Naturally Occurring Cinnamic Acid Sugar Ester Derivatives

Cinnamic acid sugar ester derivatives (CASEDs) are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3′,6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM), presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds.


Introduction
As a class of natural products, cinnamic acid sugar ester derivatives (CASEDs) have become a research focus owing to their structural diversity, together with distinctive and remarkable pharmacodynamic actions, such as anti-depression, anti-cancer, anti-oxidant, anti-inflammatory and anti-viral activities [1][2][3][4][5]. They have one or more phenylacrylic (Ph-CH=CH-CO-) moieties or their derivatives linked to the non-anomeric carbon skeletons of the glycosyl part through ester linkage-bonds. The phenylacrylic group, also named cinnamic acid part, may usually contain hydroxyl or methoxy substituted groups (Figure 1). The aglycone group is the core structure, and includes monosaccharides, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, hexsaccharides and heptasaccharides. There are one or several -OH groups on the non-anomeric carbon skeleton, connected with the cinnamic acid moiety. Since 1968 [6], more than 330 CASEDs have been found in the medicinal plants of the families Polygalaceae, Scrophulariaceae, Liliaceae, Oleaceae, Bignoniaceae, Polygonaceae, Orobanchaceae, Rosaceae, Lamiaceae, Labiatae, Gesneriaceae, Rubiaceae, Cruciferae, Plantaginaceae, Verbenaceae, Magnoliaceae, Amaranthaceae, Smilacaeae, Sterculiaceae, Hymenophyllaceae and Asclepiadaceae (Table 1). Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae, which is used for tranquilizing the mind and promoting intelligence as in Traditional Chinese Medicine (TCM) [1]. Yuanzhi, the dried root of Polygala tenuifolia, a representative plant from the Polygalaceae, is a well-known TCM used for its sedative, psychotic, cognitive and depressant effects. It is used in the clinic for tranquilizing and reinforcing the mind, and is commonly applied to physical and mental illness.  Since 1968 [6], more than 330 CASEDs have been found in the medicinal plants of the families Polygalaceae, Scrophulariaceae, Liliaceae, Oleaceae, Bignoniaceae, Polygonaceae, Orobanchaceae, Rosaceae, Lamiaceae, Labiatae, Gesneriaceae, Rubiaceae, Cruciferae, Plantaginaceae, Verbenaceae, Magnoliaceae, Amaranthaceae, Smilacaeae, Sterculiaceae, Hymenophyllaceae and Asclepiadaceae (Table 1). Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae, which is used for tranquilizing the mind and promoting intelligence as in Traditional Chinese Medicine (TCM) [1]. Yuanzhi, the dried root of Polygala tenuifolia, a representative plant from the Polygalaceae, is a well-known TCM used for its sedative, psychotic, cognitive and depressant effects. It is used in the clinic for tranquilizing and reinforcing the mind, and is commonly applied to physical and mental illness.  [20,21] 3 Osmanthuside E Osmanthus asiaticus [22] 4 1,6-Diferuloyl glucose Sterculia foetida [23] 5 Eutigoside A Ligustrum purpurascens [24] 6 Osmanthuside A Ligustrum purpurascens [24]

Disaccharide Esters
Disaccharide esters 28-162 (Figures 6-16) [4,5,10,13,15,17,19,24,25,29, constitute the largest group among CASEDs. Their glycosyl parts include glycosyl groups, with glucopyrannosyl, rhamnopyranosyl, fructofuranosyl, and arabinopyranosyl ones being the most important and sucrose units as found in compounds 28-120, 162 are more rare,. Among them, the glycosyl unit in 28-120 has the anomeric carbon on α-D-glucose linked to a β-D-fructose. The ester bond is often formed at the C-6 position of α-D-glucose and C-3 position of β-D-fructose. The compounds 122-140 are composed of α-L-rhamnose and β-D-glucose, with a connection between the C-1 location of α-L-rhamnose and C-3 position of β-D-glucose. The cinnamic acid unit is mainly connected to the C-4 position of β-D-glucose, and less often in the C-6 location. The glycosyl moieties of compounds 145-147 are similar to those of 122-140, and the configuration of the hydroxyl attached to the anomeric carbon of glucose could not be determined. The aglycone part of compounds 150-155 is two β-D-glucoses joined by C-1 and C-6, and the functional group is attached to the C-2 position of the parent nucleus.                Sibiricose A5 (28), tenuifoliside A (51) and DISS (73) from the root of Polygala sibirica (Yuanzhi) [13], have the same core sucrose unit and the ester is always connected at the C-6 position of α-D-glucose and C-3 position of β-D-fructose. These compounds have anti-depression properties. In 1968, verbascoside (=acteoside 131) was the first CASED isolated from the medical plant Syringa vulgaris (Oleaceae) [3]. So far, it has been reported in nine families. Magnoloside A (121) from medicinal plants of the Magnoliaceae family is unique among the phenylpropanoids in rarely occurring alone as the core glycosyl [62]. In addition, crenatoside (157) has a novel annular framework which attaches the C-1 and C-2 of the glucose to a hexatomic oxygen ring [91]. Glomeratose E (162) possesses a (E,E)-β,β′-bis-sinapoyl group between the α-D-glucose and β-D-fructose [38].

