Steroidal Saponins from the Genus Smilax and Their Biological Activities

Abstract The Smilax species, widely distributed in tropical region of the world and the warm areas of East Asia and North America, are extensively used as folk medicine to treat inflammatory disorders. Chemical investigation on Smilax species showed they are rich sources of steroidal saponins with diversified structure types, including spirostane, isospirostane, furostane, pregnane, and cholestane. This review mainly summarizes the steroidal saponins (1–104) reported from the genus Smilax between 1967 and 2016, and their biological activities. The relationship between structures of steroidal saponins and related biological activities were briefly discussed. Graphical Abstract


Introduction
The genus Smilax (Liliaceae family) comprises about 300 species of climbing shrubs. Plants of the genus are widely distributed in tropical region of the world, and also found in warm areas of East Asia and North America [1]. The juvenile leaves of S. riparia are used as vegetable product. The rhizomes of S. glabra are used in Southeast of China as food supplementary for health. Noteworthily, the rhizomes of Smilax species are most famous for their medical use. The rhizomes of S. china and S. glabra, called ''Jin Gang Teng'' and ''Tu Fu Lin'' in Pharmacopoeia of People's Republic of China respectively, are clinically used to treat chronic pelvic inflammatory disease, rheumatic arthritis and so on [2]. The rhizomes of S. riparia, S. nipponica, S. bockii, S. microphylla, and S. discotis were recorded in the Chinese Herbal Medicines to treat joint pain, edema, and rheumatoid arthritis [3].
Previous studies on chemical constituents of Smilax species have disclosed the presence of steroidal saponins, flavonoids, phenylpropanoids, and stilbenoids [4]. Astilbin, a main flavonoid among Smilax species [5], showed unique immunosuppressive activity, and proved to be the active material basis of Smilax species for the treatment of human immune diseases [6]. Steroidal saponins are characteristic bioactive components of the genus Smilax in terms of chemotaxonomic value and biological activities [7]. So far, 104 steroidal saponins have been reported from 20 different Smilax species. These steroidal saponins showed significant antifungal, cytotoxic, anti-inflammatory, as well as cAMP phosphodiesterase inhibitory activities.
In this review, steroidal saponins reported from the genus Smilax between 1967 and 2016 were listed, and the biological activities of steroidal saponins were also included.

Furostane-Type Saponins 48-93
Furostane-type saponins, F ring opened spirostanol glycosides, are another important group of steroidal saponins within Smilax species. The hemiketal hydroxy attached to the C-22 position of furostanol glycosides were sometimes methylated or dehydrated. The methylated derivatives were generally considered to be artifacts. Furostanol glycosides with both 25R and 25S configurations were reported from the genus Smilax. Additionally, furostanol glycosides always have two sugar chains attached to the C-3 and C-26 positions of the aglycone moiety (Fig. 4). Methylprotodioscin (48), protodioscin (59), and pseudoprotodioscin (60) were common constituents among the different Smilax species (Table 1). Compounds 50, isolated from the roots of S. bockii, increased the nerve growth factor (NGF)-induced neurite outgrowth in PC 12D cells by 49% in comparison with the blank control at the concentration of 60 lg/mL [19]. Compounds 53-55, identified from the rhizomes of S. excelsa, were the only three steroidal saponins with acylated sugars moieties within the genus Smilax [17]. Furostane glycosides 62 and 63, with an oxygenated C-15, were isolated from the tubers of S. china [27]. Interestingly, the spirostane or isospirostane glycosides with an oxygenated C-15 have never been reported from Smilax so far. Compounds 67-70 with carbonylation on C-6 were isolated from the roots and rhizomes of S. scobinicaulis, together with a spirostane glycoside 35, and three furostane glycosides 89-91 [28]. Compounds 76 and 77, isolated from the root of S. officinalis, are the diastereoisomers with opposite configuration at C-5 [29]. Smilaxosides A-C (84, 86, 87), and (25R)-Smilaxchinoside A (85) were obtained tubers from S. china [30]. Of them, compounds 84 and 85 are diastereoisomers with opposite configuration at C-25. Compounds 92 and 93, identified from S. aspera [31], were rare examples with hydroxyl substitution on C-1 within the genus Smilax.

Rhizomes and roots
Roots [8] [37] S. riparia Rhizomes and roots [8] 3     Steroidal Saponins from the Genus Smilax and Their Biological Activities 289           S. riparia Roots [52] Steroidal Saponins from the Genus Smilax and Their Biological Activities 291      Pregane-type saponin 94 Trinervuloside A S. trinervula Rhizomes and roots [32] open chain saponins in another way of saying [34]. S. riparia saponins, from which compounds 18-22, 57-59, 66, 85, 87, 95-97, and 102 were identified, exhibited the synergistic effects with allopurinolin in reducing serum uric acid levels and increasing the urine uric acid level in a hyperuricemic mouse model [20]. The attenuation of hyperuricemia-induced renal dysfunction was linked to the inhibition of serum and hepatic xanthine oxidase, the down-regulation of renal mURAT1 and GLUT9, and the up-regulation of mOAT1. Structures of steroidal saponins (94-104) are shown in Fig. 5.

Biological Activities of Steroidal Saponins
Steroidal saponins are considered to be responsible for pharmacological properties of Smilax species. Many pharmacological in vitro and in vivo studies revealed significant biological activities, including cAMP phosphodiesterase inhibitory, anti-fungal, cytotoxic, and antiinflammatory activities.

Prospects
The plants of the genus Smilax are widely spread in China. Their medical use for the treatment of inflammation and rheumatism has a long history in folk China. Previous studies on chemical constituents of Smilax sp. yielded diversified steroidal saponin. However, the biological activities studies of these isolated steroidal saponins lag behind, especially in anti-inflammatory related activities.