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The genus Perovskia Kar.: ethnobotany, chemotaxonomy and phytochemistry: a review

Majid Mohammadhosseini, Alessandro Venditti & Abolfazl Akbarzadeh

To cite this article: Majid Mohammadhosseini, Alessandro Venditti & Abolfazl Akbarzadeh (2019): The genus Perovskia Kar.: ethnobotany, chemotaxonomy and phytochemistry: a review , Toxin Reviews, DOI: 10.1080/15569543.2019.1691013 To link to this article: https://doi.org/10.1080/15569543.2019.1691013

Published online: 29 Nov 2019.

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REVIEW ARTICLE The genus Perovskia Kar.: ethnobotany, chemotaxonomy and phytochemistry: a review

Majid Mohammadhosseinia , Alessandro Vendittib and Abolfazl Akbarzadehc aDepartment of Chemistry, College of Basic Sciences, Shahrood Branch, Islamic Azad University, Shahrood, Iran; bDipartimento di Chimica, Universita di Roma “La Sapienza”, Rome, Italy; cDrug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

ABSTRACT ARTICLE HISTORY Perovskia Kar. is a small genus from the Lamiaceae family which includes a variety of promising Received 19 May 2019 medicinal and phytochemical properties. This review paper was undertaken to integrate all the Accepted 6 November 2019 data published about the ethnobotany, phytochemistry and biological activities of species KEYWORDS belonging to the genus Perovskia during the past decades. A literature survey showed that to Biological activity; date more than forty new compounds belonging to different classes of natural products have chemotaxonomy; ethno- been isolated and successfully characterized from different Perovskia species worldwide. These botany; lamiaceae; Perovskia compounds are extensively discussed in this review article, also from the chemosystematic Kar.; Phytochemistry standpoint. Moreover, these herbal plants and their phytoconstituents have a great potential of biological activity that are described in detail, too.

Introduction these species are endemic in Iran, namely P. abrota- noides Karel., P. artemisoides Boiss. and P. atriplicifolia Herbal plants are of paramount interest for human Benth, which are vegetating in mountain environ- beings and have direct impacts on their lifestyle ments at an average altitude of 2200–4200 m above (Wansi et al. 2018, 2019, Sarker and Nahar 2018a, 2018b). In fact, medicinal plants possessing a large sea level (Mozaffarian 1996, Khaliq et al. 2006). number of phytochemicals and phytoconstituents are According to the literature, there are seven species for among the best remedies for the treatment of a wide this genus in Pakistan (Nasir and Ali 1990, Perveen spectrum of persistent and dangerous diseases et al. 2006). The vernacular names attributed to this “ ” “ ” (Mohammadhosseini 2017b, Mohammadhosseini et al. genus in Persian are Berazamble , Domou and “ ” 2017b). The chemotaxonomy is based upon the classi- Gevereh (Mozaffarian 1996). The photographs of fication of plant species regarding their most abun- three Perovskia species, namely P. abrotanoides Karel., dant and similar constituent compounds in the P. atriplicifolia Benth. and P. scrophulariifolia Bunge are corresponding chemical profiles (Mohammadhosseini shown in Figure 1. et al. 2019) and nowadays this approach of study is Among the Perovskia genus, there is also an entity growing remarkably (Venditti et al. 2018). of problematic classification, namely P. angustifolia The genus Perovskia Kar. (Lamiaceae family) is a Kudr. whose name is currently unresolved (www.the- small genus belonging to the Nepetoideae subfamily, plantlist.org). As shown by Rechinger (1982), the main tribe Mentheae, subtribe Salviinae (Olmstead 2005), distribution regions of the endemic species of this which comprises nine species, also known collectively genus are concentrated in North (Mazandaran), North with the popular name “Russian Sage”: P. abrotanoides Eastern (Golestan, Khorasan Razavi), central (Isfahan) Kar., P. angustifolia Kudrjasch. (syn. P. kudrjaschevii and Southeastern (Khorasan Jonoobi and Sistan & Gorschk. & Pjat.), P. artemisioides Boiss., P. atriplicifolia Baloutchistan) provinces of Iran. Benth. (syn. P. pamirica C.Y.Yang & B.Wang), P. bot- The aim of this review article is to integrate the schantzevii Kovalevsk. & Kochk., P. kudrjaschevii published and available data concerning the genus Gorschk. & Pjataeva, P. linczevskii Kudrjasch., P. scro- Perovskia. To conduct this study, the data were phulariifolia Bunge and P. virgata Kudrjasch. Three of collected through a comprehensive search on

CONTACT Majid Mohammadhosseini [email protected] Department of Chemistry, College of Basic Sciences, Shahrood Branch, Islamic Azad University, Shahrood, Iran ß 2019 Informa UK Limited, trading as Taylor & Francis Group 2 M. MOHAMMADHOSSEINI ET AL.

Figure 1. The photographs of three Perovskia species: A: P. abrotanoides Karel., B: P. atriplicifolia Benth. and C: P. scrophulariifo- lia Bunge.

Scopus database under the title “Perovskia” accessed species type, major constituent components, dominant on 12 September 2017 and revisited on 29 group of constituting natural compounds, the mean October 2019. yield of the obtained essential oils, part(s) of the studied species, sampling area as well as number and Results and discussion total percentage of each profile have been repre- sented. Accordingly, in most of the reported chemical Chemical profiles of the extracted essential oils profiles, oxygenated monoterpenes are among the (1995 to date) major constituent components of the corresponding Many herbal plant species are rich sources of essential oils (Abduganiev et al. 1996, Basher et al. 1997, oils which are stored in their secretory glands and Nuriddinov et al. 1997, Morteza-Semnani 2004, Sajjadi released upon heating. To separate volatile essential et al. 2005, Arabi et al. 2008, Kakhky et al. 2009, oils, traditional hydrodistillation technique has been Sardashti et al. 2013, Hafez Ghoran et al. 2016). In frequently used from long time ago (Akhlaghi et al. accordance with these studies, the main characterized 2009, Shafaghat et al. 2017). However, during the oxygenated monoterpenes were bornyl acetate, 1,8- recent years, some fairly advanced methods have cineole and camphor, among which the highest fre- been employed for fast and effective isolation of quency is due to 1,8-cineole. A perusal of this table essential oils as secondary metabolites from a wide also demonstrates that in some of the reported chem- variety of plant materials (Hashemi-Moghaddam et al. ical profiles (Jassbi et al. 1999, Dabiri and Sefidkon 2014, 2015, 2018). These methods are based on direct 2001, Pourmortazavi et al. 2003, Erdemgil et al. 2008), application of microwave radiation on plant materials despite the negligible differences, the total percentage in a couple of strategies, named microwave assisted- of oxygenated monoterpenes and monoterpene hydrodistillation (MAHD) (Mohammadhosseini 2017a, hydrocarbons were approximately the same and com- Mohammadhosseini et al. 2017a) and solvent free parable. Sesquiterpene hydrocarbons like b-caryophyl- microwave extraction (SFME) (Mohammadhosseini lene, a-caryophyllene and a-humulene were also the et al. 2016), among others. On the other hand, volatile dominant fraction of some of the other profiles of fractions can be separated from different plant organs Perovskia plants (Abduganiev et al. 1996, Dabiri and when using headspace analysis which are either dir- Sefidkon 2001). Regarding the general categories, ectly introduced onto the injection port of GC-MS or a-pinene, limonene, d-3-carene, b-pinene, camphene trapped on the surface of solid phase microextraction and (E)-b-ocimene were found as the predominant (SPME) fibers prior to their injection to gas chromatog- natural compounds in some of the other profiles with raphy instrumentation (Mohammadhosseini 2015a, monoterpene hydrocarbons prevailing groups (Dabiri 2015b). and Sefidkon 2001, Inouye et al. 2001, Nezhadali et al. Characterization of chemical profiles of volatile 2009, Oreizi et al. 2014). Compared to the oxygenated essential oils relating to some species of the genus monoterpenes, non-terpene hydrocarbons were very Perovskia has been the subject of some previous uncommon in the identified profiles of Perovskia spe- reports. In this relation, the brief data concerning each cies with (E)-9-dodecenal, octadecanoic acid methyl chemical profile of the studied plants have been sum- ester, isopropylhexadecanoate as well as 2,2,5,5-tetra- marized in Table 1. As can be seen in this table, the methyl hexane (Ashraf et al. 2014). On the other hand, Table 1. Main components of essential oils, volatile constituents and extracts from different species of Perovskia genus worldwide. Characterization Identified Dominant Extraction or analysis Plant name (s) Main components (%) YEOa group method (s) methods (s) Part(s) Country Num. % Ref. P. scrophulariifolia bornyl acetate (17.8%),b-caryophyllene NRb OMc and SHd HDe GC-MS Whole part Uzbekistan 20 100 (Abduganiev Bunge. (14.2%),a-caryophyllene (11.7%), 7- et al. 1996) isopropyl-5,10-dimethyIbicyclo[4.4.0]- deca-l-3.4-triene (10.1%) and farnesol (7.6%) P. angustifolia 1,8-cineole (12.0–27.5%), a-pinene NR OM HD GC-MS Leaves Kyrgyzystan 37–52 92.2–97.1 (Basher Kudrjasch. (7.3–14.7%), epi-13-manool et al. 1997) (3.8–12.6%), bornyl acetate (1.2–8.7%), camphene (2.5–6.8%), camphor (4.3–6.5%), b-caryophyllene (3.2–6.5%), caryophyllene oxide (1.7–5.9%), a-humulene (2.1–5.2%), humulene epoxide II (1.9–4.8%), caryophylladienol (1.4–4.3%) and borneol (3.0–3.2%) P. scrophulariifolia 1,8-cineole (11.0%), caryophyllene 0.54 OM HD GC-MS Herbal parts Uzbekistan 71 95 (Nuriddinov Bunge oxide (10.0%), camphor (9.0%), et al. 1997) humulene epoxide II (7.9%), bornyl acetate (7.8%) and p-cymene (5.7%) P. atriplicifolia Benth 1,8-cineole (27.5%), d-3-carene (22.3%), 1.32 OM and MHf HD GC, GC-MS and Aerial parts Iran 19 96.4 (Jassbi b-caryophyllene (10.8%) and 13 C-NMR et al. 1999) a-humulene (5.7%) P. atriplicifolia Benth. b-caryophyllene (15.9%), a-humulene 1.69 SH SD GC and GC-MS Aerial parts Iran 38 99.3 (Dabiri and (14.4%), limonene (11.4%), d-3- Sefidkon 2001) carene (9.8%), and T-cadinol (5.4%)g b-caryophyllene (15.5%), a-humulene 1.69 SH 35 99.6 (13.5%), limonene (11.4%), d-3- carene (10.8%), camphor (8.2%) and 1,8-cineole (8.0%)g b-phellandrene (13.6%), camphor 1.57 MH 33 >100 (13.5%), d-3-carene (13.2%), b-caryophyllene (11.7%), 1,8-cineole (10.3%), a-humulene (9.7%) and limonene (9.0%)g 1,8-cineole (19.5%), a-pinene (14.0%), 1.60 MH and OM 39 94.1 camphor (8.6%), limonene (8.6%), b-caryophyllene (8.4%) and a-humulene (6.4%)h 1,8-cineole (15.7%), b-caryophyllene 1.06 OM 37 99.3 (12.3%), camphor (10.2%), a-humulene (9.5%), limonene (7.6%), REVIEWS TOXIN a-pinene (6.3%) and d-3- carene (5.7%)i 1,8-cineole (20.7%), camphor (14.5%), 1.45 OM and MH 38 99.4 limonene (8.6%), b-caryophyllene (7.9%), a-pinene (7.8%), a-humulene (6.3%) and d-3-carene (6.0%)i (continued) 3 Table 1. Continued. 4 Characterization Identified