Other Sugar Esters
To our knowledge, pentasaccharide esters 280-320 (Figures 61-64) [11,12,46,92,93,107,[108][109][110], hexsaccharide esters 321-333 (Figures 65-71) [11,12,56,107,109,110], heptasaccharide esters 334 ( Figure 72) [56] were all found in the Polygalaceae family and most of them form a series of similar type compounds. That is to say, CASEDs with higher carbon numbers are rarely found in plants outside the Polygalaceae. The phenylacrylic groups usually locate at C-1 of fructose, C-4 of glucose, as well as C-4 of fucose. Most glycosyl moieties of pentasaccharide esters are four glucoses and a fructose with different locations and sequence. Tenuifolioses A and B (285,288), obtained from Polygala tenuifolia Willd, showed neuroprotective activity. Tenuifolioses A and B have the same glycosyl core, with β-D-glucoses connected at the C-1 and C-4 position and the first glucose combined with another glucose at C-2 and β-D-fructose at C-1 [12]. Compounds 280-294 with this same sugar core serve to remind researchers of the need for more studies on these compounds to find more precursor compounds of anti-depression drugs. The tenuifoliose A-E (284-288), senegose A-E (301-305), J-O (295-300) type of oligosaccharide multi-esters are esterified with coumaric and ferulic acids [108,111]. Compounds 306-307, 311 [93] are pentasaccharide esters having the same glycosyl connection sequence as that of reiniose G (265) and have a p-coumaroyl residue at C-6 of glucose [38]. Compounds 308-310, 312-316 are also pentasaccharide esters, but with a feruloyl residue at C-6 of glucose. Compounds 319-320 and 325-330 are CASEDs belonging to the oleanane-type saponins and

Other Sugar Esters
To our knowledge, pentasaccharide esters 280-320 (Figures 61-64) [11,12,46,92,93,107,[108][109][110], hexsaccharide esters 321-333 (Figures 65-71) [11,12,56,107,109,110], heptasaccharide esters 334 ( Figure 72) [56] were all found in the Polygalaceae family and most of them form a series of similar type compounds. That is to say, CASEDs with higher carbon numbers are rarely found in plants outside the Polygalaceae. The phenylacrylic groups usually locate at C-1 of fructose, C-4 of glucose, as well as C-4 of fucose. Most glycosyl moieties of pentasaccharide esters are four glucoses and a fructose with different locations and sequence. Tenuifolioses A and B (285,288), obtained from Polygala tenuifolia Willd, showed neuroprotective activity. Tenuifolioses A and B have the same glycosyl core, with β-D-glucoses connected at the C-1 and C-4 position and the first glucose combined with another glucose at C-2 and β-D-fructose at C-1 [12]. Compounds 280-294 with this same sugar core serve to remind researchers of the need for more studies on these compounds to find more precursor compounds of anti-depression drugs. The tenuifoliose A-E (284-288), senegose A-E (301-305), J-O (295-300) type of oligosaccharide multi-esters are esterified with coumaric and ferulic acids [108,111]. Compounds 306-307, 311 [93] are pentasaccharide esters having the same glycosyl connection sequence as that of reiniose G (265) and have a p-coumaroyl residue at C-6 of glucose [38]. Compounds 308-310, 312-316 are also pentasaccharide esters, but with a feruloyl residue at C-6 of glucose. Compounds 319-320 and 325-330 are CASEDs belonging to the oleanane-type saponins and

