%), heptacosane (2.3%), nonacosane (1.2%), hexadecanoic acid (4.9%) 4-Hydroxy-4-methyl-2pentanone (15.0%) Demirci et al. (2008) Germacrene D (23.6%), ␤-caryophyllene (6.7%). Morteza-Semnani and Saeedi (2005) FAP: fresh aerial part; DAP: dried aerial part, FDAP; flowered dried aerial part; H: hydrodistillation. 3.4. Specific culinary use of some Phlomis species Several Phlomis species have culinary uses. For example, the leaves of Phlomis fruticosa are browned in olive oil or butter or in bacon fat and used to prepare a sauce for paste in Italy (Lentini and Venza, 2007). 4. Secondary metabolites of Phlomis species Phytochemical investigations of Phlomis species were the subject of several studies, and, consequently, essential oils (summarized in Table 2), flavonoids, iridoids, phenylethylalcohol glycosides and other components were isolated (summarized in Table 3). 4.1. Essential oils The essential oils from many Phlomis species has been studied by means of gas chromatography coupled to mass spectrometry (GC–MS) techniques. From the data reported in Table 2, we can see variable oil compositions. Indeed, these differences often separate Phlomis species into four chemotypes: • the first chemotype is rich in sesquiterpene: in this group, the two 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 main components of this class are ␣-pinene (3), limonene (4), linalool (5), germacrene D (1) and ␤-caryophyllene (2) (Fig. 1) (Ristic et al., 2000; Aligiannis et al., 2004; Celik et al., 2005; Liolios et al., 2007); • fatty acids, aliphatic compounds and alcohol (diterpenoic alcohol, fatty acid alcohol, . . .) constitute the main components of the third chemotype: this group contains a high percentage of hexadecanoic acid (6), trans-phytol (7) and 9,12,15octadecatrien-1-ol (8) (Fig. 1) (Zhang and Wong, 2008); • the last chemotype is rich in terpene, fatty acids, aliphatic compounds and alcohol (diterpenoic alcohol, fatty acid alcohol, . . .) as its main constituents: this mixed group contains hexadecanoic acid (6), ␣-pinene (3) and germacrene D (1) as major fatty acid, monoterpene and sesquiterpene, respec- tively (Zhang and Wong, 2008; Morteza-Semnani et al., 2004). It is possible that the chemical differentiation of essential oils for Phlomis species is correlated to the existence of many chemotypes, provoked either by different climatic factors, or as a result of pollination caused by genetic differences (intraspecific or intrapopulation crosspollination). The considerable differences among Phlomis species may depend on the extraction procedure, the season, the stage of development and the distinct habitat in which the plant has been collected. It can be concluded that the composition of oils varies greatly with respect to the geographical proximity (different species collected in the same region have similar compositions), mainly for the proportion of aliphatic compounds and terpenoids. All of these differences suggest further investigations on other Phlomis species may further confirm their biodiversity (Zhang and Wong, 2008). 4.2. Flavonoids As can be seen in Table 3, flavonoids are the major phytoconstituents isolated from the Phlomis genus. These include apigenin (9), luteolin (10), naringenin (11), eriodictyol (12), chryseriol (13), kaempferol (14) and their glycosides (Fig. 1). The majority of flavonoids identified in Phlomis genus are flavones, flavonols and frequently 7- or 3-glycosylated. Luteolin-7-glucoside, luteolin7-O-␤-glucopyranoside, chrysoeriol-7-p-coumaroylglucoside and chrysoeriol-7-glucoside constitute the most commonly glycosylated flavonoids founded in the Phlomis genus (ElNegoumy et al., 1986; Kyriakopoulou et al., 2001; Marin et al., 2007). The flavone glycoside, tricin 7-O-glucoside, which is found in Phlomis fruticosa is rather unusual in the Lamiaceae family, but has been reported previously from the Stachys subgenus Betonica (Marin et al., 2004). The flavonoid glycosides 7-O-glucosides, 7-Oglucuronides and 7-rutinoside, of apigenin (9), luteolin (10) and chrysoeriol (13), the flavone C-glycoside vicenin-2 (15) and the flavanones, naringenin (11) and eriodictyol (12) (Fig. 1) (Hegnauer, 1989; Tomas-Barberan et al., 1992) occur in the majority of Phlomis species (Azizian and Cutle, 1986; Barberan, 1986) and in the Lamiaceae family. Flavone p-coumaroylglycosides appears to be a unique 191 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 3 Compounds identified in Phlomis species. Compounds Species References Flavonoids Acacetin-7-O-␤-glucopyranoside Phlomis aurea Mohamed et al. (2000) Apigenin Phlomis lychnitis Phlomis samia Tomas et al. (1986) Kyriakopoulou et al. (2001) Apigenin-7-glucoside Phlomis aurea Phlomis floccose Phlomis lychnitis El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Apigenin-7-rutinoside Phlomis aurea Phlomis floccose El-Negoumy et al. (1986) El-Negoumy et al. (1986) Apigenin-7-p-coumaroylglucoside Phlomis aurea Phlomis floccose Phlomis lychnitis El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Astragalin Phlomis spinidens Takeda et al. (2001) Chryseriol Phlomis lychnitis Phlomis samia Phlomis fruticosa Tomas et al. (1986) Kyriakopoulou et al. (2001) Marin et al. (2007) Chryseriol-7-glucuronide Phlomis fruticosa Marin et al. (2007) Chrysoeriol-7-glucoside Phlomis aurea Phlomis floccosa Phlomis lychnitis Phlomis fruticosa Phlomis caucasica El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Marin et al. (2007) Delazar et al. (2008) Chrysoeriol-7-rutinoside Phlomis aurea Phlomis floccosa Phlomis caucasica El-Negoumy et al. (1986) El-Negoumy et al. (1986) Delazar et al. (2008) Chryseriol-7-rhamnosylglucoside Phlomis fruticosa Marin et al. (2007) Chrysoeriol-7-p-coumaroylglucoside Phlomis aurea Phlomis floccosa Phlomis lychnitis Phlomis purpurea Phlomis fruticosa Phlomis fruticosa Phlomis crinita El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Tomas-Barberan