Dominant Extraction or analysis AL. ET MOHAMMADHOSSEINI M. Plant name (s) Main components (%) YEOa group method (s) methods (s) Part(s) Country Num. % Ref. 1,8-cineole (19.5%), a-pinene (14.0%), 1.47 OM and MH Flowers 40 96.9 camphor (8.6%), limonene (8.6%), b-caryophyllene (8.4%) and a-humulene (6.4%)i b-caryophyllene (12.5%), 1,8-cineole 2.1 OM and MH Leaves 42 95.2 (11.7%), limonene (9.7%), a-humulene (9.4%) and camphor (8.0%)i 1,8-cineole (15.6%), b-caryophyllene 1.64 OM Stems 25 92.5 (11.9%), camphor (11.6%), a-humulene (9.6%), a-terpinyl acetate (6.3%) and bornyl acetate (6.0%)i P. abrotanoides Rakaposhi region: 1,8-cineole (24.4%), NR MH HD GC-MS Aerial parts Japan 9 90.3 (Inouye Karel. a-pinene (23.2%), borneol (10.4%), et al. 2001) d-3-carene (9.2%) and b-pinene (6.2%) Hunza region: 1,8-cineole (27.1%), OM 9 89.7 a-pinene (18.2%), borneol (9.5%), bornyl acetate (8.2%), b-caryophyllene (6.5%), limonene (5.3%) and b-pinene (5.3%) Passu region: 1,8-cineole (25.0%), OM 9 89.1 a-pinene (20.7%), b-caryophyllene (12.3%), borneol (7.9%), d-3-carene (5.3%) and a- humulene (5.3%) P. atriplicifolia Benth. 1,8-cineole þ limonene (4.9–37.3%), NR OM þ MH SFEj GC and GC-MS Aerial parts Iran 11–28k 99.3–100k (Pourmortazavi a-pinene (3.7–15.1%), camphene et al. 2003) (0–6.8%), b-pinene (1.2–5.0%), d-3- carene (1.7–10.3%), camphor (4.2–22.6%), b-caryophyllene (0–10.1%), a-humulene (0–8%) and T-cadinol (0–8.6%) 1,8-cineole þ limonene (29%), camphor SDl 28 100 (14.8%), b-caryophyllene (8.7%), a-pinene (7.3%), a-humulene (6.7%), d-3-carene (5.4%), T-cadinol (3.5%), camphene (2.7%) and b-pinene (2.7%) P. abrotanoides camphor (34.1%), 1,8-cineole (18.0%), 0.97 OM HD GC and GC-MS Flowering Iran 21 100 (Morteza-Semnani Karel. b-caryophyllene (8.2%) and aerial parts 2008) a-humulene (6.5%) P. abrotanoides 1,8-cineole (32.4%), myrcene (13.0%), 2.0 OM HD GC and GC-MS Aerial parts Iran 29 98.9 (Sajjadi Karel. a-pinene (10.2%), camphor (9.1%), et al. 2005) b-caryophyllene (7.9%), a-humulene (6.4%), camphene (5.0%) and a-bisabolol (2.6%) (continued) Table 1. Continued. Characterization Identified Dominant Extraction or analysis Plant name (s) Main components (%) YEOa group method (s) methods (s) Part(s) Country Num. % Ref. P. atriplicifolia Benth. camphor (28.9%), limonene (16.7%), 3.2 OM HD GC-MS Aerial parts Pakistan 18 96.1 (Erdemgil a-globulol (10.2%), trans- et al. 2008) caryophyllene (9.3%) and a-humulene (9.2%) P. abrotanoides camphor (28.4%) and 1,8- 2.41 OM HD GC and GC-MS Aerial parts Iran 24 98.8 (Arabi et al. 2008) Karel. cineole (23.2%) P. abrotanoides camphor (41.6%), 1,8-cineole (10.2%), 0.55 OM HD GC and GC-MS Stem Iran 25 96 (Kakhky Karel. d-3-carene (7.5%), a-pinene (5.8%) et al. 2009) and comphene (4.1%) camphor (32.4%), 1,8-cineole (32.1%), 0.60 Leaf 21 99.5 d-3-carene (9.2%), a-pinene (7.6%), and comphene (6.3%) camphor (26.2%), 1,8-cineole (18.0%), 0.65 Flower 24 94.9 a-pinene (16.0%), d-3-carene (6.2%), and comphene (5.0%) camphor (32.2%), 1,8-cineole (24.5%), 0.50 Root 11 92.4 d-3-carene (6.0%), a-pinene (5.0%), and comphene (3.9%) P. abrotanoides 1,8-cineole (14.8–22.9%), a-pinene 1.69 MH HD GC-MS Flowers Iran 36n 97.5n (Nezhadali Karel. (9.5–31.8%), (E)-ocimine (3.6–9.1%), et al. 2009) b-pinene (3.2–5.6%),@@camphene (3.1–6.4%), b-caryophyllene (2.7–4.4%), a-humulene (2.3–3.9%) and borneol (2.3–3.3%)m 23o 99.4o 37p 97.6p 27q 99.8q P. abrotanoides PFSr: linalool (19.1%), d-3-carene 2.19 OM HD GC-MS Aerial parts Iran 71 96.2 (Sardashti Karel. (18.2%), 1,8-cineole (15.8%), et al. 2013) a-humulene (8.1%) and trans- caryophyllene (8.1%) FSs: b-ocimene (13.9%), 1,8-cineole 2.45 76 97.0 (11.2%), geranyl acetate (10.49), trans-caryophyllene (8.8%), a-humulene (6.6%) and linalool (3.3%) PoFSt: Post flowering stage: b-ocimene 2.35 54 100 (12.9%),@@linalool (11.0%), neryl acetate (8.5%), trans-caryophyllene (5.2%), linaly acetate (5.1%) and a-humulene (4.9%) P. abrotanoides (E)-9-dodecenal (66.5%), octadecanoic NR NH HD GC-MS Stems Pakistan 13 97.4 (Ashraf REVIEWS TOXIN Karel. acid, methyl ester (8.4%) and et al. 2014) 2,2,5,5-tetramethyl hexane (4.0%) hexadecanoic acid, methyl ester Leaves 15 97.5 (27.8%), lupeol (21.5%), octadecenoic acid, methyl ester (18.4%), eicosane (6.2%) and tetradecane (5.2%) (continued) 5 Table 1. Continued. 6 Characterization Identified

Dominant Extraction or analysis AL. ET MOHAMMADHOSSEINI M. Plant name (s) Main components (%) YEOa group method (s) methods (s) Part(s) Country Num. % Ref. Fixed oil: a-amyrin (47.0%), Stems 25 86.0 a-amyrenone (11.8%) and isopropyl- hexadecanoate (6.6%) Fixed oil: a-copaene (11.0%), trans- Leaves 34 86.4 phytol (7.3%), isopropyl hexadecanoate (6.7%) and a-amyrenone (5.2%) P. abrotanoides Baluchistan province: 1,8-cineole NR MH HD GC-MS Air- Iran 41 94.9 (Oreizi Karel. (14.4%), d-3-carene (8.6%), dried et al. 2014) a-humulene (8.3%), b-caryophyllene flowers (8.2%), a-pinene (7.0%) and borneol (6.2%) Khorasan province: camphor (19.2%), OM 29 96.6 1,8-cineole (15.5%), epi-a-cadinol (7.0%), a-pinene (8.4%), d-3-carene (6.3%), borneol (5.6%) and b-caryophyllene (5.6%) P. artemisioides 1,8-cineole (29.9%), camphor (29.5%), NAu OM HD GC-FID and Flowers Iran 29 94.1 (Hafez Ghoran Boiss. a-pinene (7.8%), d-3-carene (5.1%), GC-MS et al. 2016) camphene (3.3%) and b-pinene (2.7%) aYEO: Yield of the essential oil; bNR: Not reported; cOM: Oxygenated monoterpene; dSH: Sesquiterpene hydrocarbon; eHD: Hydrodistillation; fMH: Monoterpene hydrocarbon; gBefore flowering stage; hBeginning of flowering stage; iComplete flowering stage; jSFE: Supercritical fluid extraction; kOver 16 SFE Runs; lSteam distillation; mFour studied samples; nSample 1; oSample 2; pSample 3; qSample 4; rPFS: Pre-flowering stage; sFS: Flowering stage; tPoFS: Post flowering stage; uNot available. TOXIN REVIEWS 7 genetical and chemical variability of the essential oil and hot water (Sairafianpour et al. 2001). It has also compositions have been assessed on twelve Iranian been suggested as an effective analgesic remedy P. abrotanoides Karel. populations (Pourhosseini et al. against rheumatic pains (Sajjadi et al. 2005). In some 2018). The nine selected intersimple sequence repeat parts of Pakistan, there are some evidences accounting (ISSR) markers produced 119 different bands with a for the use of this medicinal plant as a cooling drug high degree of polymorphism (80.7%). The genetic to control fever (Parvez et al. 1992) and as a refriger- variability among the studied populations ranged ant agent (Aoyagi et al. 2006). In the traditional between 0.07 and 0.79 indicating a high level of gen- Chinese medicine, P. abrotanoides Karel. has been etic variation. Polymorphic information content (0.31), widely used to treat liver fibrosis, atherosclerosis, cor- resolving power (6.14) and marker index (3.32) onary and cardiovascular diseases (Moallem and obtained by ISSR primers showed that these popula- Niapour 2008, Beikmohammadi 2012). tions may be grouped into four main clusters which On the other hand, P. atriplicifolia Benth., known as correspond to the four chemotypes of essential oil Russian sage, growing wild in different parts of arid compositions. This was further confirmed by principal and semi-arid regions of Iran, Pakistan, Turkmenistan component analysis and cluster analysis giving rise to and Afghanistan, is capable of lowering the body tem- four chemotypes, namely I (camphor/1,8-cineole); II perature and hence acts as a cooling remedy for the (1,8-cineole/camphor); III (camphor/1,8-cineole/a-bisa- treatment of severe typhoid fevers and diabetes bolol) and IV (camphor/d-3-carene/a-bisabolol). (Tareen et al. 2010, Majetich et al. 2011, Shah et al. Furthermore, in a different work by Ilkaee et al.(2017), 2013, Tarawneh et al. 2015). The flowers of this plant it was observed that the essential oil composition is are highly recommended for culinary purposes, par- significantly influenced by abiotic factors such as ticularly in the preparation of salads as a spicy garnish environmental and climatic conditions. In addition, (Pourmortazavi et al. 2003). Since this plant has a pun- phosphorus content of soil and precipitation had gent and pleasant odor, it can attract honey bees and more influence on the production of the principal the obtained honey is very sweet and delicious components of oils including camphor and 1,8-cineole. (Erdemgil et al. 2007 ). Finally, in the Uzbekistan folk “ ” This pronounced remarkable tendency to the chemical medicine, P. atriplicifolia Benth. known as Avruk in variability being observed in the essential oil composi- Uzbek and Tajik languages, has been frequently used tions should be deeply taken into consideration when from long time ago. In this regard, the extract of a plant species is used in phytomedicine and botanical P. atriplicifolia Benth. prepared in the hot water has disciplines. Therefore, the importance of the phyto- been considered as a strong remedy against dermatitis chemical analysis of plant raw materials collected for and sunburn (Takeda et al. 2006). Furthermore, the these medicinal scopes should be underlined (Toniolo decoction from its different parts has been prescribed et al. 2014). in traditional medicine of some Asian countries to remove intestinal parasites from the human body (Takeda et al. 2006). In the traditional Tibet and Ethnobotany of different species of the Chinese medicine, it has been claimed that P. atriplici- genus Perovskia folia Benth. is a powerful analgesic and parasiticide In the Iranian folk medicine, different species from the agent (Jiang et al. 2013). genus Perovskia have a variety of medicinal applica- tions (Mohammadhosseini 2016). These plants are Biological activities often recommended as powerful tonic and carmina- Antioxidant activity tive agents. In many localities of Iran, particularly in the desert In the literature, there are only few reports discussing and central regions of the country, the rural people antioxidant activities of different species of the genus and nomads have traditionally used different plant Perovskia. In one of the related reports (Ghafourian organs of diverse Perovskia species for the treatment and Mazandarani 2016), the ethanolic extracts from of a wide spectrum of diseases. Accordingly, a poultice the aerial parts of P. abrotanoides Karel., growing wild from the crushed roots of P. abrotanoides Karel., the in Semnan province, Iran, showed satisfied antioxidant “ ” Caspian Russian sage or wisk , has been suggested as activity with an IC50 of 15.03 ± 1.2 mg/mL when using a proper remedy to treat the cutaneous leishmaniasis, 1,1-diphenyl-2-picrylhydrazyl (DPPH· ) radical scaveng- skin burn and to heal infectious wounds. The used ing capacity assay. In addition, the evaluation of poultice consists of the plant material, sesame oil, wax reducing power assay resulted in an IC50 of 8 M. MOHAMMADHOSSEINI ET AL.