Other Sugar Esters
To our knowledge, pentasaccharide esters 280-320 (Figures 61-64) [11,12,46,92,93,[107][108][109][110], hexsaccharide esters 321-333 (Figures 65-71) [11,12,56,107,109,110], heptasaccharide esters 334 ( Figure 72) [56] were all found in the Polygalaceae family and most of them form a series of similar type compounds. That is to say, CASEDs with higher carbon numbers are rarely found in plants outside the Polygalaceae. The phenylacrylic groups usually locate at C-1 of fructose, C-4 of glucose, as well as C-4 of fucose. Most glycosyl moieties of pentasaccharide esters are four glucoses and a fructose with different locations and sequence. Tenuifolioses A and B (285, 288), obtained from Polygala tenuifolia Willd, showed neuroprotective activity. Tenuifolioses A and B have the same glycosyl core, with β-D-glucoses connected at the C-1 and C-4 position and the first glucose combined with another glucose at C-2 and β-D-fructose at C-1 [12]. Compounds 280-294 with this same sugar core serve to remind researchers of the need for more studies on these compounds to find more precursor compounds of anti-depression drugs. The tenuifoliose A-E (284-288), senegose A-E (301-305), J-O (295-300) type of oligosaccharide multi-esters are esterified with coumaric and ferulic acids [108,111]. Compounds 306-307, 311 [93] are pentasaccharide esters having the same glycosyl connection sequence as that of reiniose G (265) and have a p-coumaroyl residue at C-6 of glucose [38]. Compounds 308-310, 312-316 are also pentasaccharide esters, but with a feruloyl residue at C-6 of glucose. Compounds 319-320 and 325-330 are CASEDs belonging to the oleanane-type saponins and found in the root parts of Polygala glomerata Lour [107], which have the same parent nuclei as polygalasaponin XLII (275). To our knowledge, only one heptasaccharide ester (polygalasaponin XXXII, 334) was reported, and it is also an oleanane-type saponin, with hippocampus-dependent learning and memory enhancing activity. Polygalasaponin XXXII [56], as the representative of oleanane-type saponins in CASEDs, has also captured attention of researchers to do more investigation on the other compounds of the class (317-320, 325-332) in order to identify compounds with the same activity or with more sugars that might improve the improve hippocampus-dependent learning and memory enhancing activity of polygalasaponin XXXII.

Biological Activities
To date, approximately 334 CASEDs have been isolated from various medicinal plants and their structures characterized. However, the biological activities, mechanism of action and structure-activity-relationships (SAR) of many CASEDs have rarely been explored up to now. Hence, an overview of the pharmacological activities of the CASED may serve as valuable indication to further probe into their full therapeutic potentials.

Anti-depression Activity and Neuroprotective Activity
Depression, one of the major mental disorders, is accompanied by symptoms such as emotional slump, reduced physical activities, feelings of helplessness and pessimism and even suicide attempts. At present there are three main points of view regarding the pathogenesis of depression, including the biogenic amine theory, the nerve nutrition theory and the cytokines theory.
[1] discovered that DISS and tenuifoliside A (TEA, 51), isolated from Radix Polygalae, showed protective effects on SH-SY5Y against Cort-induced injury. A study by Ikeya et al. [112] showed that tenuifoliside B (52) improved the scopolamine-induced impairment of passive avoidance response by promoting the cholinergic system. Buergerisides A1 (13), B1 (12), B2 (15) and C1 (11) from the roots of Scrophularia buergeriana exhibit protective activity on primary cultures of rat cortical cells after exposure to excitotoxin, glutamate according to an investigation by Kim et al. [18]. Further findings demonstrate that a possible mechanism of the antidepressant action of DISS maybe be related with hippocampal neuroplasticity and neuroproliferation. DISS possesess potent and rapid antidepressant activity, which are mediated via brain MAO-A and MAO-B activity and upregulated serum cortisol levels induced by CMS [113]. In neuronal cells, DISS-mediated regulation of BDNF gene expression is associated with CREB-mediated transcription of BDNF upstream activation of ERK1/2 and CaMKII to cause neuroprotective and antidepressant effects [114]. Dong et al. [8] discovered that the neurotrophic mechanism of TEA (b24) in C6 cells correlates with TrkB/BDNF/ERK and TrkB/BDNF/PI3K.