et al. (1992) Marin et al. (2007) Marin et al. (2007) Kabouche et al. (2005) Chrysoeriol 7-O-(3′′ -p-coumaroyl)-␤-glucoside Chrysoeriol-7-O(6′′ -␤-d-apiofuranosyl)-␤-d-glucopyranoside Phlomis nisssoli Bucar et al. (1998) Chrysoeriol-7-O-␤-glucopyranoside Phlomis aurea Phlomis integrifolia Phlomis lunariifolia Phlomis brunneogaleata Mohamed et al. (2000) Saracoglu et al. (2003) Calis and Kirmizibekmez (2004) Kirmizibekmez et al. (2004) Eriodictyol Ermanin Hesperetin Hispidulin-7-glucoside Isoquercitrin Isorhamnetin-3-p-coumaroylglucoside Phlomis fruticosa Phlomis samia Phlomis fruticosa Phlomis aurea Phlomis spinidens Phlomis purpurea Marin et al. (2007) Kyriakopoulou et al. (2001) Marin et al. (2007) El-Negoumy et al. (1986) Takeda et al. (2001) Tomas-Barberan et al. (1992) Kaempferol-3-glucosides Phlomis spectabilis Phlomis caucasica Kumar et al. (1985) Delazar et al. (2008) Kaempferol-3-p-coumaroylglucoside Kaempferol-3-(6′′ -(E)-p-coumaroyl)glucosides Kaempferol (7,4′ dimethyl ether)-3-glucoside Kaempferol (7,4′ dimethyl ether)-3-(6′′ -(E)-p-coumaroyl)glucosides Kaempferol-3-O-␤-d-glucopyranosyl-(1-6)-␤-d-glucopyranoside Phlomis purpurea Phlomis spectabilis Phlomis spectabilis Phlomis spectabilis Phlomis aurea Tomas-Barberan et al. (1992) Kumar et al. (1985) Kumar et al. (1985) Kumar et al. (1985) Aboutabl et al. (2002) Lucenin-2 Phlomis aurea Phlomis floccosa El-Negoumy et al. (1986) El-Negoumy et al. (1986) Luteolin Phlomis lychnitis Phlomis crinita Tomas et al. (1986) Kabouche et al. (2005) Luteolin-7-glucoside Phlomis aurea Phlomis floccosa Phlomis lychnitis Phlomis purpurea Phlomis fruticosa El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Tomas-Barberan et al. (1992) Marin et al. (2007) Luteolin-7-rutinoside Phlomis aurea Phlomis floccose El-Negoumy et al. (1986) El-Negoumy et al. (1986) 192 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 3 (Continued ) Compounds Species References Luteolin-7-diglucoside Phlomis aurea Phlomis floccose El-Negoumy et al. (1986) El-Negoumy et al. (1986) Luteolin-7-p-coumaroylglucoside Phlomis aurea Phlomis floccosa Phlomis lychnitis Phlomis fruticosa El-Negoumy et al. (1986) El-Negoumy et al. (1986) Tomas et al. (1986) Marin et al. (2007) Luteolin-7-glucuronide Luteolin-7-rhamnosylglucoside Luteolin-7-O-[4-O-acetyl-␣-rhamnopyranosyl-(1→2)]-␤-glucuronopyranoside Phlomis fruticosa Phlomis fruticosa Phlomis lunariifolia Marin et al. (2007) Marin et al. (2007) Calis and Kirmizibekmez (2004) Luteolin-7-O-␤-glucopyranoside Phlomis aurea Phlomis lunariifolia Phlomis brunneogaleata Phlomis crinita Phlomis tuberosa Phlomis younghusbandii Mohamed et al. (2000) Calis and Kirmizibekmez (2004) Kirmizibekmez et al. (2004) Kabouche et al. (2005) Calis et al. (2005) Gao et al. (2007) Luteolin-7-O-(6′′ -␤-d-apiofuranosyl)-␤-d-glucopyranoside Phlomis nisssoli Bucar et al. (1998) Naringenin Phlomis angustissima Phlomis fruticosa Phlomis caucasica Yalcin et al. (2005) Marin et al. (2007) Delazar et al. (2008) Naringenin-7-glucoside Naringenin-7-p-coumaroylglucoside Phlomisflavosides A Phlomisflavosides B Quercetin-3-O-␤-d-glucopyranoside Rutin Tricin-7-glucoside Phlomis aurea Phlomis aurea Phlomis spinidens Phlomis spinidens Phlomis aurea Phlomis caucasica Phlomis fruticosa El-Negoumy et al. (1986) El-Negoumy et al. (1986) Takeda et al. (2001) Takeda et al. (2001) Aboutabl et al. (2002) Delazar et al. (2008) Marin et al. (2007) Vicenin-2 Phlomis aurea Phlomis floccosa Phlomis fruticosa El-Negoumy et al. (1986) El-Negoumy et al. (1986) Marin et al. (2007) Phlomis tuberose Ersöz et al. (2001b) 8-O-Acetylshanzhiside methyl ester Phlomis rigida Phlomis spinidens Phlomis medicinalis Phlomis umbrosa Phlomis younghusbandii Takeda et al. (2000) Takeda et al. (2001) Yu et al. (2006) Liu et al. (2007) Gao et al. (2007) 8-Acetylshanzhigenin methyl ester and 8-acetyl-1-epishanzhigenin methyl ester 6-O-Acetyl-shanzhiside methyl ester Phlomis umbrosa Phlomis medicinalis Guo and Cheng (2001) Yu et al. (2006) Auroside Phlomis linearis Phlomis aurea Phlomis angustissima Calis et al. (1991) Mohamed et al. (2000), Aboutabl et al. (2002) Yalcin et al. (2005) Barlerin 141 Barlerin (8-O-acetylshanzhiside methyl ester) Brunneogaleatoside Chlorotuberoside Phlomis rotata Phlomis younghusbandii Phlomis brunneogaleata Phlomis tuberosa Zhang et al. (1991) Kasai et al. (1994) Kirmizibekmez et al. (2004) Calis et al. (2005) Dehydropentstemoside Phlomis rotata Phlomis medicinalis Zhang et al. (1991) Yu et al. (2006) Iridoids 8-O-Acetylshanzhiside Deoxypulcheloside I Phlomis rigida Takeda et al. (2000) 5-Deoxypulchelloside I Phlomis longifolia var. longifolia Phlomis lunariifolia Ersöz et al. (2001a) Calis and Kirmizibekmez (2004) 5-Desoxysesamoside Phlomis tuberosa 3-Epiphlomurin 8-Epiloganin Phlomis aurea Phlomis grandiflora var. grandiflora Phlomis aurea 6-␤-hydroxyipolamide Phlomis rigida Alipieva et al. (2000), Calis et al. (2005) Mohamed et al. (2000) Takeda et al. (1999) Mohamed et al. (2000), Aboutabl et al. (2002) Takeda et al. (2000) Ipolamiide Phlomis linearis Phlomis armeniaca Phlomis aurea Phlomis brunneogaleata Calis et al. (1991) Saracoglu et al. (1995) Mohamed et al. (2000) Kirmizibekmez et al. (2004) Lamalbide Phlomis longifolia var. longifolia Phlomis tuberosa Ersöz et al. (2001a) Alipieva et al. (2000), Ersöz et al. (2001b), Calis et al. (2005) 193 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 3 (Continued ) Compounds Species References Phlomis linearis Phlomis aurea Phlomis herba-ventis ssp. pungens Phlomis pungens var. pungens Phlomis physocalycoside Phlomis angustissima Calis et al. (1991) Mohamed et al. (2000), Aboutabl et al. (2002) Alipieva et al. (2000) Ismailoglu et aL. (2002) Ersöz et al. (2003) Yalcin et al. (2005) Lamiridoside Phlomis rigida Phlomis spinidens Takeda et al.