A Review on the Terpenes from Genus Vitex

The genus Vitex, which belongs to the Verbenaceae family, includes approximately 250 species. Some species of the genus Vitex have traditionally been used for the treatment of headaches, ophthalmodynia, coughs, asthma, premenopausal syndrome, etc. Chemical investigations indicate that the characteristic constituents of the genus Vitex are terpenes, and 210 of these compounds, including monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids, have been obtained from 12 species. Pharmacological studies had shown that these terpenes possess anti-inflammatory, antitumor, antibacterial, antioxidant activities, and so on. In this paper, the identity of these terpenes and their pharmacological effects are reviewed, which can provide references for further research regarding the chemistry and utilization of the Vitex species.


Introduction
The genus Vitex is one of the largest genus in the Verbenaceae family, with approximately 250 species. It is widely distributed, but mainly found in the tropical areas with a few in subtropical regions. The plants are mostly shrubs or arbors [1]. Many species in the Vitex genus have significant medicinal effects. The fruits of Vitex trifolia L. var. simplicifolia Cham. and Vitex trifolia L. are named Manjingzi in the 2015 edition of Chinese Pharmacopoeia. Manjingzi is a traditional Chinese medicine with wind-heat-dispersing action used in treating headaches, migraines and ophthalmodynia. The leaves of V. negundo var. cannabifolia have been used in China for the treatment of coughs, phlegm, and asthma [2]. Various parts of V. negundo, including the leaves, roots and seeds, have been locally used as traditional folk medicines since antiquity, particularly in China. It is commonly used for its analgesic, anti-inflammatory, anti-rheumatism, and insecticidal effects [3]. Many other species of the genus also have been explored and researched. These include V. agnus-castus, V. limonifolia, V. altissima, V. rotundifolia, V. peduncularis, V. negundo var. cannabifolia, V. vestita, V. rehmannii, etc.

Sesquiterpenoids
Apart from the monoterpenoids, only eight sesquiterpenoids 35-42 were found in the Vitex plants (Table 2, Figure 2). Among them, negunfurol (35) is a new sesquiterpenoid from V. negundo containing a

Pharmacological Effects
Terpenes isolated from Vitex plants have been evaluated for their anti-inflammatory, anti-tumor, antibacterial, antioxidant and other pharmacological effects, which provide potential explanations for their use in the treatment of various diseases in folk medicine. It was proved that terpenes were the principal active constituents for the aforementioned effects. A detailed summary of their pharmacological studies is given below.

Anti-Inflammatory Activity
Many plants from Vitex genus have been used for the treatment of inflammatory diseases. And pharmacological studies have also shown that some terpenes isolated from the genus have significant anti-inflammatory effects. Agnuside (3) exerted significant anti-inflammatory activity using carrageenan-, histamine-and dextran-induced acute inflammation models in rats. The inhibitory effect seemed independent of activation of the pituitary-adrenal axis because the inhibition effects against carrageenan-induced oedema in normal and adrenalectomized rats after oral administration of agnuside (3) were highly comparable. Furthermore, oral administration of agnuside (3) to arthritic rats can decrease the levels of intracellular interleukin-17 (IL-17) in lymphocytes with values of 12.17% and 11.04% at doses of 6.12 and 12.5 mg/kg, compared with non-agnuside-fed control groups 19.71% [20]. Twenty-four different compounds were isolated from V. rotundifolia by Lee et al., and their anti-inflammatory activities were tested by the Griess method. The results revealed that five diterpenoids (compounds 57, 61, 106, 141, 138 [69] isolated fourteen triterpenoids from V. negundo var. cannabifolia, of which five compounds (192, 198,  159, 199, and 160) demonstrated moderate inhibitory effects on NO production, with IC 50 values of 24.9 ± 4.6, 26.1 ± 3.6, 27.7 ± 3.3, 34.0 ± 4.1, 40.5 ± 4.9 µM, respectively. Zheng et al. [37] have isolated nine diterpenoids (compounds 97, 98, 123-125, 131, 145, 151, 156) from the seeds of V. negundo. Among these, negundoin C (125) and negundoin E (98) showed the most significant inhibitory effects on NO production using LPS-stimulated RAW 264.7 cells, with IC 50 values of 0.12 and 0.23 µM, respectively, compared with the positive control indomethacin at 45.51 µM. Additionally, the authors demonstrated the protein expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthetase (iNOS) with western blot analysis to describe the possible mechanism of their anti-inflammatory activity, and it was an interesting finding that the level of COX-2 protein and iNOS protein were decreased by 98 and 125.

Antioxidant Activity
Results from different studies have demonstrated that many terpenes in the Vitex genus have significant antioxidant activites. Sridhar et al. [13] isolated six new acylated iridoid glucosides (compounds 17-22) from V. altissima, and each compound was tested for its superoxide radical-scavenging activity using the McCord and Fridovich method and 1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging effect with the Lamaison method.

Other Pharmacological Activities
Additionally, some of the terpenes also have analgesic, endocrinological, anti-hyperglycemic, antifeedant effects, etc. Okuyama et al. [15] verified the analgesic effect of two iridoids agnuside (3) and 10-O-vanilloylaucubin (4) by the acetic acid induced writhing test in mice. At a dose of 50 mg/kg compounds 3 and 4 exerted analgesic effects of 56% (p < 0.001) and 20% (p < 0.05), respectively. Extracts of V. agnus-castus have been used for amelioration of premenopausal syndrome, especially mastodynia, which were most likely caused by hypersecretion of prolactin. The proposed mechanism of action was due to dopaminergic and estrogenic principle. The mixture of clerodane-type diterpenoids (BNO-diterpenoids), isolated from 70% ethanolic extract of V. agnus-castus, showed the highest dopaminergic activity by reducing cyclic AMP (cAMP) formation and prolactin secretion [41]. Sundarama et al. [26] obtained the iridoid glucoside 23 from leaves of V. negundo, which could reduce the levels of blood glucose and glycoproteins, and increase the level of plasma insulin in streptozotocin diabetic rats. Compound 23 also showed anti-hyperlipidemic activity [27]. Additionally, hepatoprotective activity of some terpenes (compounds 23, 164) from genus Vitex plants was discovered by Indian scholars [24,75,85]. Ursolic acid (185) and betulinic acid (205) showed antifeedant activity against the larvae of Achoea janata [81].

Conclusions
In this review, we summarize the research progress on terpenes of the genus Vitex and their pharmacology. These findings indicate that this genus is a valuable source of bioactive molecules. Phytochemical and pharmacological studies of the compounds isolated from the genus Vitex have attracted more attention in recent years. Terpenes, including monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids were identified as the main chemical constituents of this genus. From the literature, there are approximately 250 species in the genus [1], but studies on terpenes had been done to some extent on only 12 species [9][10][11][12][13][14][15][16][17][18][19][20][21]30,55,56,62]. Considering the many bioactive terpenes isolated from the plants in this genus, further investigations on terpenes and their pharmacological effects of the other species are very necessary. In the pharmacology domain, most of the isolated terpenes have been evaluated for various activities in vitro without being further tested in vivo. Thus the promising pharmacological activities should be confirmed by in vivo assay using diverse rat models to prove them. In addition, taking into account their therapeutic efficiency, validating the relationships between chemical constituents, pharmacological effects and traditional uses of plants in this genus is still remains a fundamental task, and should be paid more attention to.