32.3 ± 0.31 mg/mL. The system used consisted of dis- oil from the leaves, while the fixed oil from the stems tinct amount of the prepared and dried extract, phos- showed only an inhibition of 45.9%. phate buffer (0.2 M, pH ¼ 6.6) and potassium ferricyanide (K3Fe(CN)6, 10 g/L) which was incubated at Antimicrobial activity: antibacterial, antiviral and 50 C for 30 min and trichloroacetic acid (100 g/L), dis- antifungal activities tilled water and FeCl3 (1 g/L) were added thereafter Nezhadali et al.(2009) have evaluated the in vitro anti- followed by the recording of the absorbance of the bacterial activities of the essential oils obtained from resulting solution at 700 nm. In this study, total anti- the flowers of P. abrotanoides Karel. against two Gram oxidant capacity (TAC) was also determined using the positive bacterial strains, namely Bacillus cereus and procedure suggested by Arabshahi-Delouee and Urooj Staphylococcus aureus as well as two Gram negative m (2007). As being reported, an IC50 of 45.3 ± 0.1 g/mL bacterial strains, namely Escherichia coli and Klebsiella was obtained in the determination of TAC. pneumoniae using the agar dilution method. In another exhaustive work focusing on antioxidant Accordingly, a simple perusal of the obtained MIC and capability of some Perovskia samples in 17 populations MBC values represents that among all the tested bac- relating to different climatic conditions of Iran, using terial strains, the highest antibacterial activity was DPPH· free radical scavenging assay (0.1 mM in metha- observed against B. cereus having the lowest MIC nol), the average values of EC50 varied over the range value (1.87 mg/mL). In addition, the average numerical 40.6–426 lg/mL (Ghaffari et al. 2018). As anticipated, a values of minimum bactericidal concentrations (MBCs) similar trend was noted for radical scavenging activity reported in this work against the tested essential oils (%) among which five growing samples of Perovskia for the Gram positive bacterial strains involving exhibited satisfied and remarkable antioxidant proper- Bacillus cereus (4.37 mg/mL) and Staphylococcus aureus ties even better than that of butylated hydroxytoluene (>60 mg/mL) were higher than the corresponding MIC (BHT) standard sample. These plant samples are values, whereas for the tested Gram negative bacterial mainly located in central part (Semnan and Isfahan strains, the obtained MIC and MBC values were the provinces), Northern (Mazandaran province) and north- same. The results of this study account for bacterio- eastern provinces (Khorasan Razavi) of Iran. Among static activity of the essential oils of P. abrotanoides the reported Iranian provinces, only the Mazandaran Karel. against the tested Gram positive bacteria in con- has humid climatic conditions, while the others have trast to the Gram negative bacterial strains. generally cold and dry weather during the year. In Ghafourian and Mazandarani (2016) have subjected the ethanol extracts of P. abrotanoides Karel., obtained other work, in vitro propagated P. abrotanoides Karel. by maceration, to antibacterial evaluations using agar plantlets were assessed for the phenolic content and well diffusion method and minimum inhibitory con- the antioxidant activity after their transferring to nat- centration (MIC) assay. In this relation, eight Gram ural conditions and the results were compared to positive strains comprising Shigella dysenteriae those observed in wild samples. The rosmarinic acid (PTCC1188), Pseudomonas aeruginosa (PTCC1430), resulted in characterization of the main polyphenols in Staphylococcus aureus (PTCC1431), Bacillus cereus both accessions. The total phenolic content of in vitro (PTCC1015), Salmonella typhimurium (PTCC1596), propagated plants (70.7 ± 9.1 mg/g on dry weight Staphylococcus epidermidis (PTCC1114), Enterococcus basis) was higher than that observed in the wild type faecalis (PTCC1393) and Klebsiella pneumoniae (54.9 ± 15.2 mg/g). However, the reported standard (PTCC1291) together with one Gram negative bacterial deviations were quite high, thus these results have a strain involving Escherichia coli (PTCC1399) were uti- low confidence level. Likewise, the antioxidant activity lized. In this study, the average inhibition zone diam- (IC50) of the in vitro propagated plant extracts were eter varied over the range 12.4 ± 0.5–32.1 ± 0.4 mm. reported to be more effective that those of the wild The highest inhibition zone diameter was seen against 1 type extracts (230.4 vs 275.7 lgmL , respectively) Staphylococcus aureus (32.1 ± 0.4 mm) and (Ghaderi et al. 2019). Staphylococcus epidermidis (28.4 ± 0.3 mm). On the Finally, in a different study, both of the essential other hand, Shigella dysenteriae, Klebsiella pneumoniae and fixed oils from the stems and leaves of P. abrota- and Salmonella typhimurium were found to have the noides Kar. were tested for the antioxidant activity least zone diameters, respectively as 12.4 ± 0.5, through inhibition of peroxidation in linoleic acid sys- 12.5 ± 0.1 and 12.7 ± 0.1 mm. Furthermore, the amount tem (Ashraf et al. 2014). Accordingly, the highest of MIC for Staphylococcus aureus and Staphylococcus inhibitory value of 76.7% was observed in the essential epidermidis bacterial strains were 45.1 and 53.2 lg/mL, TOXIN REVIEWS 9 respectively. As expected, the highest values were same concentrations. The inhibition zones were of the observed for Shigella typhimurium (172 lg/mL), same magnitude order with that observed for ampho- Salmonella dysenteriae (134.3 lg/mL) as well as tericin B as positive control, while Aspergillus niger Klebsiella pneumoniae (132.9 lg/mL). resulted to be no sensitive. The hydrodistilled essential oil obtained from the In a different study by Erdemgil et al.(2007), the flowers of P. artemisioides Boiss., with 1,8-cineole antimicrobial activity of P. atriplicifolia Benth. essential (29.9%), camphor (29.5%), a-pinene (7.8%), d-3-carene oil was evaluated using both agar diffusion and agar (5.1%), camphene (3.3%) and b-pinene (2.7%) as the dilution methods. Taking into account the obtained main components, was assessed for the potential anti- results, the oil showed a significant potential of anti- bacterial activity using the disc diffusion test against microbial activity against 10 bacteria, namely Bacillus five microbial strains. In accordance with this study, a cereus NRRL B-3711, Bacillus cereus subsp. mycoides high inhibition was observed against Staphylococcus NRRL B-4379, Bacillus subtilis NRRL B-209, Micrococcus aureus, Escherichia coli and Salmonella typhi. The inhib- luteus NRRL B-1018, Staphylococcus aureus ATCC ition zones were found to be 26.14 ± 0.02 mm, 25923, Staphylococcus epidermidis NRRL B-4268, 23.74 ± 0.03 mm and 21.29 ± 0.02 mm, respectively for Streptococcus faecium NRRL B-3502, Escherichia coli the aforementioned bacterial strains. Furthermore, a ATCC 25922, Enterobacter aerogenes NRRL B-3567, moderate activity was noted against Bacillus cereus Pseudomonas aeruginosa ATCC 10145, Klebsiella pneu- and Pseudomonas aeruginosa with inhibition zones of moniae (clinical isolate) and Yersinia enterocolitica as 15.43 ± 0.05 mm and 18.86 ± 0.01 mm, respectively. In well as 5 fungal strains involving Candida albicans particular, Bacillus cereus was found to be more sus- NRRL Y-12983, Aspergillus niger ATCC 10549, ceptible to the essential oil than to both standard Aspergillus flavus NRRL 1957, Aspergillus fumigatus antibiotic drugs, namely gentamicine and tetracycline NRRL 163, Aspergillus parasiticus NRRL 465 and used as positive controls (Hafez Ghoran et al. 2016). Geotricum candidum (wild type). In this context, the The essential and fixed oils from stems and leaves essential oil of P. atriplicifolia Benth. showed an inhib- of P. abrotanoides Boiss. were tested for the antimicro- ition zone at a concentration of 15 lL/disk over the bial properties against different microorganisms such range 9–14 mm against the bacterial strains, compared as Escherichia coli, Staphylococcus aureus, Bacillus cer- to penicillin (10 U/disc), tetracycline (30 lg/disc) and eus, Nitrospira spp, Staphylococcus epidermis, Aspergillus cephotaxime (30 lg/disc) having inhibition zone niger, Aspergillus flavus and Candida albicans. The ranges of 11–46, 16–40 and 8–46 mm, respectively higher inhibition zone was obtained by the essential when using as positive control drugs. This report oil from the leaves of P. abrotanoides Boiss. (15.2 mm revealed that among the tested bacteria, Pseudomonas on Bacillus cereus) in comparison to those resulted aeruginosa and Klebsiella pneumoniae were found to from the fixed oil of the stems (8.34 mm on be insensitive to the oil. However, at the same con- Staphylococcus aureus) and the leaves (11.2 mm on centration of oil, the inhibition zone observed against Staphylococcus aureus), thus revealing that the essen- the tested fungal strains was comparable to those tial oils from the stems and the leaves of P. abrota- obtained with amphotericin B (10 lg/mL) as standard noides Boiss. could be considered as promising antimycotic drug (8–14 and 7–13 mm, respectively). antimicrobial agents (Ashraf et al. 2014). Using the Concerning the essential oils, it should be also under- disc diffusion assay, the inhibitory activities of the lined that, in general, they possess also some toxic essential oil obtained from P. abrotanoides Boiss. aerial properties and this may limit their usage, i.e. the parts (10 to 29 mm at 3–10 lL/mL of oil) were also administrable doses. Furthermore, several essential oils reported by Mahboubi and Kazempour (2009). The oil components are known to be sensitizing compounds inhibited the microorganisms of Staphylococcus aureus and/or allergens which should be mentioned in the and Bacillus cereus which were remarkably comparable list of ingredients for cosmetics and detergents (Sun with those observed for the standard drugs like vanco- 2007, Vigan 2010). mycin, erythromycin and gentamycin used as positive Ghafourian and Mazandarani (2016) have also controls. Conversely, Escherichia coli and Pseudomonas determined the antifungal activity of the ethanol aeruginosa resulted to be not sensitive at all of the extracts of P. abrotanoides Karel. against Candida albi- tested concentrations. In the same work, the antifun- cans (PTCC5027). According to this study, the antifun- gal activity of the P. abrotanoides Karel essential oil gal activity of this extract was remarkable and even was also reported against Candida albicans with inhib- higher if compared to what observed for the most ition zones varying over the range 7.6–14 mm, at the susceptible bacterial strains like Staphylococcus aureus 10 M. MOHAMMADHOSSEINI ET AL. and Staphylococcus epidermidis. The average zone are agents which are capable of destroying protozoa or inhibition diameters and MIC values against Candida inhibiting the trends of their growth or reproduc- albicans were reported to be 34.1 ± 0.4 mm and tion features. 58.3 lg/mL, respectively. In the work of Tabefam et al.(2018a), the n-hexane Conversely, the ethyl acetate extract from the flow- and ethyl acetate extracts obtained from P. abrota- ers and leaves of P. abrotanoides Karel. of Karakoram- noides Karel. showed strong inhibitory activities Himalaya growing wild sample at 2000–3500 meters against Trypanosoma brucei rhodesiense and above mean sea level (M. a. s. l.), showed no signifi- Leishmania donovani. Among the components cant activity as an antifungal agent (Inouye et al. obtained by extensive chromatographic purification, 2001). The remarkable difference of effectiveness the following ones were found to be particularly reported for the two extracts [ethanolic (Ghafourian active: 7a-ethoxyrosmanol (IC50 of 0.8 mM against T. b. and Mazandarani 2016) and ethyl acetate (Inouye rhodesiense (Selective Index ¼ 14.9); IC50 of 1.8 mM, et al. 2001)] obtained from P. abrotanoides Karel. is Selective Index ¼ 6.9, against L. donovani); ferruginol possibly due to the chemical variability owned by the (IC50 of 2.9 mM, Selective Index ¼ 19.2, against P. fal- species and depending on both climatic and genetic ciparum); miltiodiol (IC50 of 0.5 mM, Selective Index ¼ differences among the two accessions. On the other 10.5, against T. b. rhodesiense). In addition, none of the side, it is also possible that the observed activity is the isolated compounds was reported to be selectively result of a synergistic action among the constituents toxic against T. cruzi. of the extracts and the polarity of the extracting solv- In another study by Sairafianpour et al.(2001), the ent may have a role in the extraction of the most diterpenoids like cryptotanshinone, 1b-hydroxycrypto- active components from the plant materials. tanshinone, 1-oxocryptotanshinone and 1-oxomiltirone