(2000) Takeda et al. (2001) Penstemoside Phlomis younghusbandii Kasai et al. (1994) Phlomiol Phlomis longifolia var. longifolia Phlomis younghusbandii Ersöz et al. (2001a) Phlomiside (=gentiobioside) Phlomurin Phlorigidoside A (2-O-acetyllamiridoside) Phlorigidoside B (8-O-acetyl-6-␤-hydroxyipolamide) Phlomis aurea Phlomis aurea Phlomis rigida Phlomis rigida Aboutabl et al. (2002) Mohamed et al. (2000) Takeda et al. (2000) Takeda et al. (2000) Phlorigidoside C (5-deoxysesamoside) Phlomis rigida Phlomis spinidens Takeda et al. (2000) Takeda et al. (2001) Phloyosides I (7-epiphlomiol) Phlomis rotata Phlomis younghusbandii Phlomis mongolica Phlomis tuberosa Phlomis medicinalis Phlomis umbrosa Zhang et al. (1991) Kasai et al. (1994) Li and Zhang (2000) Calis et al. (2005) Yu et al. (2006) Liu et al. (2007) Phloyosides II Phloyosides II Pulchelloside-I Phlomis younghusbandii Phlomis mongolica Phlomis younghusbandii Kasai et al. (1994) Li and Zhang (2000) Gao et al. (2007) Sesamoside Phlomis tuberosa Phlomis younghusbandii Phlomis medicinalis Alipieva et al. (2000), Calis et al. (2005) Kasai et al. (1994), Gao et al. (2007) Yu et al. (2006) Shanzhigenin methyl ester and 1-epishanzhigenin methyl ester Phlomis umbrosa Guo and Cheng (2001) Shanzhiside methyl ester Phlomis rotata Phlomis younghusbandii Phlomis rigida Phlomis spinidens Phlomis longifolia var. longifolia Phlomis tuberosa Zhang et al. (1991) Kasai et al. (1994), Gao et al. (2007) Takeda et al. (2000) Takeda et al. (2001) Ersöz et al. (2001a) Ersöz et al. (2001b), Alipieva et al. (2000), Calis et al. (2005) Calis and Kirmizibekmez (2004) Yu et al. (2006) Liu et al. (2007) Lamiide Gao et al. (2007) Phlomis lunariifolia Phlomis medicinalis Phlomis umbrosa 6′′ -Syringyl-sesamoside Phenylethyalcohol glycosides Phlomis umbrosa Liu et al. (2007) Acteoside = verbascoside Phlomis armeniaca Phlomis grandiflora var. grandiflora Phlomis aurea Phlomis longifolia var. longifolia Phlomis tuberosa Phlomis samia Phlomis phsocalys Phlomis lunariifolia Phlomis brunneogaleata Phlomis crinita Phlomis umbrosa Phlomis caucasica Phlomis lanceolata Saracoglu et al. (1995) Takeda et al. (1999) Mohamed et al. (2000) Ersöz et al. (2001a) Ersöz et al. (2001b), Calis et al. (2005) Kyriakopoulou et al. (2001) Ersöz et al. (2003) Calis and Kirmizibekmez (2004) Kirmizibekmez et al. (2004) Kabouche et al. (2005) Liu et al. (2007) Delazar et al. (2008) Nazemiyeh et al. (2008) Decaffeoylacteoside Phlomis tuberosa Phlomis umbrosa Calis et al. (2005) Liu et al. (2007) Dimethylether myricoside Echinacoside Phlomis oppostiflora Phlomis brunneogaleata Calis et al. (2005) Kirmizibekmez et al. (2004) Forsythoside B Phlomis armeniaca Phlomis longifolia var. longifolia Phlomis tuberosa Saracoglu et al. (1995) Ersöz et al. (2001a) Ersöz et al. (2001b), Calis et al. (2005) 194 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 3 (Continued ) Compounds Species References Phlomis spinidens Phlomis aurea Phlomis pungens var. pengens Phlomis phsocalys Phlomis lunariifolia Phlomis brunneogaleata Phlomis caucasica Phlomis lanceolata Takeda et al. (2001) Aboutabl et al. (2002) Ismailoglu et al. (2002) Ersöz et al. (2003) Calis and Kirmizibekmez (2004) Kirmizibekmez et al. (2004) Delazar et al. (2008) Nazemiyeh et al. (2008) Glucopyranosyl-(1→G (i)-6)-martynoside 3-Hydroxy-4-methoxy-␤-phenylethoxy-O-[2,3-diacetyl-␣-l-rhamnopyranosyl(1→3)]-4-O-feruloyl-[␤-d-apio-furapiofuranosyl-(1→6)]-␤-dglucopyranoside(2′′ ′ ,3′′ ′ -diacetyl-O-detonyoside D) 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) Isoverbascoside Phlomis brunneogaleata Phlomis umbrosa Kirmizibekmez et al. (2004) Liu et al. (2007) Phlomis umbrosa Liu et al. (2007) Phlomis brunneogaleata Phlomis umbrosa Kirmizibekmez et al. (2004) Liu et al. (2007) Integrifoliosides A (3,4-dihydroxy-␤-phenylethoxy-O-␤-d-apiofuranosyl-(1→4)-␣l-rhamnopyranosyl-(1→3)-4-O-feruloyl-␤-d-glucopyranoside) 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 integrifolia Phlomis brunneogaleata Saracoglu et al. (2003) Kirmizibekmez et al. (2004) Leucosceptoside A Phlomis armeniaca Phlomis longifolia var. longifolia Phlomis physocalyx Phlomis tuberosa Saracoglu et al. (1995) Ersöz et al. (2001a) Ersöz et al. (2003) Calis et al. (2005) Martynoside Myricoside Myricoside-3′′ -O-methylether {3,4-dihydroxy-␤-phenylethoxy-O-␤-d-apiofuranosyl-(1→>3)-␣-lrhamnopyranosyl-(1→3)-4-O-feruloyl-␤-d-glucopyranoside} 2-Phenylethyl-O-␤-Xylopyranosyl-(1→2)-␤-glucopyranoside Phlomisethanoside Physocalycoside (3-hydroxy-4-methoxy-␤-phenylethoxy-O-[␣-l-rhamnopyranosyl(1→2)-␣-l-rhamnopyranosyl-(1→3)]-4-O-feruloyl-[␤-d-glucopyranosyl-(1→6)]-␤d-glucopyranoside) Samioside Phlomis physocalyx Phlomis oppostiflora Phlomis oppostiflora Ersöz et al. (2003) Calis et al. (2005) Calis et al. (2005) Phlomis aurea Phlomis grandiflora var. grandiflora Phlomis physocalycoside Mohamed et al. (2000) Takeda et al. (1999) Ersöz et al. (2003) 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) Serratumoside A {3-hydroxy,4-methoxy-␤-phenylethoxy-O-␤-d-apiofuranosyl(1→3)-␣-l-rhamnopyranosyl-(1→3)-4-O-feruloyl-␤-d-glucopyranoside} Wiedemannioside C Phlomis samia Phlomis umbrosa Phlomis oppostiflora Kyriakopoulou et al. (2001) Liu et al. (2007) Calis et al. (2005) Phlomis physocalyx Ersöz et al. (2003) Alyssonoside Phlomis pungens var. pengens Phlomis integrifolia Phlomis angustissima Phlomis umbrosa Ismailoglu et al. (2002) Saracoglu et al. (2003) Yalcin et al. (2005) Liu et al. (2007) Cistanoside B Phlinoside A (3,4-dihydroxy-␤-phenylethoxy-O-␤-d-glucopyranosyl-(1→2)-␣-lrhamnopyranosyl-(1→3)-4-O-caffeoyl-␤-d-glucopyranoside) Phlinoside B (3,4 dihydroxy-␤-phenylethoxy-0-␤-d-xylopyranosyl-(1→2)␣-l-rhamnopyranosyl-(1→3)-4-O-caffeoyl-␤-d-glucopyranoside) Phlomis mongolica Phlomis linearis Li and Zhang (2000) Calis et al. (1990) Phlomis linearis Phlomis armeniaca Calis et al. (1990) 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 Phlomis armeniaca Phlomis