Biological Activities
To date, approximately 334 CASEDs have been isolated from various medicinal plants and their structures characterized. However, the biological activities, mechanism of action and structure-activity-relationships (SAR) of many CASEDs have rarely been explored up to now. Hence, an overview of the pharmacological activities of the CASED may serve as valuable indication to further probe into their full therapeutic potentials.

Anti-Depression Activity and Neuroprotective Activity
Depression, one of the major mental disorders, is accompanied by symptoms such as emotional slump, reduced physical activities, feelings of helplessness and pessimism and even suicide attempts. At present there are three main points of view regarding the pathogenesis of depression, including the biogenic amine theory, the nerve nutrition theory and the cytokines theory.
[1] discovered that DISS and tenuifoliside A (TEA, 51), isolated from Radix Polygalae, showed protective effects on SH-SY5Y against Cort-induced injury. A study by Ikeya et al. [112] showed that tenuifoliside B (52) improved the scopolamine-induced impairment of passive avoidance response by promoting the cholinergic system. Buergerisides A 1 (13), B 1 (12), B 2 (15) and C 1 (11) from the roots of Scrophularia buergeriana exhibit protective activity on primary cultures of rat cortical cells after exposure to excitotoxin, glutamate according to an investigation by Kim et al. [18].
Further findings demonstrate that a possible mechanism of the antidepressant action of DISS maybe be related with hippocampal neuroplasticity and neuroproliferation. DISS possesess potent and rapid antidepressant activity, which are mediated via brain MAO-A and MAO-B activity and upregulated serum cortisol levels induced by CMS [113]. In neuronal cells, DISS-mediated regulation of BDNF gene expression is associated with CREB-mediated transcription of BDNF upstream activation of ERK1/2 and CaMKII to cause neuroprotective and antidepressant effects [114]. Dong et al. [8] discovered that the neurotrophic mechanism of TEA (b24) in C6 cells correlates with TrkB/BDNF/ERK and TrkB/BDNF/PI3K.

Anticancer Activity
Belonging to the family of serine/threonine protein kinases that are activated by Ca 2+ , Protein Kinase C (PKC) is involved in signal transduction, and cellular proliferation and differentiation. It also plays an important role in cell cycle control, tumor genesis, antitumor drug resistance and apoptosis. PKC has been proved to be related with the activation of HIV-1 gene expression, tumor promotion, and the inhibition of apoptosis in leukemia cells. Therefore, it makes a lot of sense to find chemical compounds from natural plants to inhibit the activity of PKC [50,54].
Takasaki et al. found that vanicoside A (102) and vanicoside B (67) from Polygonum pensylvanirum inhibited PKC activity with IC 50 values of 44 µg/mL and 31 µg/mL, respectively [54]. After this preliminary work, LaVerne et al. [50] continued the isolation work on this plant in order to obtain possible homologues via HPLC-MS and isolated vanicosides C-F (104, 57, 113, 91). Regretfully, LaVeme did not to do much research on the pharmacological activity of the vanicosides. Notably, acteoside (=verbascoside, 131) from Lantana camara also shows PKC inhibitory activity in the rat brain with an IC 50 of 25 µM [29]. With the widest distribution in the plant kingdom, acteoside has been widely applied to treat diseases such as cancer, inflammation, or immune disorders.
In the virus family, the Epstein-Barr virus (EBV) is a type of herpes virus causing cancer. EBV has been considered one of the causes of many kinds of malignant tumors such as nasopharyngeal carcinoma. EBV infection mainly occurs human oropharyngeal epithelial cells and B lymphocytes. Lapathoside A (63), lapathoside D (31), vanicoside B (67) and hydropiperoside (37) exhibit remarkable inhibitory effects on the EBV, which is early antigen induced by tumor-promoters, so it makes sense to focus on these four compounds as worthy anti-tumor-promoters for cancer chemoprevention [2,39].