Obviously, both of these hypotheses need to be con- showed in vitro leishmanicidal activity with IC50 values firmed or not by further studies. ranging from 18 to 47 lM, so providing a phytochem- Two new abietanes (atriplicones A-B), together with ical rationale for the traditional usage of the corre- five known compounds (rosmaqunione B, arucatriol, sponding roots (P. abrotanoides Karel.) as one of the 6b-hydroxycarnosol, galdosol, and rosmadial) obtained main constituents of poultices for the treatment of from the 90% EtOH extract of P. atriplicifolia Benth. cutaneous leishmaniasis in the Iranian traditional were tested for their antiviral properties against medicine. In the same work, these diterpenoids were Hepatitis B Virus (HBV) by Jiang et al.(2015b). Among also shown to be effective in inhibiting the growth of these, atriplicone B, rosmaquinone B and rosmadial cultured Plasmodium falciparum 3D7 strain with IC50 showed notable inhibitory activity against HBV sup- values ranging from 12.5 to 26.9 lM. pressing the secretion of the surface antigen (HBsAg). In this relation, rosmadial was found to be significantly Cytotoxic activity effective in inhibiting the secretion of the other HBV Nine abietane constituents isolated from the methanol antigen (HBeAg), as well. extract of P. abrotanoides Karel. were tested for their In a different work on P. atriplicifolia Benth., the cytotoxic potential on P388 murine leukemia cells. The same research group (Jiang et al. 2015a) tested the structure activity relationships (SAR) of the natural and antiviral activity of two new isolated compounds, semisynthetic analogs of the isolated abietane diterpe- namely norperovskatone and biperovskatone. These noids were also studied (Aoyagi et al. 2006). In accord- compounds showed a remarkable in vitro anti-HBV ance with this study, the characterized abietane activity by suppressing the secretion of both viral sur- constituents showed IC values ranging from 0.22 to face markers HBsAg with IC values of 0.11 and 50 50 8.2 lg/mL. Moreover, the SAR analysis showed that 0.33 mM and HBeAg having IC values of 0.18 and 50 the acetylation of phenolic functions led to a decrease 0.12 mM, respectively. Furthermore, they significantly in the cytotoxic effect, while the presence of the o- inhibited HBV DNA replication with high selective quinone or the catechol functionalization, which can index values of 647.2 and 709.1, respectively, thus be easily oxidized to o-quinone, resulted an essential revealing promising properties for the therapy of structural requirement to exert the cytotoxic activity in hepatitis B. this kind of compounds. In addition, cryptotanshinone, 1b-hydroxycryptotan- Antiprotozoal activity shinone, 1-oxocryptotanshinone and 1-oxomiltirone, According to the definition given by MedicineNet isolated from the roots of the Iranian medicinal plant (https://www.medicinenet.com), antiprotozoal compounds P. abrotanoides Karel., showed cytotoxic action toward TOXIN REVIEWS 11 several cell lines involving drug-sensitive KB-3–1 Benth. have been evaluated (Perveen et al. 2014). human carcinoma cell line, multidrug-resistant KB-V1 Among the tested compounds, the oleanane and cell line, and human lymphocytes activated with ursane derivatives, namely 2a,3b,24-trihydroxyolean- phytohaemagglutinin A with IC50 values over the 12-en-28-oic acid and 2a,3b,19b-trihydroxyurs-12-en- range 5–45 lM (Sairafianpour et al. 2001). 28-oic acid were reported as the most effective

In this context, it is noteworthy to mention the compounds in inhibiting the acetyl (IC50 9.50 mM) and embryotoxicity of the ethanolic and aqueous extracts butyryl cholinesterase. The latter case resulted to be obtained from P. abrotanoides L. flowers at doses of most significantly inhibited (IC50 13.52 mM) in 0.125 and 0.25 g/kg which was observed in a mice respect to the former, as well as when compared to model by Moallem and Niapour (2008). In this study, galanthamine standard drug and positive control several abnormalities were observed in the embryos (IC50 8.51 mM). development such as resorption, stillborn as well as fetal malformations like polydactyly, spina bifida, Management of neuropathic pain aglossia, tarsal extensor and gastroschisis. Numerous The most used drugs to manage the neuropathic pain, skeletal abnormalities were mainly detected in the a physiopathological condition very common in sev- group exposed to the ethanolic extract compared to eral chronic and degenerative diseases, are opioids the group treated with the aqueous extract. On the such as morphine. To limit the insurgence of hyperla- contrary, a minimal maternal toxicity was recorded. On gesia and allodynia, there are two approaches: one is the basis of these results, it could be concluded that the inhibition of the opioid metabolism (Antonilli et al. the use of P. abrotanoides L. should be strictly avoided 2013) and the other is to find other kinds of ligands during pregnancy. for the opioid receptors. To give a deeper insight into the latter research approach, the case of quite Spasmolytic activity widespread flavonoids like 5-hydroxy-6,7,30,40-tetrame- In a study projected to investigate the composition thoxyflavone, 5,7-dihydroxy-6,30,40-trimethoxyflavone, and the pharmacological basis as the rationale for the 5-hydroxy-6,7,40-trimethoxyflavone and 5,7-dihydroxy- traditional use of P. abrotanoides Karel. essential oil in 6,40-dimethoxyflavone, isolated from the ethanolic gastrointestinal disorder, a notable calcium antagonist extract of P. atriplicifolia Benth. leaves could be activity was observed, with a comparable effectiveness referred. These compounds showed a selective affinity to that caused by verapamil, a standard calcium chan- for specific opioid receptors (Tarawneh et al. 2015). nel blocker. The study was conducted on isolated rab- In particular, a displacement of the [3H]-DPDPE radioli- bit jejunum preparation by Shah et al.(2013). As gand up to 86.0% at a concentration of 10 lM was shown in this report, the exposure to the essential oil observed when testing the tetramethoxyflavone- inhibited both the spontaneous and high potassium derivative. These results confirmed the potential use concentration-induced contractions ([Kþ] ¼ 80 mM), of flavonoids as a new scaffold for the development with respective EC50 values of 0.13 (0.08–0.20; n ¼ 4) of new opioid receptor ligands and P. atriplicifolia and 0.90 mg/mL (0.50–1.60; n ¼ 5). Therefore, the spas- Benth. leaves could be a suitable natural source for molytic activity might be mediated by calcium channel these compounds. The flavonoids are known to play blockade. This kind of action was confirmed after pre- important roles as tranquillizers in the traditional med- treatment of the essential oil of the tissues which icines due to their sedative and antispasmodic proper- resulted in a rightward shift in the [Ca2þ] concentra- ties (Venditti et al. 2014, 2015a, 2017a). Furthermore, tion/response curves, comparable to that observed several species of Perovskia traditionally used for the after verapamil treatment. anxiolytic and sedative properties have the flavonoids as the main phytocomponents, as in the case of Anti-cholinesterase inhibitory activity Hypericum spp. (Venditti and Bianco 2018). The anti-cholinesterase activity of nine compounds, Insecticidal activity namely b-amyrin, erythrodiol, oleanolic acid, 3b- hydroxy-11,13(18)-oleanadien-28-oic acid, glycyrrhe- The hydrodistilled essential oil obtained from P. abro- tinic acid, 2a,3b-dihydroxyolean-12-en-28-methyl ester, tanoides Karel. dry flowering aerial parts was tested by 2a,3b-dihydroxyolean-12-en-28-oic acid, 2a,3b,24-trihy- Arabi et al.(2008) for the fumigant toxicity against droxyolean-12-en-28-oic acid and 2a,3b,19b-trihydrox- Sitophilus oryzae (L.) and Tribolium castaneum (Herbst), yurs-12-en-28-oic acid isolated from P. atriplicifolia two stored grain pests. The fumigant toxicity was 12 M. MOHAMMADHOSSEINI ET AL. tested against 1- to 7-day-old adults. It was observed Unfortunately, there is no information about the stereo- that the mortality rate increased with concentrations chemistry of the sterol backbone of (1) in the original ranging from 32 to 645 lL/L with the exposure time publication (Ali et al. 2001), but due to the structural varying over the range 2–15 h. Furthermore, the oil similarity with b-sitosterol, and also its characterization caused 100% of mortality at the lowest concentration in the reported profile, it would be much likely possible (32 lL/L) after 15 and 8 h for S. oryzae and T. casta- that the compound (1)isab-sitosterol derivative. neum, respectively. LC50 values showed that T. casta- neum was more susceptible than S. oryzae ((LC 11.39 50 Triterpenoids vs 18.75 lL/L, respectively). Therefore, the essential oil of P. abrotanoides Karel. could be effective in stored From the ethyl acetate extract (whole plant) of P. atri- grain protection and may reduce the use of synthetic plicifolia Benth., Perveen et al.(2007), have isolated insecticides (Arabi et al. 2008). one new pentacyclic glycoside, namely atripliside A (2) (Figure 2). We take the occasion to underline that the Mutagenic and antimutagenic potential second compound indicated as a newly described one was instead a glycosidic flavanone and trivially named The mutagenic and antimutagenic activity of P. atripli- atripliside B (3)(Figure 2). However, it should be cifolia Benth. essential oil was assessed using 3 Salmonella/microsome system, with and without S9 underlined that the compound ( ) can not be consid- metabolic fraction in Salmonella typhimurium TA98 ered as a new compound in absolute at the time of and TA100 (Erdemgil et al. 2007). Accordingly, none of its isolation from P. atriplicifolia Benth., but only as a the tested concentrations of the oil was found to have new constituent of the studied species. This is because a remarkable mutagenic characteristic. However, all the assigned structure is the same of hesperidine – the tested concentrations exhibited an increase in ((2S)-5-hydroxy-2 (3-hydroxy-4-methoxyphenyl)-7-[(2S,3 antimutagenic activity in the presence or absence of R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-tri- S9 fraction against 2-aminofluorene and daunomycin, hydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxy-2, but not against sodium azide. 3-dihydrochromen-4-one)), a glycosidic (rutinoside) fla- vanone which was firstly recognized in the mesocarp Phytochemistry of the genus perovskia of several Citrus spp. by Lebreton (1828). In another report by Perveen et al.(2009), two new The phytochemical pattern observed in Perovskia spp. triterpenes with oleanane skeleton, namely atricin A resulted to be mainly composed of terpenoids belong- (4) and atricin B (5)(Figure 2) have been separated ing to several different classes, in particular diterpe- from the CHCl3-soluble fraction of the MeOH extract noids, sterols and triterpenoids, as well as those in of P. atriplicifolia Benth. and subsequently character- glycosilated form. Other constituents belonging to the ized using 1 D and 2 D-NMR spectroscopic approaches. phenylpropanoids, aromatic acids and catechols were also identified. Those not previously isolated from other sources are reported in detail in the following Abietanes subsections. Gao et al.(2017) have separated four new diterpene glucosides with abietane skeleton, namely perovskiadi- Terpenoids terpenoside A (6), perovskiaditerpenoside B (7), perov- skiaditerpenoside C (8) and perovskiaditerpenoside D Sterols (9)(Figure 2) from the BuOH extract of P. atriplicifolia Ali et al.(2001) have successfully isolated an acylated Benth. In this sense and out of eight characterized abie- steroid glucoside, namely atroside (1)(Figure 2), from P. tane diterpenoids, three ones, namely atriplicone A atriplicifolia Benth. growing wild in Pakistan, together (10), atriplicone B (11) and atriplicone C (12)(Figure 3) with other known compounds such as b-sitosterol, have been identified for the first time from the ethanol b-sitosterol glucoside, stigmasterol (sterol, sterol gluco- extract of P. atriplicifolia Benth (Jiang et al. 2015b). side), safficinolide, ethoxyrosmanol (diterpenoids) 4,7- dimethoxyscutellarein (flavonoid), lariciresinol (lignan), Nor-abietanes p-methoxybenzoic acid, p-propoxybenzoic acid, methyl- 2,4-dihydroxybenzoate (aromatic organic acids and From a non-polar fraction (n-hexane) extract obtained ester) and 2a-hydroxyursolic acid, oleanolic acid and from the roots of P. atriplicifolia Benth., eight nor- oleanolic acid acetate (pentacyclic triterpenes). abietanoid diterpenes (13–20)(Figure 3) have been TOXIN REVIEWS 13