lanceolata Calis et al. (1990) Saracoglu et al. (1995) Nazemiyeh et al. (2008) Phlinoside D (3,4-dihydroxy-␤-phenylethoxy-O-␤-d-xylopyranosyl-(1→2)-␣-lrhamnopyranosyl-(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 Teucrioside Phlomis linearis Calis et al. (1991) Phlomis linearis Calis et al. (1991) Phlomis angustissima Yalcin et al. (2005) Phlomis armeniaca Saracoglu et al. (1995) Phlomis younghusbandii Gao et al. (2007) Phlomis lunariifolia Calis and Kirmizibekmez (2004) Acetophenone glycosides 4-Hydroxyacetophenone 4-O-(6′ -O-␤-d-apiofuranosyl)-␤-d-glucopyranoside Acridone alkaloid Daucosterol Aliphatic alcohol glycoside Lunaroside-1-octen-3-yl-O-␤-apiofuranosyl-(1→6)-O-[␤-glucopyranosyl-(1→2)]␤-glucopyranoside 195 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 3 (Continued ) Compounds Species References Benzyl alcohol glycosides Benzyl alcohol-O-␤-xylopyranosyl-(1→2)-␤-glucopyranoside Caffeic acid esters Phlomis aurea Mohamed et al. (2000) Chlorogenic acid Phlomis brunneogaleata Phlomis longifolia var. Longifolia Kirmizibekmez et al. (2004) Ersöz et al. (2001a) 3-O-Caffeoylquinic acid methyl ester 5-O-Caffeoylshikimic acid Phlomis brunneogaleata Phlomis brunneogaleata Kirmizibekmez et al. (2004) Kirmizibekmez et al. (2004) Phlomis medicinulis Phlomis younghusbandii Katagari et al. (1991) Katagari et al. (1991), Kasai et al. (1994) Katagari et al. (1991) Diterpenoid glycosyl esters Baiyunoside Phlomisoside I Phlomisoside II Phlomis medicinalis Phlomisoside III (␤-d-xylopyranosyl(l→2)-␤-d-glucopyranosyl ester-15,16-epoxy-8,13 (16),14-labdatrien-19-oic acid) Phlomis younghusbandii Phlomisoside IV (␣-l-rhamnopyranosyh (1→2)-␤-d-glucopyranosyl ester-15,16-epoxy-8,13 (16),14-labdatrien-19-oic acid) Phlomis younghusbandii Katagari et al. (1991), Kasai et al. (1994) Phlomis spinidens Takeda et al. (2001) Phlomis aurea Phlomis brunneogaleata Mohamed et al. (2000) Kirmizibekmez et al. (2004) Phlomis grandiflora var. grandiflora Phlomis spinidens Takeda et al. (1999) Takeda et al (2001) Phlomis aurea Phlomis lunariifolia Mohamed et al. (2000) Calis and Kirmizibekmez (2004) Phlomis armeniaca Phlomis lunariifolia Saracoglu et al. (1995) Calis and Kirmizibekmez (2004) Phlomis armeniaca Saracoglu et al. (1995) Phlomis lunariifolia Phlomis tuberosa Calis and Kirmizibekmez (2004) Calis et al. (2005) (7S, 8R)-Dehydroconiferyl alcohol-8-5′ -dehydroconiferyl aldehyde 4-O-␤-d-glucopyranoside Dihydrodehydrodiconiferyl alcohol-9-O-␤-d-glucopyranoside Phlomis oppostiflora Calis et al. (2005) Phlomis chimerae Phlomis lunariifolia Phlomis tuberosa Ersöz et al. (2002) Calis and Kirmizibekmez (2004) Calis et al. (2005) Dihydrodehydrodiconiferyl alcohol 9′ -O-␤-d-glucopyranoside Phlomis lunariifolia Phlomis tuberosa Calis and Kirmizibekmez (2004) Calis et al. (2005) Longifloroside A ((−)-4-O-methyldehydrodiconiferyl alcohol-9′ -O-␤-d-glucopyranoside) (−)-4-O-Methyldihydrodehydrodiconiferyl alcohol-9′ -O-␤-d-glucopyranoside Phlomis chimerae Ersöz et al. (2002) Phlomis chimerae Ersöz et al. (2002) Phlomis spectabilis Phlomis spectabilis Phlomis viscosa Kumar et al. (1992) Kumar et al. (1992) Çalis et al. (2004) Phlomis viscosa Phlomis viscosa Çalis et al. (2004) Çalis et al. (2004) Phlomis aurea Phlomis lunariifolia Mohamed et al. (2000) Calis and Kirmizibekmez (2004) Phlomis brunneogaleata Kirmizibekmez et al. (2004) Phlomis tuberosa Phlomis angustissima Calis et al. (2005) Yalcin et al. (2005) Katagari et al. (1991), Kasai et al. (1994) Phlomis medicinalis Lignans Lariciresinol-4′ -O-␤-d-glucoside Liriodendrin Megastigmane glucosides Citroside Phlomuroside Monoterpen glycosides Betulalbuside A 8-Hydroxylinaloyl 3-O-␤-d-glucopyranoside Neolignan glucosides Dehydrodiconiferylalcohol 9′ -O-␤-d-glucopyranoside Nortriterpens 28-Noroleana-16,21-diene-3␣,19 ␣,23,29-tetrol 28-Noroleana-l6,21-diene-3 ␣,19 ␣,29-triol-23-al. (17S)-2␣,18 ␤,23-Trihydroxy-3,19-dioxo-19(18→17)-abeo-28-norolean-12-en-25-oic acid ␤-d-glucopyranosyl ester Oleanane-type triterpen glycosides 29-(␤-d-glucopyranosyloxy)-2␣,3 ␤,23-trihydroxyolean-12-en-28-oic acid 30-(␤-d-glucopyranosyloxy)-2␣,3 ␤,23-trihydroxyolean-12-en-28-oic acid Phenolic glycosides Syringin 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 ␤-Sitosterol 3-O-␤-d-glucopyranoside and 1-methyl-O- ␤-d-glucopyranoside Syringaresinol-4-O-␤-d-Glucopyranoside 196 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Fig. 1. Main components present in Phlomis species. characteristic of the Lamioideae subfamily, as indicated by reports of their presence in the genus Anisomeles, Ballota, Galeopsis, Leonurus, Marrubium, Phlomis, Sideritis and Stachys (Marin et al., 2004; Tomas-Barberan et al., 1992; Gil Munoz, 1993). They have not been detected in the subfamily Nepetoideae of the Lamiaceae, and are encountered infrequently in other plant families. This is in contrast to flavonol 3-O-p-coumaroylglycosides, which are relatively common. Within the Lamioideae, the 7-O-p-coumaroylglycosides of apigenin (9) are more widespread than the corresponding chrysoeriol derivatives. However, the (E)- and the (Z)-forms of chrysoeriol 7-O-(3′′ -p-coumaroyl) glucoside, as reported in Phlomis fruticosa, also occur in Phlomis lychnitys L. (Tomas et al., 1986) and Ballota acetabulosa (Sahpaz et al., 2002), and the (E)-form is known from Stachys chrysantha, Stachys candida (Skaltsa et al., 2000), Marrubium cylleneum (Michelis et al., 2002), Phlomis integrifolia (Saracoglu et al., 2003) and Phlomis crinita (Kabouche et al., 2005). Chryso- eriol 7-O-(3′′ ,6′′ -di-(E)-p-coumaroyl)glucoside was reported from Marrubium velutinum (Karioti et al., 2003) and chrysoeriol 7-O-pcoumaroylglucosides, in which the linkage of the acid to the sugar was not determined, were detected in the leaves or trichomes of Phlomis aurea, Phlomis floccosa (El-Negoumy et al., 1986), Ballota acetabulosa (Mericli et al., 1988), Phlomis purpurea and Ballota hirsute (Gil Munoz, 1993). Therefore, p-coumaroyl esters of chrysoeriol 7-O-glucoside are characteristic of the Lamioideae genus Phlomis, Ballota and Marrubium, and to some extent Stachys, although the corresponding apigenin (9) glycoside is more common (Marin et al., 2004). 