Phytochemical and pharmacological progress on the genus Syringa

Genus Syringa, belonging to the Oleaceae family, consists of more than 40 plant species worldwide, of which 22 species, including 18 endemic species, are found in China. Most Syringa plants are used in making ornaments and traditional medicines, whereas some are employed for construction or economic use. Previous studies have shown that extracts of Syringa plants mainly contain iridoids, lignans, and phenylethanoids that have antitumor, antihypertensive, anti-oxidant, and anti-inflammatory activities. This study reviews phytochemical and pharmacological progress on Syringa in the recent 20 years and discusses the future research prospects to provide a reference in further promotion and application of the genus. Graphical Abstract Phytochemical and pharmacological progress on the genus Syringa


Introduction
Plants belonging to the family Oleaceae, which consists of 27 genera and 400 species worldwide, have important applications in the daily life of people living in developing countries. Plants of many well-known genera, including Forsythia, Syringa, and Osmanthus, have been widely used for medicinal and industrial purposes. For instance, the stems and roots of S. pinnatifolia var. alashanensis is the major composition of atraditional formula 'Ba wei chenxiang' powder that is used for treatment of asthma, cardiopalmus, and angina [1].
Most Syringa plants are deciduous shrubs and arbors and include more than 40 species distributed around Europe and Asia [2]. At present, 22 species are found in China, of which 18 are endemic species that are mainly distributed in the southwestern part of Sichuan, Yunnan, Tibet, and other Northwestern regions. Many Syringa species, such as S. chinensis, S. meyeri, and S. pekinensis, are used for making ornaments. Flowers of S. oblata and S. reticulata var. mandshurica are an ideal source of aroma oils or nectar. Some Syringa plants are also used for construction purposes or for manufacturing furniture [1].
Previous phytochemical studies on Syringa species have revealed the presence of more than 140 secondary metabolites, including iridoids, lignans, phenylethanoids, their glycosides, minor organic acids, and essential oils [3,4]. Modern pharmacological studies have shown the bioactivities of these metabolites, such as antitumor, antihypertensive, anti-oxidant, anti-inflammatory activities, and so on [5]. However, a systematic review of these studies has not been performed to date. This review summarizes the phytochemical and pharmacological progress on Syringa to date by focusing on its chemical classification, structural features, and biological and pharmacological applications to provide information for further research on this genus.
Besides the abovementioned compounds, Syringa plants contain essential oils that form the most important constituents not only because of their economic utility but also because of their potential medicinal value as antimicrobial, antipyretic, and antiviral agents. Multiple analytical techniques such as headspace solid-phase microextraction, gas chromatography-mass spectrometry (GC-MS), GC-MS coupled with heuristic evolving latent projections, moving subwindow searching, nuclear magnetic resonance spectroscopy, and X-ray single-crystal diffraction analysis have been used to identify essential oils from fresh flowers of S. oblata var. alba. For instance, 39 volatile oil constituents were identified, including four characteristic isomers of lilac alcohols (lilac alcohols A-D) and lilac aldehydes A-D [38]. Ninety-five components, including 15 terpenes, 14 oxygenated terpenes, 10 aromatic compounds, and 13 n-alkanes were quantitatively analyzed from S. oblata buds [39]. Forty-nine components were described from essential oil of S. pubescens flowers, most of which are monoterpenes and sesquiterpenes [40]. Thirtyfour volatile oil components, accounting for around 64.7% (zerumbone) of the toil oil, were identified from roots and barks of S. pinnatifolia var. alashanensis [4]. These data imply that Syringa plants could be considerably different from each other in terms of their essential oil components.

Pharmacological activities
Various crude extracts and isolated compounds from Syringa plants have shown significant antitumor, antihypertensive, anti-inflammatory, anti-oxidant, and antifungal activities.     . Preliminary analysis of structure-activity relationship suggested that C-5′-OH plays an important role in this cytotoxic activity [11]. Isooleoacteoside (40) showed weak cytotoxicity against LOX-IMVI melanoma cell line, with GI 50 value of 16 μM, and syringopicroside B (33) showed weak cytotoxic activity against NCI-H522 lung cancer cell line, with GI 50 value of 13 μM [9]. MTT assay used to assess the cytotoxicities of syringaresinol (78) and oleoside 11-methyl ester (3) showed that compound 78 had a strong dose-dependent effect on HepG2 cell line, with an IC 50 value of 94.6 μM, and compound 3 has a dose-response curve of low slope, with a high IC 50 value of 186.5 μM, compared with positive controls dexamethasone (IC 50 14.2 μM) and paclitaxel (IC 50 700 nM). However, compound 78 was cytotoxic even at the lowest concentration of 29.9 μM. β-Amyrin acetate (139) showed weak cytotoxicity against A2780 human ovarian cancer and HepG2 cell lines [5]. Oleuropein (4) and 2-(3, 4-dihydroxy)-phenylethyl-β-D-glucopyranoside (83) showed evident cytotoxicities against P-388, L-1210, SNU-5, and HL-60 cell lines, with IC 50 values varying from 8.5 to 139.8 μM [12]. Verbascoside (86) showed moderate cytotoxic activity against SNB-75 (brain cancer) and SNB-78 cell lines, with GI 50 values of 7.4 and 7.7 μM, respectively [9]. A pharmacokinetic study showed that compound 86 interacted with the catalytic domain of PKC and acted as a competitive inhibitor of adenosine triphosphate (K i = 22 μM) and non-competitive inhibitor of phosphate acceptor (histone III). Because 83 is one part of 86 in its molecular structure, the cytotoxic effect could be attributed to 3, 4-dihydroxyphenylethoxy moiety, which may act as a competitive inhibitor to the catalytic domain of PKC. Therefore, 83 is a potentially essential skeleton of most cytotoxic phenylethanoid glycosides [12].