Figure 2. Molecular structures of triterpenoids and sterols: atroside (1)fromP. atriplicifolia Benth (Ali et al. 2001); atripliside A (2) and atripliside B (3) isolated from the methanol extract of P. atriplicifolia Benth (Perveen et al. 2007); two oleanane triterpenes: atricin A(4) and atricin B (5) separated from the CHCl3-soluble fraction of the MeOH extract of P. atriplicifolia Benth (Perveen et al. 2009). separated and characterized using LC-MS/MS spectro- On the other hand, among 17 diterpenoids involv- metric methods (Slusarczyk et al. 2015). The quali- ing 14 abietane, two icetexane, and one isopimarane- quantitative analysis was performed by multiple type derivatives separated from n-hexane extracts reaction monitoring (MRM) using the most representa- of P. abrotanoides Karel., three ones were reported tive transitions from the precursor ions. In this regard, for the first time. The IUPAC names assigned to seven identified compounds (14–20) were ortho- these compounds were (5 R,10S)11-hydroxy-12- quinone tanshinones comprising miltirone, tanshinone methoxy-20-norabieta-8,11,13-triene (24), 12-hydroxy- IIa, 1-oxomiltirone, cryptotanshinone, 1,2-didehydromil- norabieta-1(10),8,11,13-tetraene-1,11-furan (25), and tirone, 1,2-didehydrotanshinone and 1b-hydroxy-crypto- 12-methoxybarbatusol (26)(Figures 3 and 4) (Tabefam tanshinone, respectively, together with rosmarinic acid. et al. 2018a). Additionally, among the identified diterpenoids only one compound (13)(Figure 3) was the non-quinone Icetexanes type arucadiol (13). The new diterpenoid 1,2-quinones 1-oxomiltirone In the study just reported at the end of the previous (21), 1b-hydroxycryptotanshinone (22) and 1-oxocryp- subsection (Tabefam et al. 2018a), an icetexane deriva- totanshinone (23)(Figure 3), in addition to one known tive was also recognized from the extracts of natural compound, cryptotanshinone having a quinoid P. abrotanoides Karel., namely 12-methoxybarbatusol diterpene and comprising a nor-abietane skeleton (26) (see Figure 4). have been originally separated by Sairafianpour et al. In a parallel work, Liu et al.(2018) have character- (2001) from an EtOAc extract obtained from the roots ized two new diterpenoids with an icetexane-type of P. abrotanoides Karel. skeleton, namely biperovskatone B (27) and 1a- 14 M. MOHAMMADHOSSEINI ET AL.

Figure 3. Abietanes and nor-abietanes: molecular structures of new diterpene glucosides perovskiaditerpenoside A (6), perovskia- diterpenoside B (7), perovskiaditerpenoside C (8) and perovskiaditerpenoside D (9) isolated from the BuOH extract of P. atriplicifo- lia Benth (Gao et al. 2017); atriplicone A (10), atriplicone B (11) and atriplicone C (12) obtained from the EtOH extract of P. atriplicifolia Benth (Jiang et al. 2015b); nor-abietanoid diterpenoids (13–20) from an n-hexane extract of the roots of P. atriplicifolia Benth (Slusarczyk et al. 2015); new diterpenoid 1,2-quinones from the EtOAc extract of the roots of P. abrotanoides Karel.: 1b- hydroxycryptotanshinone (22), 1-oxocryptotanshinone (23) and 1-oxomiltirone (21) (Sairafianpour et al. 2001); nor-diterpenoids (24–25) separated from n-hexane extracts of P. abrotanoides Karel. (Tabefam et al. 2018a).

hydroxyl-demethylsalvicanol quinine (28)(Figure 4), reported, compound 27 contained two unusual icetex- together with two known rearranged 9(1 0 !20) ane diterpenoid moieties: unit A resulted the same abeoabietanes from an alcoholic (EtOH) extract of a biperovskatone which was previously isolated from cultivated P. atriplicifolia Benth plant using MS, IR, the same species by Jiang et al.(2015c), while unit B 1 D and 2 D NMR spectroscopic methods. As being showed an extra oxygenated methine in 70 position in TOXIN REVIEWS 15 respect to unit B of biperovskatone. The structure of rearranged structure, namely peradione (41) was iso- compound 28 was also similar to those of demethyl- lated from the same plant species by Ahmad et al. salvicanol quinine with an additional hydroxyl func- (1993). It is also interesting to note that these kinds of tional group at ring A. natural products showed a pronounced antiprotozoal From the ethanol extract of P. atriplicifolia Benth., activity (Tabefam et al. 2018b), but none of the com- five new icetexane diterpenoids, namely perovskatone pounds isolated from Perovkia spp has been tested in B(29), perovskatone C (30), perovskatone D (31), 1a- this context of bioactivities until now and this could hydroxybrussonol (32) and 1a-hydroxypisiferanol (33) be an argument which deserves further studies. along with a new o-quinone natural compound (34) which was previously obtained only by a synthetic Phenylpropanoid derivatives procedure (Majetich and Zou 2008)(Figure 4), have been reported (Jiang et al. 2015c). In this work, other Perveen et al.(2006) have also reported two new nat- two natural compounds (przewalskin E: 35 and brusso- ural compounds of phenylpropanoid nature from the nol (36) have been isolated and identified for the first methanol extract of P. atriplicifolia Benth. of which time from the studied species, as well. one (perovskoate) (42) belongs to isorinic acid deriva- tives and the other (perovskoside) is of catechol type glucoside (43)(Figure 5). C diterpenoids (dinor-sesterpenoids) 23 In addition, two new phenylpropanoids showing an From the ethanol extract of P. atriplicifolia Benth isoferulyl backbone with respectively an aldehydic and (whole plant), Jiang et al.(2013) have successfully iso- carboxylic function, namely pervoside A (44) and per- lated a new C23 terpenoid with a unique 6/7/7 tricyclic voside B (45)(Figure 5), have been separated and system ring, namely perovskatone A (37)(Figure 4), characterized from the EtOH-soluble part of P. atriplici- along with nine other known natural compounds, folia Benth. by the same group (Perveen et al. 2008). namely demethylsalvicanol, 7-methoxy-epirosmanol, hinokiol, isorosmanol, rosmanol, atuntzensin A, 7- Chemotaxonomic significance of perovskia spp. methoxyrosmanol (diterpenoids), oleanic acid and metabolites ursolic acid (pentacyclic triterpenoids). The specialized metabolites pattern recognized from Perovskia spp. comprise a wide array of natural com- Unusual diterpenoids polycyclic skeleton pounds belonging to different classes: terpenoids like In the work of Khaliq et al.(2006), two new diterpenes sterol, mono-, sesqui-, di- and triterpenes, aromatic with a unique 6/5/6/6 tetracyclic ring system having organic acids and esters, lignans, flavonoids and phe- a trans-1,1-dimethylcyclohexano[e,b]tetrahydrofuran nylpropanoids. Among these, there are not peculiar element perpendicular to a benzodihydropyran sys- compounds, namely the sterols b-sitosterol and stig- tem, namely abrotandiol (38) and abrotanone (39) masterol and the pentacyclic triterpenoids such as (Figure 4), have been reported among the compo- ursolic and betulinic acids, the lignan lariciresinol and nents isolated from the methanol extract of the aerial the flavonoids related to scutellarein, already observed parts of P. abrotanoides Karelin together with several in not systematically related species, i.e. Stachys alope- known compounds of flavonoids, phenolic acids, ster- curos subsp. divulsa (Venditti et al. 2013), Pentas lan- ols and pentacyclic triterpenoids, namely cirsimaritin, ceolata (Venditti et al. 2015b), Hypericum hircinum hesperidin, rosmarinic acid, stigmast-5-en-3b-ol, stig- (Esposito et al. 2013), Camellia sinensis (Wu et al. 2019) mast-5,22-dien-3b-ol, stigmast-5-en-3b,7a-diol, ursolic and Wollemia nobilis (Venditti et al. 2019), all species acid and betulinic acid. belonging to different genus, family and even order of Another polycyclic terpenoid was isolated from P. systematic classification. In fact, more strictly related abrotanoides Karel. for the first time by Parvez et al. compounds from the chemosystematic standpoint are (1992). This compound which is trivially called perov- instead the flavonoid cirsimaritin, already recognized skone (40) is a heptacyclic isoprenoid and conjugated from near species of Lamiaceae family such as diterpene-monoterpene with 6/7/6/6/5 membered car- Teucrium polium (Venditti 2017, Venditti et al. 2017d) bon ring skeleton fused with two tetrahydrofuran and the phenylpropanoid rosmarinic acid isolated rings. Biogenetically, it may be resulted from the add- from Mentha aquatica (Venditti et al. 2017b), Ajuga ition of geranyl pyrophosphate to an icetexone precur- genevensis (Venditti et al. 2016) and Hyssopus officinalis sor. In 1993, another compound with a complex subsp. aristatus (Venditti et al. 2015a), all species 16 M. MOHAMMADHOSSEINI ET AL.