4.3. Iridoids A number of iridoid glycosides have been isolated from the Phlomis species. The most frequent iridoids are shanzhiside methyl I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 ester (16), 8-O-acetylshanzhiside methyl ester (17) and lamiide (18). For example shanzhiside methyl ester (16) (Fig. 1) was reported in nine Phlomis species including Phlomis rotate (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 tubrosa (Ersöz et al., 2001b; Alipieva et al., 2000), Phlomis lunariifolia (Calis and Kirmizibekmez, 2004), Phlomis medicinalis (Yu et al., 2006), Phlomis umbrosa (Liu et al., 2007). Several new iridoid structures have been isolated from Phlomis species. 3-epiphlomurin, phlomurin and phlomiside were characterized from Phlomis aurea (Mohamed et al., 2000). In addition, in Phlomis longifolia var. longifolia, a new iridoid structure was identified as phlomiol (Ersöz et al., 2001a). Ersöz et al. (2001b) purified 8-O-acetylshanzhiside, from Phlomis tuberosa. Phloyosides I and II (from Phlomis younghusbandii) and III (from Phlomis mongolica) were purified by Kasai et al. (1994) and Li and Zhang (2000), respectively. Takeda et al. (2000) isolated three new iridoids; phlorigidosides A, B and C from Phlomis rigida. 4.4. Phenylethylalcohol glycosides structures The genus Phlomis is rich in phenylethylalcohol glycosides, e.g., verbascoside (acteoside) (19) and forsythoside B (20) (Fig. 1), which have been reported, respectively, from 13 and 11 Phlomis species as seen in Table 3. However, within the Lamiaceae family, verbascoside (19) was reported previously from Faradaya, Lamium, Leonurus, Marrubium, Phlomis, Prostanthera, Oxera, Scutellaria, Sideritis, and Stachy. However, forsythoside B (20) was only found in the genera Ballota, Phlomis, Marrubium, Scutellaria and Stachy. Caffeic acid conjugates are considered to be chemotaxonomically important characters within the Lamiaceae family (Hegnauer, 1989; Grayer and Kok, 1998). Verbascoside (19) and related compounds that contain a caffeic acid moiety, sugars and a phenylethyl group occur characteristically in the ajugoid Lamiaceae (Grayer and Kok, 1998). Several new phenylethylalcohol structures have been identified from Phlomis genus. In Phlomis linearis, five new structures were identified as Phlinoside A, B, C, D and E (Calis et al., 1990, 1991). Indeed, the same compounds were isolated from Phlomis armeniaca (phlinoside B) and from Phlomis armeniaca and Phlomis lanceolata (phlinoside C) in addition to their identification in Phlomis linearis. In Phlomis longifolia var. longifolia, another structure has been elucidated and named phlomisethanoside (Takeda et al., 1999), and samioside has been characterized from Phlomis samia (Kyriakopoulou et al., 2001). Alyssonoside was characterized from Phlomis pungens var. pungens (Ismailoglu et al., 2002), Phlomis integrifolia (Saracoglu et al., 2003) and Phlomis umbrosa (Liu et al., 2007) and teucrioside was isolated from Phlomis armeniaca (Saracoglu et al., 1995). 4.5. Other secondary metabolites In the Phlomis genus, many other secondary metabolites are encountered such as acetophenone glycoside, acridone alkaloid, aliphatic alcohol glycoside, benzyl alcohol glycoside, caffeic acid esters, diterpenoid glycosyl ester, lignan, megastigmane glucoside, monoterpene glycosides, neolignan glucoside, nortriterpenes, oleanane-type triterpene glycoside, phenolic glycosides and pyrrolidinium derivatives. Katagiri et al. (1991) purified and characterized four new diterpene glycosyl ester structures (Phlomisoside I, II, III and IV) from Phlomis younghusbandi and Phlomis medicinalis. 197 5. Pharmacological properties of Phlomis species 5.1. Antidiabetic activity (in vivo) Several Phlomis species are recognized for their antidiabetic properties, i.e., Phlomis aurea, Phlomis ocymifolia (Table 1). Their activity may be due essentially to their ability to protect liver and pancreas integrity by reducing the oxidative stress in diabetes or by stimulating the production of enzymes implicated in glucose metabolism. Sarkhail et al. (2007) evaluated the antihyperglycemic activity of Phlomis anisodonta methanolic extract (PAME) in a streptozocin (STZ)-induced model of diabetes in rats. Streptozocin provokes an irreversible destruction of pancreatic ␤-cells, causing degranulation and reduced secretion of insulin. STZ-induced diabetes is characterized by severe loss in body weight, and the presence of diabetic complications such as, myocardial, cardiovascular, gastrointestinal, nervous, kidney and urinary bladder dysfunction due to oxidative stress. The administration of PAME (400 mg kg−1 ) for 10 days showed a significant reduction in blood glucose, an increase in plasma insulin levels and a decrease in body weight loss in STZtreated rats. The observed antihyperglycemic effect was the result of the ability of PAME to improve plasma ferric reducing antioxidant power, reduce liver lipid peroxidation and combat oxidative stress through the activation of hepatic antioxidant enzymes. PAMEtreated diabetic rats indicated a significant increase in hepatic superoxide dismutase, catalase, and glutathione peroxidase activities (Sarkhail et al., 2007). 