Hypotensive activity
Syringin (110) and kaempferol-3-O-rutinoside (125) showed antihypertensive activity. Intravenous injection of 10 mg/kg of compound 86 significantly decreased systolic, diastolic, and mean arterial blood pressure in Pentothal-anesthetized rats. Moreover, the depressor effect of compound 86 was independent of muscarinic and histaminergic receptors because it did not block the effect of atropine (an antimuscarinic agent) and chlorpheniramine/cimetidine (antihistaminergic agents) [36].
In vitro studies showed that oleuropein (4) significantly lowered blood pressure. It is interesting to note that antihypertensive effect of compound 4 (33% at 30 mg/kg dose) on the blood pressure of anesthetized rats was similar to that of compound 86 (39.04% ± 2.38% at 10 mg/kg dose) [14,36], which is probably because of the similarity in their structures, with both possessing the same aromatic fragment having two hydroxy groups.

Antioxidant activity
A 70% EtOH extract of S. reticulata barks showed potent superoxide anion and DPPH free radical scavenging activities, with EC 50 values of 5.88 and 38.10 μg/mL, respectively [10].
Eugenol (112) inhibited the catalytic activity of H 2 O 2 / Ca 2+ human erythrocyte membrane lipid peroxidation at a concentration of 200 μmol/L, with an inhibition rate of 62%, and completely suppressed the catalytic activity of dibenzoyl peroxide/Ca 2+ human erythrocyte membrane lipid peroxidation at a concentration of 100 μmol/L. Compound 112 exerted its effect in a non-competitive manner by reacting with Ca 2+ and inhibiting the formation of hydroxyl radicals, thus, protecting the cell membrane lipid from oxidation [2].

Others
Essential oils from the stems and roots of S. pinnatifolia var. alashanensis (SPEO) reduced the deviation of ST segment; decreased the levels of lactate dehydrogenase, creatine kinase, and troponin T; and increased the activity of SOD. These protective effects were further confirmed by histopathological examination [58]. Treatment with both 8 and 32 mg/kg SPEO prolonged the survival of mice under hypoxia conditions, showing a remarkable protective effect against H 2 O 2 -induced death in cultured rat myocytes. Moreover, 5, 2.5 and 1.25 μg/mL doses of SPEO inhibited ADP-induced rat platelet aggregation by 47.4%, 37.0%, and 32.9%, respectively [58], implying that SPEO exerted protective effects against myocardial ischemia.
Oral and intraperitoneal administration of 0.2-0.4 g of leaf extract of S. vulgaris in cats or rabbits exerted an antipyretic effect that was equal to the effect of 0.1-0.3 g of aminopyrine administered orally or intraperitoneally. However, leaf extracts of S. vulgaris are considerably more toxic than aminopyrine, with their toxic dosages being 0.4 and 1.2 g/kg, respectively [59]. In vitro evaluation of leaf extract of S. aramaticum showed its antiviral activity against herpes simplex virus at concentrations 1.25%-2.5%. The protective effect was more obvious when controlling the amount of virus attacks at 9.2-92 tissue culture infective dose (TCID50), suggesting that S. aramaticum effectively killed the virus without any harmful side effects [60][61][62].
Studies have reported that leaf extracts of S. aramaticum could be used for treating hemorrhoids [63].

Review and conclusions
This review describes phytochemical and pharmacological progress on the genus Syringa in the recent 20 years and discusses the future research prospects.
Syringa plants are used not only as traditional medicines to treat rheumatoid arthritis, asthma, cardiopalmus, and angina pectoris by natives in China but also for making ornaments, volatile oils, food additives, and bactericides worldwide, particularly in developing countries. Previous phytochemical studies on crude extracts from various species of this genus have identified iridoids, lignans, phenylpropanoids, and phenylethanoids having antitumor, antihypertensive, anti-oxidant, and anti-inflammatory activities. Iridoids, lignans, and phenylethanoids are the most predominant compounds in Syringa plants that probably contribute independently or synergistically to their main biological activities.
To the best of our knowledge, 46 iridoid representatives have been reported in Syringa plants, with high concentrations present in the leaves of S. vulgaris, S. pubescens, S. afghanica, S. reticulata, and S. velutina and barks of S. vulgaris and S. reticulata and low concentrations present in the flowers (S. pubescens), seeds, and seeds crust (S. oblata). This difference may be associated with their ecological roles, because iridoids are produced mainly to fight predators and/or microbes. Moreover, high concentrations of lignans in the stems and roots can be attributed to the rigidity of these plants. This may be the reason for the absence of iridoids in S. pinnatifolia var. alashanensis because materials used for chemical investigation included peeled stems and roots. Anti-inflammatory effects of extracts from these plants are mainly responsible for their applications in traditional medicine. However, only preliminary work has been performed on most isolated compounds, such as in vitro cytotoxicity screening (1, 2, 78, and 139). Limited studies have been performed on the in vivo effects of these compounds; thus, providing opportunities for further detailed research. It is particularly worthy to mention that China has an abundant resource of Syringa, with many endemic species. For instance, S. pinnatifolia var. alashanensis is a well-known Mongolian medicine traditionally used for myocardial ischemia in clinical practice. However, no substantial evidence is available on its bioactive ingredients and mechanisms of action underlying this effect. Therefore, it deserves further phytochemical and pharmacological studies.