Figure 4. Icetexanes, dinor-sesterpenes and diterpenoids with unusual skeleton: molecular structures of the icetexane diterpenoid (26) isolated from P. abrotanoides Karel (Tabefam et al. 2018a); biperovskatone B (27) and 1a-hydroxyl demethylsalvicanol quinine (28) from an EtOH extract of a cultivated sample of P. atriplicifolia Benth (Liu et al. 2018); molecular structures of five icetexane diterpenoids: perovskatone B (29), perovskatone C (30), perovskatone D (31), 1a-hydroxybrussonol (32) and 1a-hydroxypisiferanol (33) as well as a new natural compound (34), przewalskin E (35) and brussonol (36) (Jiang et al. 2015c); perovskatone A (37), a C23 terpenoid, isolated from and ethanol extract of P. atriplicifolia Benth (Jiang et al. 2013); abrotandiol (38) and abrotanone (39) found in non-polar, semi polar and polar fractions from the MeOH extract of the aerial parts of P. abrotanoides Karel; polycyclic terpenoids from P. abrotanoides, perovskone (40) (Parvez et al. 1992) and peradione (41) (Ahmad et al. 1993). TOXIN REVIEWS 17

Figure 5. Phenylpropanoids: molecular structures of perovskoate, an isorinic acid methyl ester (42) and perovskoside (43) obtained from the methanol extract of P. atriplicifolia Benth (Perveen et al. 2006); pervosides A (44) and pervosides B (45) from the EtOH-soluble fraction of P. atriplicifolia Benth (Perveen et al. 2008).; the diglycosidic flavonoid atripliside B (3) isolated from the methanol extract of P. atriplicifolia Benth (Perveen et al. 2007).

belonging to subfamilies comprised in the Lamiaceae. Lamioideae subfamily (Wink 2003). This differentiation Yet, the rosmarinic acid is considered as one of the is much in accordance with both the current system- chemotaxonomic markers in the Nepetoideae subfam- atic classification of the Perovskia genus, which is cur- ily where the Perovskia genus is also currently com- rently comprised in the Nepetoideae subfamily, and prised. Anyway, the most peculiar features in the with the phytochemical pattern of specialized metabo- phytochemical pattern of Perovskia spp. is the pres- lites owned by the species of the genus. Among these ence of unusual diterpenoids such as abeoabietanes metabolites, the rosmarinic acid is one phenylpropa-

(icetexanes) and nor-terpenoids (C23 terpenoids and noid well-distributed among the Nepetoideae and sys- nor-abietanoid) which seems to be strictly related to tematically related species (Venditti et al. 2015a, 2016, the genus and therefore are eligible to be chemotaxo- 2017d). It should be also noted that the isorinic nomic markers at the genus and even at the spe- derivative (perovskoate) (38) recognized in P. atriplici- cies level. folia Benth. is structurally related to rosmarinic acid. The absence of iridoids in the botanical entities However, from the chemotaxonomic standpoint, classified in the Perovskia genus is also noteworthy. the most interesting compounds identified in the Iridoids are monoterpenoids, mainly glycosidic deriva- Perovskia genus are the 9(1 0 !20)-abeo-abietanes or tives, and are considered as main chemotaxonomic icetexanes, nor-diterpenoids and heptacyclic isopre- markers in the Lamiaceae family (Kooiman 1972, noid with 6/7/6/6/5 membered carbon ring skeleton Frezza et al. 2019a, 2019b). In particular, in the fused with two tetrahydrofuran rings. It is noteworthy Lamiales order, the biogenesis of iridoids led to the that the occurrence of isoprenoids with this kind of production of derivatives with the 8a-stereochemistry rearranged polycyclic carbon skeleton, such as 40 and through the biogenetic pathway Route II (Jensen 41, are rare in nature and, to date, have been 1992), involving the epi-deoxyloganic acid among the reported only from two other species; Salvia bucharica precursors. Several authors reported the splitting of and Salvia hydrangea (Ahmad et al. 1999, Moridi the Lamiaceae family into two main groups: one com- Farimani et al. 2011, 2012, Tabefam et al. 2018b) both prising aromatic plants producing essential oils and species belonging to the Salviinae subtribe (Mentheae corresponding to the subfamily Nepetoideae, the tribe) of Nepetoideae subfamily of Lamiaceae. second one comprising poor oil-producer species, but Similarly, nor-diterpenoids are not common derivatives in turn richer in iridoids and belonging to the and their distribution seems quite discontinuous 18 M. MOHAMMADHOSSEINI ET AL. among the Plantae, being rare compounds in partially justify the apparent random distribution of Gymnosperms (Venditti et al. 2017c), while resulting icetexanes among plant species. The structural com- more widespread in Angiosperms, but with no appar- plexity of icetexane skeleton (tricyclic 6/7/6 system) ent systematic relationship, since they have been rec- has also stimulated the curiosity of organic chemists ognized from species belonging to different plant giving rise to several synthetic approaches which are families such as Compositae (Domınguez et al. 1986), extensively available in the literature (de Jesus Cortez Rubiaceae (Parra-Delgado et al. 2005) and et al. 2013, Nisigaki et al. 2016, Thommen et al. 2017, Euphorbiaceae (Kubo et al. 1991). Thus, this is an Moon et al. 2018). aspect which deserves further phytochemical studies also at biogenetic and molecular levels. Equally inter- Conclusions esting, is the occurrence of icetexanes since these are diterpenoids with peculiar structural features, mainly In the present review, all the studies about the trad- rearrangements of the polycyclic skeleton. A peculiar itional medicine, the phytochemistry, the studied bio- structural feature, which often occurs in the diterpe- activities and chemosystematic relevance of noids derivatives isolated from this genus, is the pres- specialized metabolites occurring in Perovskia spp ence of vicinal diol functionalization of the have been collected. The peculiarities of several cyclohexadiene moiety which could be easily con- metabolites, from both the chemistry of natural prod- verted to o-quinone systems. This specific structural ucts and bioactivity standpoints, are clearly evident motif resulted strictly to be related to the bioactivity and regarding the facts that several species of this of several abeo-abietanes recognized in Perovskia spp., genus have not been investigated so far, we believe as previously reported. that other interesting phytoconstituents, even not The icetexanes were also recognized from other already described, could be further identified from species of Lamiaceae such as several Salvia spp., Pervskia spp. It should be underlined that several namely S. uliginosa Benth., S. ballotiflora Benth., S. thy- metabolites displayed uncommon bioactivities such as the potentiality to control the neuropathic pain, the moides Benth. and S. corrugata Vahl. (Esquivel and anticholinesterase and spasmolitic activities besides Sanchez 2005, Bisio et al. 2016, Jassbi et al. 2016, the more common potentialities, interesting antioxi- Esquivel et al. 2017, Cezarotto et al. 2019) among the dant one, since being involved in several health pro- others and Rosmarinus officinalis (Shrestha et al. 2016). moting aspects. We deeply hope that the arguments These are botanical entities systematically related to collected in the present review could renew the inter- the Perovskia genus, since are formerly included in the est of researchers toward this interesting genus and subtribe Salviinae, as well. Icetexanes have also been its undisclosed potentialities. recognized in Premna tomentosa Willd. (Ayinampudi et al. 2012, Vgm et al. 2014), Premna obtusifolia R.Br. (syn. of Premna serratifolia L.) (Salae and Boonnak Disclosure statement 2013), Premna latifolia Roxb. (syn. of Premna mollissima The authors report no declaration of interest. The authors Roth) (Suresh et al. 2011) and Dracocephalum komaro- alone are responsible for the content and writing of vii Lipsky (Uchiyama et al. 2003) etc. The Premna the paper. genus is comprised in the Viticoideae subfamily of Lamiaceae, while the Dracocephalum genus is com- ORCID prised in the Mentheae tribe, Nepetoideae subfamily of Lamiaceae family. Therefore, both genera are sys- Majid Mohammadhosseini http://orcid.org/0000-0002- 3188-4924 tematically related to the Perovskia. In this context, it Alessandro Venditti http://orcid.org/0000-0003-1492-6739 is worth mentioning that icetexane derivatives have Abolfazl Akbarzadeh http://orcid.org/0000-0001- also been observed in fossil sediments from Miocene 9941-0357 and Late Triassic, as well as from Chamaecyparis pisi- fera (Cupressoideae) (Nytoft et al. 2019), Fokienia hodg- References insii (Dunn) A.Henry & H H.Thomas (Cupressaceae) (Wu et al. 2013) and Amentotaxus formosana H.L.Li Abduganiev, B.E., Abdullaev, U.A., and Plugar, V.N., 1996. (Taxaceae) (Chen et al. 2011). The co-occurrence of ice- Qualitative and quantitative compositions of the essential oil of Perovskia scrophulariifolia. Chemistry of natural com- texane in these species and in fossil sediments may pounds, 31 (4), 475–477. suggest that the biogenetic pathway for the biosyn- Ahmad, V.U., Parvez, A., and Hassan, N.M., 1993. Isolation thesis of such compounds is very old and could and structure determination of peradione (1) a novel TOXIN REVIEWS 19