5.2. Antinociceptive activity (in vivo) Analgesic properties have been reported for some Phlomis species like Phlomis caucasica, Phlomis fruticosa, Phlomis herba-venti, Phlomis lychnitis (Table 1). Sarkhail et al. (2003) confirmed the analgesic properties of three Phlomis species and proved their pain reliving activity. Total extract of Phlomis olivieri and Phlomis anisodonta at a dose of 150 mg kg−1 and Phlomis persica at a dose of 100 mg kg−1 reduce significantly the number of acetic acid-induced writhes in mice, revealing antinociceptive properties comparable to indomethacin (Sarkhail et al., 2003). Mohajer et al. (2005) reported analgesic properties 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 both formalin 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 commonly used as digestive aid and to treat gastric ulcers and aches. Thus, it is not surprising to find that extracts of Phlomis species are antiulcerogenic. Two different studies have confirmed the gastroprotective activity of Phlomis grandiflora and Phlomis crinita subsp. mauritanica aqueous extract (Gürbüz et al., 2003, Limem-Ben Amor et al., 2009). Aqueous extracts of P. grandiflora were shown to possess a high protective effect (100% inhibition) against EtOH-induced ulcerogenesis in rats. Ethanol induces longitudinal ulcer lesions in the glandular part of the stomach and stimulates leukotrienes, the 5lipoxygenase 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 extract of P. grandiflora were completely protected from any visible damage (Gürbüz et al., 2003). Upon histopathological examination the aqueous (2.67 g/kg) and methanol extracts (2.41 g/kg) of P. 198 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 grandiflora exhibited high inhibitory activity of the ethanol effect in stomach sections. Gastric protection provided by these plant extracts was better than the reference drug misoprostol (400 ␮g/kg) (Gürbüz et al., 2003). The study of Gürbüz et al. (2003) supports the ethnopharmacological use of P. grandiflora. It demonstrates that these species possess high gastroprotective activity. Limem-Ben Amor et al. (2009) demonstrated that the aqueous extract (300 mg kg−1 ) of Phlomis crinita subsp. mauritanica reduced ulcerogenesis induced with alcohol 50◦ , in mice. It reduces ulcerogenesis by 91% in comparison to cimetidine (the positive control), which itself inhibits ulcerogenesis by 71%. Phlomis crinita subsp. mauritanica is used in folk medicine to treat lesions and burns, but, in the work realized by Limem-Ben Amor et al. (2009), it was used to protect the stomach epithelia against lesions induced by the alcohol. These finding supports the ethnopharmacological uses of Phlomis species as gastroprotective plants. PUAE may be beneficial in the treatment of allergic diseases (Shin et al., 2008). Passive cutaneous anaphylaxis is one of the most important in vivo models of anaphylaxis for local allergic reactions. The local extravasations can be induced by a skin injection of the antibody anti-dinitrophenyl (anti-DNP IgE) followed by an antigenic challenge. Both oral and intraperitoneal administrations of PUAE (0.001–1 g/kg) dose dependently inhibit passive cutaneous anaphylaxis and histamine release from rat peritoneal mast cells activated by 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-1 cells) when PUAE (1 mg/mL) was added, transiently and significantly increased compared with that of basal cells. In HMC-1 cells induced with the calcium ionophore A23187 and phorbol 12-myristate 13-acetate, PUAE (0.1 and 1 mg/mL) inhibited the secretion of tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-6 and interleukin (IL)-1␤ (Shin et al., 2008; Shin and Lee, 2003). 5.4. Protection of the vascular system (in vitro) 5.6. Anticancer activity (in vitro) Aortic rings, isolated from rats, can be induced to contract upon treatment with phenylephrine. Conversely, acetylcholine can induce relaxation. Electrolysis of a physiological solution has been shown to generate free radicals such as superoxide radical (O2− ), hydrogen peroxide (H2 O2 ) and hydroxyl radical (• OH). Interestingly, the incubation of aortic rings with the aqueous extract (200 ␮g/ml), phenylethylalcohol fraction (100 ␮g/ml) and iridoid fraction (150 ␮g/ml), prepared from Phlomis pungens var. pungens, prevented the inhibition of acetylcholine response induced by electrolysis. However, the protection afforded by these fractions was partial, as acetylcholine-induced relaxation was still reduced as compared to the control response obtained before electrolysis (Ismailoglu et al., 2002). Major components of the phenylethylalcohol fraction including forsythoside B and alyssonoside provided partial protection at a concentration of 10−4 M against the electrolysis-induced inhibition of the acetylcholine response in aortic rings. The major component of the iridoid fraction, lamiide, was also tested and was found ineffective at a concentration of 10−4 M in preventing electrolysisinduced impairment of the acetylcholine response (Ismailoglu et al., 2002). The protective activity of different extracts and compounds isolated from Phlomis pungens var. pungens against free radicalinduced impairment of endothelium-dependent relaxation may be related to their free radical scavenging property (Ismailoglu et al., 2002). It is true that Phlomis pungens var. pungens is not reported in folk medicine (Table 1) but found that some Phlomis species like Phlomis lychnitis or Phlomis rotate, Phlomis purpurea possess antihemorrhoidal and cardiotonic activities, and promotes blood circulation and eliminates blood stasis. Although detailed studies are lacking, future work will likely produce interesting results. 