Antioxidant Activity
Plenty of CASEDs were found to possess antioxidant activities, mainly related to their substituted acid groups. The antioxidant properties of these compounds were tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays. Probably thanks to the presence of the 3,4-dihydroxy (catechol) moiety in the structure, compound 2 showed significant antioxidant activities, compared to caffeic acid [21]. Compound 21 from Globularia orientalis also exhibited antioxidant potential, indicating that it could efficiently scavenge free radicals [32].
Zhang et al. [15] found that smilasides G-L (38, 106, 46, 41, 105, 42) showed moderate scavenging activities against DPPH radicals and smilasides J-L (41, 105, 42) exhibited stronger antioxidant activity, which was quite similar to that in positive control ((±)-α-tocopherol). These results support the idea that the substituted feruloyl group plays a key role in the antioxidant activity of phenylpropanoid sugar esters. Heterosmilaside (95), helonioside B (45) and compound 98 showed strong antioxidant DPPH radical scavenging activity with IC 50 values of 12.7, 9.1 and 8.7 µg/mL, respectively [46]. Compounds 28, 32 and 44 exhibited higher activity on scavenging the DPPH radical, compared to L-cysteine at the concentration of 0.02 mM, and the antioxidant activity of compound 32 was almost as same as that of α-tocopherol [36]. Compound 62 and verbascoside showed antioxidant potential pointing out their ability to efficiently scavenge free radicals. 6-O-Sinapoyl sucrose (75) showed weak activity in the DPPH test, but in the superoxide scavenging test, its antioxidative activity increased slightly, hence, a sucrose moiety esterified by sinapic acid seems to regulate the antioxidative activity [115]. Lapathoside D (31) showed DPPH radical scavenging activity with an IC 50 of 0.088 mM [3]. Kiem et al. [53] found that vanicoside A (102), hydropiperoside B (103) and vanicoside E (113) exhibited significant DPPH radical scavenging properties, with IC 50 values of 23.4, 26.7 and 49.0 µg/mL, respectively. However, compounds 66, 67 and 113 were inactive, probably due to the non-existence of acetyl groups in their molecules compared with 102, 103 and 113. Wang et al. discovered that diboside A (58) and lapathoside A (63) only showed low activities in the DPPH test [51].

Other Activities
Compounds 138,131, 159, 158 isolated from Paulownia tomentosa stems were texted for in vitro cytotoxity against Streptococcus pyogenes (A308 and A77), Staphylococcus aureus (SG511, 285 and 503), Streptococcus faecium MD8b, etc. All the compounds exhibited remarkable antibacterial activity. Compound 159 showed a minimal inhibitory concentration (MIC) value of 150 µg/mL against Staphylococcus and Streptococcus species [76]. A mixture of poliumoside (216) and lamalboside (227) revealed moderate antibacterial activity. Compounds 130, 205 and 218 also possess antimicrobial activity [119]. Vanicoside A (102) and B (67) showed β-glucosidase inhibitory activity, with IC 50 values of 59.8 and 48.3 µg/mL (59.9 and 50.5 µM), respectively [120]. The activity of forsythoside B (205) and alyssonoside (206) against free radical-induced impairment of endothelium-dependent relaxation in isolated rat aorta was investigated. Both provided partial protection at 10 −4 M concentration against the electrolysis-induced inhibition acetylcholine response [121]. Senegin II (319) was tested for hypoglycemic activity in normal and KK-Ay mice. Under similar conditions, senegin II not only reduced the level of blood glucose in normal mice 4 h after intraperitoneal administration, but also significantly lowered the blood glucose level of KK-Ay mice [122]. Tenuifolioses B (288), and C (284) potentiated basal synaptic transmission in the dentate gyrus of anesthetized rats [12]. The only septsaccharide ester, polygalasaponin XXXII (334), could improve hippocampus-dependent learning and memory. The result suggests that it may be through the enhancement of synaptic transmission, activation of the MAP kinase cascade and improvement of BDNF level [56].
The rhizome extracts of Smilax glabra Rox B., which is called tufuling in Traditional Chinese Medicine, show many kinds of pharmacological activities like hypoglyceaemic, immuno-modulatory, free-radical scavenging and antioxidant enzyme fortifying activities. Compounds 32, 90, 100, 101, 108, 111, 112 were purified from the S. glabra which should impulse scientistc to perform more research on these compounds [40].

Conclusions
Because of the wide range of distribution, diverse structures and significant pharmacological activities of the CASEDs, more natural product researchers are paying great attention to these compounds. However, most studies on the CASED since 1977 are still isolated and report simple pharmacological activities. More in-depth research on the pharmacological mechanisms of action should be performed. Full exploitation on the broad array of biological activities of CASEDs awaits more researchers to devote themselves to this field.