triterpene with a rearranged perovskane skeleton from Domınguez, X.A., et al., 1986. A nor-diterpene and other con- Perovskia abrotanoides. Tetrahedron letters, 34 (33), stituents from Isocoma coronopifolia. Phytochemistry,25 5337–5340. (12), 2893–2895. Ahmad, V.U., Zahid, M., and Ali, M.S., 1999. Salvadiones-A Erdemgil, F.Z., et al., 2007. Chemical composition and bio- and -B: two terpenoids having novel carbon skeleta from logical activity of the essential oil of Perovskia atriplicifolia. Salvia bucharica. The journal of organic chemistry, 64 (23), from Pakistan. Pharmaceutical biology, 45 (4), 324–331. 8465–8467. Esposito, F., et al., 2013. Hypericum hircinum L. components Akhlaghi, H., Saiidi Asl, M.-R., and Mohamad-Hosseini, M., as new single-molecule inhibitors of both HIV-1 reverse 2009. Composition of the essential oil of Hymnocrater pla- transcriptase-associated DNA polymerase and ribonucle- tystegius in Iran. Chemistry of natural compounds, 45 (3), ase H activities. Pathogens and disease, 68 (3), 116–124. 448–449. Esquivel, B., and Sanchez, A.A., 2005. Rearranged icetexane Ali, M.S., Saleem, M., and Erian, A.W., 2001. A new acylated diterpenoids from the roots of Salvia thymoides (Labiatae). steroid glucoside from Perovskia atriplicifolia. Fitoterapia, Natural product research, 19 (4), 413–417. 72 (6), 712–714. Esquivel, B., et al., 2017. Structure, absolute configuration, Antonilli, L., et al., 2013. Pivaloylcodeine, a new codeine and antiproliferative activity of abietane and icetexane derivative, for the inhibition of morphine glucuronidation. diterpenoids from Salvia ballotiflora. Molecules, 22 (10), An in vitro study in the rat. Bioorganic and medicinal 1690. chemistry, 21 (24), 7955–7963. Frezza, C., et al., 2019a. Preliminary study on the phytochem- Aoyagi, Y., Takahashi, Y., and Satake, Y., 2006. Cytotoxicity of ical evolution of different Lamiaceae species based on iri- – abietane diterpenoids from Perovskia abrotanoides and of doids. Biochemical systematics and ecology, 82, 44 51. their semisynthetic analogues. Bioorganic and medicinal Frezza, C., et al., 2019b. Phytochemistry, chemotaxonomy, ethnopharmacology, and nutraceutics of Lamiaceae. chemistry, 14 (15), 5285–5291. – Arabi, F., Moharramipour, S., and Sefidkon, F., 2008. Chemical Studies in natural products chemistry, 62, 125 178. Gao, L., et al., 2017. Four new diterpene glucosides from composition and insecticidal activity of essential oil from Perovskia atriplicifolia. Chemistry and biodiversity, 14. Perovskia abrotanoides (Lamiaceae) against Sitophilus ory- Ghaderi, S., et al., 2019. In vitro propagation and phytochem- zae (Coleoptera: Curculionidae) and Tribolium castaneum ical assessment of Perovskia abrotanoides Karel. (Coleoptera: Tenebrionidae). International journal of trop- (Lamiaceae) – A medicinally important source of phenolic ical insect science, 28 (03), 144–150. compounds. Biocatalysis and agricultural biotechnology, 19, Arabshahi-Delouee, S., and Urooj, A., 2007. Antioxidant prop- 101113. erties of various solvent extracts of mulberry (Morus indica Ghaffari, Z., Rahimmalek, M., and Sabzalian, M.R., 2018. – L.) leaves. Food chemistry, 102 (4), 1233 1240. Variations in essential oil composition and antioxidant Ashraf, S.N., et al., 2014. Compositional studies and biological activity in Perovskia abrotanoides Kar. collected from dif- activities of Perovskia abrotanoides Kar. oils. Biological ferent regions in Iran. Chemistry and biodiversity, 15 (6), research, 47, 12. e1700565. Ayinampudi, S.R., et al., 2012. New icetexane diterpenes with Ghafourian, M., and Mazandarani, M., 2016. intestinal alpha-glucosidase inhibitory and free-radical Ethnopharmacology, ecological requirements, antioxidant scavenging activity isolated from Premna tomentosa roots. and antimicrobial activities of Perovskia abrotanoides – Fitoterapia, 83 (1), 88 92. Karel. extract for vaginal infections from semnan province. Basher, K.H.C., et al., 1997. Essential oil of Perovskia angustifo- International journal of women’s health and reproduction lia from Kyrgyzystan. Chemistry of natural compounds,33 sciences, 5 (4), 295–300. – (3), 296 298. Hafez Ghoran, S., Azadi, B., and Hussain, H., 2016. Chemical Beikmohammadi, M., 2012. The evaluation of medicinal composition and antimicrobial activities of Perovskia arte- properties of Perovskia abrotanoides Karel. Middle East misioides Boiss. essential oil. Natural product research,30 journal of scientific research, 11, 189–193. (17), 1997–2001. Bisio, A., et al., 2016. Establishment and analysis of in vitro Hashemi-Moghaddam, H., Mohammadhosseini, M., and Azizi, biomass from Salvia corrugata Vahl. and evaluation of Z., 2018. Impact of amine- and phenyl-functionalized mag- antimicrobial activity. Phytochemistry, 122, 276–285. netic nanoparticles impacts on microwave-assisted extrac- Cezarotto, C.S., et al., 2019. Leishmanicidal and antichemo- tion of essential oils from root of Berberis integerrima tactic activities of icetexanes from Salvia uliginosa Benth. Bunge. Journal of applied research on medicinal and aro- Phytomedicine , 58, 152748. matic plants, 10, 1–8. Chen, H.L., et al., 2011. New diterpenoids and cytotoxic and Hashemi-Moghaddam, H., Mohammadhosseini, M., and anti-inflammatory diterpenoids from Amentotaxus formo- Basiri, M., 2015. Optimization of microwave assisted sana. Fitoterapia, 82 (2), 219–224. hydrodistillation on chemical compositions of the essen- Dabiri, M., and Sefidkon, F., 2001. Analysis of the essential oil tial oils from the aerial parts of Thymus pubescens and from aerial parts of Perovskia atriplicifolia Benth. at differ- comparison with conventional hydrodistllation. Journal of ent stages of plant growth. Flavour and fragrance journal, essential oil bearing plants, 18 (4), 884–893. 16 (6), 435–438. Hashemi-Moghaddam, H., Mohammdhosseini, M., and Salar, de Jesus Cortez, F., et al., 2013. Synthetic studies on the ice- M., 2014. Chemical composition of the essential oils from texones: enantioselective formal syntheses of icetexone the hulls of Pistacia vera L. by using magnetic nanopar- and epi-icetexone. Tetrahedron, 69 (27–28), 5665–5676. ticle-assisted microwave (MW) distillation: Comparison 20 M. MOHAMMADHOSSEINI ET AL.

with routine MW and conventional hydrodistillation. Mohammadhosseini, M., 2015a. Chemical composition of the Analytical methods, 6 (8), 2572–2579. essential oils and volatile fractions from flowers, stems Ilkaee, M.N., et al., 2017. Effect of abiotic environmental fac- and roots of Salvia multicaulis Vahl. by using MAHD, SFME tors on growth and essential oil characteristics of and HS-SPME methods. Journal of essential oil bearing Perovskia abrotanoides Karel. Journal of essential oil bear- plants, 18 (6), 1360–1371. ing plants, 20 (3), 729–743. Mohammadhosseini, M., 2015b. Chemical composition of the Inouye, S., et al., 2001. Volatile aroma constituents of three volatile fractions from flowers, leaves and stems of Salvia Labiatae herbs growing wild in the Karakoram-Himalaya mirzayanii by HS-SPME-GC-MS. Journal of essential oil bear- District and their antifungal activity by vapor contact. ing plants, 18 (2), 464–476. Journal of essential oil research, 13 (1), 68–72. Mohammadhosseini, M., 2016. A comprehensive review on Jassbi, A.R., Ahmad, V.U., and Tareen, R.B., 1999. Constituents new methods for processing, separation and identification of the essential oil of Perovskia atriplicifolia Benth. Flavour of the essential oils. Shahrood, Iran: Islamic Azad University and fragrance journal, 14 (1), 38–40. of Shahrood Press. Jassbi, A.R., et al., 2016. Bioactive phytochemicals from Mohammadhosseini, M., 2017a. Essential oils extracted using shoots and roots of Salvia species. Phytochemistry reviews, microwave-assisted hydrodistillation from aerial parts of – 15 (5), 829 867. eleven Artemisia species: Chemical compositions and Jensen, S.R., 1992. Systematic implications of the distribution diversities in different geographical regions of Iran. of iridoids and other chemical compounds in the Records of natural products, 11, 114–129. Loganiaceae and other families of the Asteridae. Annals of Mohammadhosseini, M., 2017b. The ethnobotanical, phyto- – the Missouri botanical garden, 79 (2), 284 302. chemical and pharmacological properties and medicinal Jiang, Z.-Y., et al., 2013. Perovskatone A: a novel C23 terpen- applications of essential oils and extracts of different oid from Perovskia atriplicifolia. Tetrahedron letters, 54 (29), Ziziphora species. Industrial crops and products, 105, – 3886 3888. 164–192. Jiang, Z.-Y., et al., 2015a. Two novel antiviral terpenoids from Mohammadhosseini, M., Akbarzadeh, A., and Flamini, G., the cultured Perovskia atriplicifolia. Tetrahedron, 71 (23), 2017a. Profiling of compositions of essential oils and vola- 3844–3849. tiles of Salvia limbata using traditional and advanced Jiang, Z.Y., et al., 2015b. Abietane diterpenoids from techniques and evaluation for biological activities of their Perovskia atriplicifolia and their anti-HBV activities. extracts. Chemistry and biodiversity, 14. ChemInform, 36, 623–627. Mohammadhosseini, M., et al., 2016. Chemical composition Jiang, Z.Y., et al., 2015c. Icetexane diterpenoids from of the essential oils from the aerial parts of Artemisia sie- Perovskia atriplicifolia. Planta Medica, 81, 241–246. beri by using conventional hydrodistillation and micro- Kakhky, A.M., et al., 2009. Composition of the essential oil of wave assisted hydrodistillation: A comparative study. Perovskia abrotanoides Karel. and Mentha longifolia L. from Journal of essential oil bearing plants, 19 (1), 32–45. Iran. Journal of essential oil bearing plants, 12 (2), 205–212. Mohammadhosseini, M., et al., 2019. The genus Ferula: Khaliq, S., Volk, F.J., and Frahm, A.W., 2006. Phytochemical – investigation of Perovskia abrotanoides. Planta Medica,73 ethnobotany, phytochemistry and bioactivities a review. – (01), 77–83. Industrial crops and products, 129, 350 394. Kooiman, P., 1972. The occurrence of iridoid glycosides in Mohammadhosseini, M., Sarker, S.D., and Akbarzadeh, A., the Labiatae. Acta Botanica Neerlandica, 21 (4), 417–427. 2017b. Chemical composition of the essential oils and Kubo, I., Asaka, Y., and Shibata, K., 1991. Insect growth extracts of Achillea species and their biological activities: a – inhibitory nor-diterpenes, cis-dehydrocrotonin and trans- review. Journal of ethnopharmacology, 199, 257 315. dehydrocrotonin, from Croton cajucara. Phytochemistry,30 Moon, D.J., et al., 2018. A strategy toward icetexane natural (8), 2545–2546. products. European journal of organic chemistry, 2018 (25), – Lebreton, M., 1828. Sur la matiere cristalline des orangettes, 3348 3351. et analyse de ces fruits non encore developpes, famille Moridi Farimani, M., et al., 2011. Triterpenoids with rare car- des. Hesperidees journal de Pharmacie et de sciences acces- bon skeletons from Salvia hydrangea: antiprotozoal activ- sories, 14, 377. ity and absolute configurations. Journal of natural Liu, W.X., et al., 2018. Two novel terpenoids from the cul- products, 74 (10), 2200–2205. tured Perovskia atriplicifolia. Fitoterapia, 130, 152–155. Moridi Farimani, M., et al., 2012. Hydrangenone, a new iso- Mahboubi, M., and Kazempour, N., 2009. The antimicrobial prenoid with an unprecedented skeleton from Salvia activity of essential oil from Perovskia abrotanoides Karel hydrangea. Organic letters, 14 (1), 166–169. and its main components. Indian journal of pharmaceutical Morteza-Semnani, K., 2004. The essential oil composition of sciences, 71 (3), 343–347. Perovskia abrotanoides from Iran. Pharmaceutical biology, Majetich, G., and Zou, G., 2008. Total synthesis of (-)-barbatu- 42 (3), 214–216. sol, (þ)-demethylsalvicanol, (-)-brussonol, and (þ)-grandi- Mozaffarian, V., 1996. A dictionary of Iranian plant names. one. Organic letters, 10 (1), 81–83. Iran: Farhang Moaser Press. Majetich, G., et al., 2011. Synthesis of (±)- and (þ)-perov- Nasir, Y. J., and Ali S. I., 1990. Flora of Pakistan. Karachi, skone. Tetrahedron, 67 (52), 10129–10146. Pakistan: Printas Press. Moallem, S.A., and Niapour, M., 2008. Study of embryotoxic- Nezhadali, A., et al., 2009. Analysis of the flower essential oil ity of Perovskia abrotanoides, an adulterant in folk-medi- at different stages of plant growth and in vitro antibacter- cine, during organogenesis in mice. Journal of ial activity of Perovskia abrotanoides Karal. Der Pharma ethnopharmacology, 117 (1), 108–114. Chemica, 1, 146–150. TOXIN REVIEWS 21