5.5. Anti-inflammatory and antiallergic activities (in vivo) Phlomis umbrosa is used in folk medicine to treat kidney and brain problems and it has been shown to have hemostatic properties. Shin et al. evaluated the anti-inflammatory properties of this specie. To assess the contribution of the aqueous extract of Phlomis umbrosa, Turcz root (PUAE) anaphylaxis, an in vivo model of systemic anaphylaxis, was used. Compound 48/80 (0.008 g/kg BW) was used as a fatal systemic anaphylaxis inducer. PUAE (0.01–1 g/kg) inhibited both the systemic allergic reaction (Shin et al., 2008) and systemic anaphylaxis (Shin and Lee, 2003) induced by 48/80. PUAE inhibited mastocyte dependent allergic reactions and reduced inflammatory cytokine and histamine secretion, suggesting that Phenyl propanoid caffeic acid, phenylethyl alcohol and phenylethylalcohol glycosides isolated from Phlomis armeniaca were found to show cytotoxic activity against several kinds of cancer cells. However they did not affect the growth and viability of primary cultured rat hepatocytes (Saracoglu et al., 1995). Verbascoside, isoverbascoside, forsythoside B and 3O-caffeoylquinic acid methyl ester isolated from Phlomis brunneogaleata 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 activities. They reduce fever, attenuate cough, treat throat infections and eliminate worm infections (Table 1). They are rich in essential oils as recognized by their antimicrobial activity. Consequently, many studies have evaluated the antimicrobial activities of essential oils extracted from Phlomis species. 5.7.1. Antibacterial activity Essential oils extracted from different Phlomis species show important antibacterial effects against a wide range of pathogenic bacteria. Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus and Pseudomonas aeruginosa seem to be the most sensitive bacteria to Phlomis essential oils (Table 4). In addition to essential oils, methanol extracts of some Phlomis species (Phlomis bruguieri, Phlomis herba-venti, Phlomis olivieri) possess antibacterial effects against Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, Staphylococcus sanguis and Pseudomonas aeruginosa (Morteza-Semnani et al., 2006). 5.7.2. Antifungal activity As can be seen in Table 4, methanol extracts, ethanol extracts and essential oils extracted from the majority of Phlomis species exhibit antifungal activity toward different Candida species (Candida albicans, Candida glabrata, Candida tropicalis). The methanol extracts of Phlomis bruguieri, Phlomis herba-venti and Phlomis olivieri inhibit the growth of Aspergillus niger (Morteza-Semnani et al., 2006). The ethanol extract of Phlomis fruticosa has antifungal activity against Aspergillus ochraceus, Cladosporium caladosporioides and Phomopsis helianthi whereas the essential oil of this Phlomis species inhibits only the growth of the two last fungi (Ristic et al., 2000). In addition to its anti-Candida activity, the essential oil of Phlomis lanata inhibits the growth of Torulopis glabrata (Couladis et al., 2000). Demirci et al. (2008) reported the antifungal activity of Phlomis russeliana and Phlomis grandiflora var. grandiflora essential oils 199 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 4 Antimicrobial activity of Phlomis species. Microbes Phlomis species (extracts and compounds) with antimicrobial activity References Phlomis fruticosa (essential oil, ethanol extract) Phlomis samia (Samoside) Phlomis crinita ssp. mauritanica Ristic et al. (2000) Kyriakopoulou et al. (2001) Limem-Ben Amor et al. (2008) Escherichia coli Phlomis fruticosa (essential oil) Phlomis lanata (essential oil) Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Phlomis russeliana (essential oil) Phlomis grandiflora var. grandiflora (essential oil) Ristic et al. (2000) Couladis et al. (2000) Kyriakopoulou et al. (2001) Aligiannis et al. (2004) Aligiannis et al. (2004) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Demirci et al. (2008) Demirci et al. (2008) Klebsiella pneumonia Phlomis lanata (essential oil) Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Couladis et al. (2000) Kyriakopoulou et al. (2001), Aligiannis et al. (2004) Ristic et al. (2000), Aligiannis et al. (2004) Aligiannis et al. (2004) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Micrococcus luteus Phlomis fruticosa (essential oil) Ristic et al. (2000) Staphylococcus aureus Phlomis fruticosa (essential oil) Phlomis samia (Samoside) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Phlomis crinita ssp. mauritanica Ristic et al. (2000) Kyriakopoulou et al. (2001) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Limem-Ben Amor et al. (2008) Staphylococcus aureus (multi-drug resistant strains) Staphylococcus epidermidis Phlomis lanceolata (forsythoside B, verbascoside) Nazemiyeh et al. (2008) Phlomis samia (Samoside) Kyriakopoulou et al. (2001) Staphylococcus sanguis Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Salmonella typhimurium Phlomis crinita ssp. mauritanica Limem-Ben Amor et al. (2008) Pseudomonas aeruginosa Phlomis lanata (essential oil) Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Couladis et al. (2000) Kyriakopoulou et al. (2001), Aligiannis et al. (2004) Aligiannis et al. (2004) Aligiannis et al. (2004) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Yersinia enterocolitica Phlomis russeliana (essential oil) Phlomis grandiflora var. Grandiflora (essential oil) Demirci et al. (2008) Demirci et al. (2008) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Aspergillus ochraceus Cladsporium cladosporioides Phlomis fruticosa (ethanol extract) Phlomis fruticosa (essential oil, ethanol extract) Ristic et al. (2000) Ristic et al. (2000) Candida albicans Phlomis lanata (essential oil) Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Phlomis bruguieri (methanol extract) Phlomis herba-venti (methanol extract) Phlomis olivieri (methanol extract) Couladis et al. (2000) Kyriakopoulou et al. (2001), Aligiannis et al. (2004) Aligiannis et al. (2004) Aligiannis et al. (2004) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Morteza-Semnani et al. (2006) Candida glabrata Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Kyriakopoulou et al. (2001), Aligiannis et al. (2004) Aligiannis et al. (2004) Aligiannis et al. (2004) Candida tropicalis Phlomis lanata (essential oil) Phlomis samia (Samoside, essential oil) Phlomis fruticosa (essential oil) Phlomis cretica (essential oil) Couladis et