Nisigaki, E., et al., 2016. Semisynthesis of ()-barbatusol, of different growth stage in Baluchestan. Middle-East jour- (þ)-demethylsalvicanol, and (þ)-rosmaridiphenol from nal of scientific research, 13, 781–784. (þ)-pisiferic Acid. Chemistry letters, 45 (7), 746–748. Sarker, S.D., and Nahar, L., 2018a. Evidence-based phytother- Nuriddinov, K.R., et al., 1997. Essential oil of Perovskia scro- apy: what, why and how? Trends in phytochemical phulariifolia. Chemistry of natural compounds, 33 (3), research, 2, 125–126. 299–300. Sarker, S.D., and Nahar, L., 2018b. Phytochemicals and Nytoft, H.P., et al., 2019. Dehydroicetexanes in sediments phyto-extracts in cosmetics. Trends in phytochemical and crude oils: Possible markers for Cupressoideae. research, 2, 185–186. Organic geochemistry, 129, 14–23. Shafaghat, A., et al., 2017. A comparative study on chemical Olmstead, R., 2005. A synoptical classification of the composition and antimicrobial activity of essential oils Lamiales. Synoptical Classification Version 2. from Tanacetum parthenium (L.) Schultz. Bip. and Oreizi, E., Rahiminejad, M.R., and Asghari, G., 2014. Influence Tanacetum punctatum (Desr.) Grierson. leaves from Iran. of environment on glandular trichomes and composition of Journal of essential oil bearing plants, 20 (4), 1143–1150. essential oil of Perovskia abrotanoides Karel. Jundishapur Shah, A.J., et al., 2013. Chemical analysis and calcium chan- journal of natural pharmaceutical products, 9 (4), e16432. nel blocking activity of the essential oil of Perovskia abro- Parra-Delgado, H., et al., 2005. Chemical constituents of tanoides. Natural product communications, 8 (11), Coutaportla ghiesbregthiana: co-crystallization of two ent- 1633–1636. nor-kaurene diterpenes. Zeitschrift Fur€ Naturforschung B, Shrestha, S., et al., 2016. Sageone, a diterpene from 60 (5), 548–554. Rosmarinus officinalis, synergizes with cisplatin cytotoxicity Parvez, A., et al., 1992. Perovskone: a triterpene with a novel in SNU-1 human gastric cancer cells. Phytomedicine: inter- carbon skeleton from Perovskia abrotanoides. The journal national journal of phytotherapy and phytopharmacology, of organic chemistry, 57 (16), 4339–4340. 23 (13), 1671–1679. Perveen, S., et al., 2006. Phenolic constituents from Perovskia Slusarczyk, S., et al., 2015. Isolation and fast selective deter- atriplicifolia. Natural product research, 20 (4), 347–353. mination of nor-abietanoid diterpenoids from Perovskia Perveen, S., et al., 2007. Atriplisides A and B, two new glyco- atriplicifolia roots using LC-ESI-MS/MS with multiple reac- sides from Perovskia atriplicifolia. Zeitschrift Fur€ tion monitoring. Natural product communications, 10 (7), Naturforschung B, 62 (6), 863–867. 1149–1152. Perveen, S., et al., 2008. Pervosides A and B, new isoferulyl Sun, J., 2007. D-Limonene: safety and clinical applications. glucosides from Perovskia atriplicifolia. Journal of Asian Alternative medicine review, 12 (3), 259–264. natural products research, 10 (11–12), 1105–1108. Suresh, G., et al., 2011. Premnalatifolin A, a novel dimeric Perveen, S., et al., 2014. Cholinesterase inhibitory triterpenes diterpene from Premna latifolia Roxb. Tetrahedron letters, from Perovskia atriplicifolia. Asian journal of chemistry,26 52 (39), 5016–5019. (18), 6163–6166. Tabefam, M., et al., 2018a. Antiprotozoal diterpenes from Perveen, S., Malik, A., and Tareen, R.B., 2009. Structural deter- Perovskia abrotanoides. Planta medica, 84 (12-13), mination of atricins A and B, new triterpenes from 913–919. Perovskia atriplicifolia, by 1D and 2D NMR spectroscopy. Tabefam, M., et al., 2018b. Antiprotozoal isoprenoids from Magnetic resonance in chemistry, 47 (3), 266–269. Salvia hydrangea. Journal of natural products, 81 (12), Pourhosseini, S.H., et al., 2018. Genetic and chemical diver- 2682–2691. sity in Perovskia abrotanoides Kar. (Lamiaceae) populations Takeda, Y., et al., 2006. Chemical constituents of an Uzbek based on ISSRs markers and essential oils profile. medicinal plant, Perovskia scrophularifolia. Journal of nat- Chemistry and biodiversity, 15 (3), e1700508. ural medicines, 61 (1), 84–85. Pourmortazavi, S.M., Sefidkon, F., and Hosseini, S.G., 2003. Tarawneh, A., et al., 2015. Flavonoids from Perovskia atriplici- Supercritical carbon dioxide extraction of essential oils folia and their in vitro displacement of the respective from Perovskia atriplicifolia Benth. Journal of agricultural radioligands for human opioid and cannabinoid receptors. and food chemistry, 51 (18), 5414–5419. Journal of natural products, 78 (6), 1461–1465. Rechinger, K. H., 1982. Ballota, stachys and perovskia, In: Tareen, R.B., et al., 2010. Indigenous knowledge of folk medi- Rechinger, K.H., Hedge, I.C., eds. Flora Iranian Labiatae No cine by the women of Kalat and Khuzdar regions of 150, Edits. Hedge IC. Graz, Austria: Akademische Druck and Balochistan, Pakistan. Pakistan journal of botany, 42, Vertagsanstalt, 350, 370 and 477. 1465–1485. Sairafianpour, M., et al., 2001. Leishmanicidal, antiplasmodial, Thommen, C., Neuburger, M., and Gademann, K., 2017. and cytotoxic activity of novel diterpenoid 1,2-quinones Collective syntheses of icetexane natural products based from Perovskia abrotanoides: new source of tanshinones. on biogenetic hypotheses. Chemistry - a European journal, Journal of natural products, 64 (11), 1398–1403. 23 (1), 120–127. Sajjadi, S.E., et al., 2005. Chemical composition of the essen- Toniolo, C., et al., 2014. HPTLC determination of chemical tial oil of Perovskia abrotanoides Karel. growing wild in composition variability in raw materials used in botanicals. Iran. Flavour and fragrance journal, 20 (4), 445–446. Natural product research, 28 (2), 119–126. Salae, A-w., and Boonnak, N., 2013. Obtusinones D and E, lin- Uchiyama, N., et al., 2003. New icetexane and 20 norabietane ear and angular fused dimeric icetexane diterpenoids diterpenes with trypanocidal activity from Dracocephalum from Premna obtusifolia roots. Tetrahedron letters, 54 (11), komarovi. Journal of natural products, 66 (1), 128–131. 1356–1359. Venditti, A., 2017. Secondary metabolites from Teucrium Sardashti, A.R., Valizadeh, J., and Adhami, Y., 2013. Variation polium L. collected in Southern Iran. Arabian journal of in the essential oil composition of Perovskia abrotonoides medicinal and aromatic plants, 3, 108–123. 22 M. MOHAMMADHOSSEINI ET AL.

Venditti, A., and Bianco, A., 2018. Secondary metabolites of Venditti, A., et al., 2017d. A new natural neo-clerodane from Hypericum richeri Vill. collected in Central Italy: chemo- Teucrium polium L. collected in Northern Iran. Industrial taxonomy and ethnomedicinal relevance. Natural product crops and products, 97, 632–638. research, 2, 155–162. Venditti, A., et al., 2018. Chemical profiling of the fruits of Venditti, A., et al., 2013. Phytochemical analysis, biological Styrax officinalis L. from Monti Lucretili (Latium region, evaluation and micromorphological study of Stachys alo- Central Italy): Chemotaxonomy and nutraceutical poten- pecuros (L.) Benth. subsp. divulsa (Ten.) Grande endemic tial. Trends in phytochemical research,2,1–12. to central Apennines, Italy. Fitoterapia , 90, 94–103. Venditti, A., et al., 2019. A syn-ent-labdadiene derivative with Venditti, A., et al., 2014. Characterization of secondary a rare spiro-beta-lactone function from the male cones of metabolites, biological activity and glandular trichomes of – Stachys tymphaea Hausskn. from the Monti Sibillini Wollemia nobilis. Phytochemistry, 158, 91 95. National Park (Central Apennines, Italy). Chemistry and bio- Vgm N., Atmakur, H., Katragadda, S.B., et al., 2014. diversity, 11 (2), 245–261. Antioxidant, hepatoprotective and cytotoxic effects of ice- Venditti, A., et al., 2015a. Essential oil composition, polar texanes isolated from stem-bark of Premna tomentosa. compounds, glandular trichomes and biological activity of Phytomedicine: international journal of phytotherapy and Hyssopus officinalis subsp. aristatus (Godr.) Nyman from phytopharmacology, 21 (4), 497–505. central Italy. Industrial crops and products, 77, 353–363. Vigan, M., 2010. Essential oils: renewal of interest and tox- Venditti, A., et al., 2015b. Iridoid glucosides from Pentas lan- icity. European journal of dermatology, 20 (6), 685–692. ceolata (Forssk.) Deflers growing on the Island of Sardinia. Wansi, J.D., et al., 2018. Bioactive essential oils from the Plant systematics and evolution, 301 (2), 685–690. Cameroonian rain forest: a review - Part I. Trends in phyto- Venditti, A., et al., 2016. Unusual molecular pattern in chemical research, 2, 187–234. Ajugoideae subfamily: the case of Ajuga genevensis L. Wansi, J.D., et al., 2019. Bioactive essential oils from the from Dolomites. Natural product research, 30 (9), Cameroonian rain forest: A review - Part II. Trends in 1098–1102. phytochemical research,3,3–52. Venditti, A., et al., 2017a. Polar constituents, essential oil and Wink, M., 2003. Evolution of secondary metabolites from an antioxidant activity of marsh woundwort. Chemistry and ecological and molecular phylogenetic perspective. biodiversity, 14, e1600401. – Venditti, A., et al., 2017b. Phytochemical comparison with Phytochemistry, 64 (1), 3 19. quantitative analysis between two flower phenotypes of Wu, X.D., et al., 2013. Diterpenoids from the twigs and leaves Mentha aquatica L.: pink-violet and white. AIMS molecular of Fokienia hodginsii. Journal of natural products, 76 (6), science, 4 (3), 288–300. 1032–1038. Venditti, A., et al., 2017c. Terpenoids and more polar com- Wu, Y., et al., 2019. A variable loop involved in the substrate pounds from the male cones of Wollemia nobilis. selectivity of pinoresinol/lariciresinol reductase from Chemistry and biodiversity, 14 (3), e1600332. Camellia sinensis. Phytochemistry, 162, 1–9. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

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