al. (2000) Kyriakopoulou et al. (2001), Aligiannis et al. (2004) Aligiannis et al. (2004) Aligiannis et al. (2004) Bacteria Bacillus subtilis Enterococcus cloacae Enterococcus feacalis Fungi Aspergillus niger 200 I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 Table 4 (Continued ) Microbes Phlomis species (extracts and compounds) with antimicrobial activity References Clostridium perfringens Phlomis russeliana (essential oil) Phlomis grandiflora var. Grandiflora (essential oil) Demirci et al. (2008) Demirci et al. (2008) Phomopsis helianti Rhizopus Torulopis glabrata Phlomis fruticosa (essential oil, ethanol extract) Phlomis lychinitis (non polar extracts) Phlomis lanata (essential oil) Ristic et al. (2000) Lopez et al. (2007) Couladis et al. (2000) Phlomis brunneogaleata (brunneogaleatoside, (2S,4R)-2carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt [(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline inner salt], 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-hydroxyacetophenone 4-O-(6′ -O-␤-d-apiofuranosyl)-␤-d-glucopyranoside, chlorogenic acid, 3-O-caffeoylquinic acid methyl ester, 5-O-caffeoylshikimic acid) Phlomis kurdica (CHCl3 -soluble portion) Kirmizibekmez et al. (2004) Parasites Leishmania donovani Tasdemir et al. (2005) Plasmodium falciparum Trypanosoma brucei rhodesiense Phlomis brunneogaleata (brunneogaleatoside, 3-O-caffeoylquinic acid methyl ester, luteolin 7-O-␤-d-glucopyranoside, chrysoeriol 7-O-␤-d-glucopyranoside, isoverbascoside) Phlomis kurdica (CHCl3 -soluble portion) Phlomis leucophracta (CHCl3 -soluble portion) Phlomis brunneogaleata (brunneogaleatoside, (2S,4R)-2carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt [(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline inner salt], verbascoside, isoverbascoside, forsythoside B, echinacoside, glucopyranosyl-(1→G (i)-6)-martynoside, luteolin 7-O-␤-d-glucopyranoside, chrysoeriol 7-O-␤-d-glucopyranoside, liriodendrin, chlorogenic acid, 3-O-caffeoylquinic acid methyl ester, 5-O-caffeoylshikimic acid) Phlomis kurdica (CHCl3 -soluble portion) Kirmizibekmez et al. (2004) Tasdemir et al. (2005) Tasdemir et al. (2005) Kirmizibekmez et al. (2004) Tasdemir et al. (2005) against Clostridium perfringens. Lopez et al. (2007) described the anti-Rhizopus activity of nonpolar extracts of Phlomis lychinitis. potent scavengers of 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical (Kyriakopoulou et al., 2001; Delazar et al., 2008). 5.7.3. Antiparasitic activity Several compounds purified from Phlomis brunneogaleata show anti-parasite activities against Leishmania donovani, Plasmodium falciparum and Trypanosoma brucei rhodesiense (Kirmizibekmez et al., 2004). The soluble portion of the Phlomis kurdica chloroform extract possesses anti-Leishmania, anti-Plasmodium and anti-Trypanosoma activity whereas the same type of extract prepared from Phlomis leucophrata inhibits only Trypanosoma growth (Tasdemir et al., 2005). The cited antiplasmodial activities are due to the inhibition ability of the purified eonyl-ACP reductase (FabI), a crucial enzyme in the fatty acid biosynthesis of Phlomis falciparum (Kirmizibekmez et al., 2004; Tasdemir et al., 2005). 6. Conclusions 5.8. Antioxidant and antiradical activities (in vitro) Phlomis fruticosa and Phlomis lanata methanol extract have antioxidant activity. They prevent bleomycin-Fe (II) catalyzed arachidonic acid superoxidation (Couladis et al., 2003). Forsythoside B, acteoside (the two major phenylethylalcohol glycoside in Phlomis genus) purified from Phlomis caucasica and samioside prepared from Phlomis samia were found to be The growing significance of natural products in drug discovery and development is obvious. Phlomis is a very valuable genus to the discovery and utilization of natural medicinal products. As future investigations continue, this genus may prove to be a rich source of new compounds for the development of new therapeutic agents. Throughout our literature review we observed that the species of the genus Phlomis is recognizable by variable contents of essential oils. Thus, the main components of Phlomis permitted us to divide this genus into four chemotypes; sesquiterpene-containing chemotypes (germacrene D (1) and ␤-caryophyllene (2)), monoterpene and sesquiterpene-containing chemotype (␣-pinene (3), limonene (4), linalool (5), germacrene D (1) and ␤-caryophyllene (2)), fatty acid, aliphatic compound and alcohol containing chemotype (hexadecanoic acid (6), trans-phytol (7) and 9,12,15-octadecatrien-1-ol (8)) and terpene, fatty acid, aliphatic compound and alcohol containing chemotype (hexadecanoic acid (6), ␣-pinene (3) and germacrene D (1)). Apigenin (9), luteolin (10), naringenin (11), eriodictyol (12) and chryseriol (13) are the most commonly occurring flavonoids in the Phlomis species. They are generally 7- or 3-glycosylated. Phlomis is rich in iridoids like 8-O-acetylshanzhiside methyl ester (17), lami- I.L.-B. Amor et al. / Journal of Ethnopharmacology 125 (2009) 183–202 ide (18) and shanzhiside methyl ester (16), and phenylethylalcohol glycosides. In this last group, we found acteoside and forsythoside B as compounds that occur frequently in this species. The remaining chemical compounds (monoterpene, sesquiterpene, nortriterpene, lignan, neolignan and caffeic acid derivatives) are not well studied with the exception of their essential oils. Studies regarding the pharmacological activity of these species have focused on the antimicrobial effects of essential oils or other extracts. The antidiabetic, the antinociceptive, antiulcerogenic, anti-inflammatory, antiallergic and antioxidant activities of some Phlomis species extracts have been also reported. Most of the mentioned studies were conducted using crude preparations of Phlomis species, and the chemical profiles were not well detailed. 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