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Send Orders for Reprints to [email protected] 56 Mini-Reviews in Medicinal , 2014, 14, 56-63 Naturally Occurring Ping Mao#, Zizhen Liu#, Meng Xie, Rui Jiang, Weirui Liu, Xiaohong Wang, Shen Meng* and Gaimei She*

School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China

Abstract: As an important part of non anti- drug (NSAIDs), salicylate has developed from natural substance salicylic to natrium salicylicum, to . Now, methyl salicylate , a new derivative of , is modified with a -COOH group integrated one methyl into formic ether, and a -OH linked with a , a or a trisaccharide unit by glycosidic linkage. It has the similar pharmacological activities, anti-inflammatory, , antipyretic and antithrombotic as the previous salicylates’ without resulting in serious side effects, particularly the gastrointestinal toxicity. Owing to the superiority of those significant bioactivities, methyl salicylate glycosides have became a hot research area in NSAIDs for several years. This paper compiles all 9 naturally occurring methyl salicylate glycosides, their distribution of the resource and pharmacological mechanism, which could contribute to the new drug discovery. Keywords: Analgesic, anti-inflammation, antipyretic, methyl salicylate glycoside, NSAIDs.

INTRODUCTION centre free salicylic acid until it passed the stomach [4, 5]. The salicylate derivatives, including aspirin (acetyl-salicylic The active centre is not exposed in the stomach to inhitibit acid), are well known as important members of NSAIDs. gastrointestinal COX. In addition, their acidic group has They are widely used as antipyretic, anti-inflammatory, been masked to minimize interaction with gastric tissues [6]. analgesic, antirheumatic, antithrombotic and antitumor So the damage to stomach can be controlled. With exhibited agents clinically [1]. From 3500 years ago with “ bark biological metabolism superiority, those derivative forms can relieve pain” to this day, salicylates especially aspirin, including chemical functional groups, the bond and the had played a critical role in treating cold, , headache, could be better NSAIDs. toothache, joint pain, rheumatism, and so on. In 1763, So far, only nine different methyl salicylate glycosides salicylic acid in willow found by Edward Stone was the have been reported from the . All of them have one effective compound [2]. Hoffman synthesized aspirin in the glucopyranosyl unit connected to the methyl salicylic acid late 1890s. It got popularity mainly because of its reduced directly. Those methyl salicylate glycosides are mainly gastrointestinal irritation [3]. However, the side effects of spread over the genus , Camellia, Polygala, long time to use aspirin have been discovered, gastrointestinal Filipendula and . Among those plants, some irritation with indigestion, gastric ulcers, bleeding and already have been found effects like anti-inflammatory, perforation being the most common. Aspirin was an orally analgesia, antipyretic and so on in modern researches. They administered drug, and this administration route allowed are also used for some corresponding treatments in the theory carboxylate radical into stomach to irritate the gastric of Traditional Chinese Medicine (TCM). G. yunnanensis can mucosa. What’s more, aspirin’s inhibition of gastrointestinal treat rheumatoid , swelling pain, trauma, chronic (COX) resulted in loss of the cytoprotective tracheitis, cold and vertigo [7]. Tea leaves of Camellia are effects of (PGs) on the gastric mucosa [1]. used to treat of heat syndrome and headache. Those applications Recently, a family of nature products derived from in TCM and modern research back each other up. salicylic acid called methyl salicylate glycosides has aroused In this review, we summarized the nine methyl salicylate widespread concerns. Structurally, a methyl group is attached glycosides, including their distributions in the nature, to the C(1) position of the mother nucleus, salicylic acid, into structure characteristics and pharmacological activities. The formic ether, while for the C(2) position, different special metabolism in vivo and the corresponding biological are connected to it by O- glycosidic bond. Some activities were the focal point to describe. of them are expected to substitute for aspirin with their long- term effects and less side effects. Pharmacokinetic studies THE HISTORY OF SALICYLATES showed that methyl salicylate glycosides with the ester The history of salicylates can be traced back to 1500 BC, and the glycosidic bond can delay the release of active when the powder of dried myrtle leaves were recorded in the most ancient medical literature the Ebers Papyrus of ancient *Address correspondence to these authors at the School of Chinese Egypt to be use for Analgesic. And it was the first effective Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China; Tel: +86-10-84738628; Fax: +86-10-84738611; analgesic document. The Assyrians also used willow leaf E-mails: [email protected]; [email protected] extract to treat pain of vascular and muscle [8]. In the 5th #These authors contributed equally to this work. century BC, the famous Ancient Greek physician Hippocrates

1875-5607/14 $58.00+.00 © 2014 Bentham Science Publishers Methyl Salicylate Glycosides Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 57 recommended the efficacy of willow bark and poplar in fever effects, but also results in the alteration of normally protective and pain [9]. As early as one of the four classics of TCM, PGs functions with serious gastrointestinal irritation [1]. Huang Di Nei Jing, there was the record that willow roots, Thereinto, two related isoforms of the COX have bark, branches, leaves had distinct hot alexipharmic effect, been studied. COX-1 and COX-2. COX-2 was the key and external treatment could be put to a toothache. But enzyme to induce inflammatory, COX-1 contributed to people made those herbs to treat fever and pain without protecting the stomach and kidney [12]. This mechanism can knowing the salicylic acid contained was the dominant chemical explain the therapeutic action and gastrointestinal irritation constituents in therapy in the early days. of aspirin, and the side effect can be the biggest obstacle to the clinical use for aspirin and this kind of NSAIDs. In 1763, Edward Stone firstly found willow bark extract Consequently, in order to improve patients’quality of life, a containing salicylic acid to relieving pain, and more studies better structure modification of salicylates is necessary to showed that all these myrtle leaves, willow and poplar barks research which can both increase effectiveness and reduce contained salicylic acid [2, 9]. With the deep research of side effects. current constituents and physic, it has been expounded that salicylic acid was abundantly distributed in THE STRUCTURAL FEATURES OF METHYL species. However, salicylic acid has not been widely SALICYLATE GLYCOSIDES used because of its bitter and chemical instability. More Structurally, all the 9 naturally occurring methyl salicylate seriously, the vomiting and stomach discomfort caused by glycosides have one glucopyranosyl unit connected to the salicylic acid were unbearable. Some people thought those C(2) position by O-glycosidic bond in the mother nucleus, owed to its acidity. Thus, in order to reduce the acidity, salicylic acid, and the group in C(1) position aspirin, an acetylated derivative of salicylic acid was integrated one methyl radical into formic ether. As for the synthesized by a French chemist Hoffman in the late 1890s glucopyranosyl unit, some other monosaccharide units are to solve this problem [3]. It retained the anti-inflammatory attached to it, such as xylose, , apiose and . action without severe gastrointestinal toxicity, and it Those 9 compounds could be broadly grouped into three improved the taste and stability as well. Almost 70 years categories, methyl salicylate-monoglycosides, -diglycosides later, the anti- activity of this agent was also found and -triglycosides, according to the number of saccharide [10]. So far, aspirin has been widely employed to treat unit (Fig. 1). rheumatic diseases for over a century. As the widely aspirin application, various side effects come out, including nausea, Methyl Salicylate Monoglycosides vomiting, and kidney injury, together with ototoxicity. On the basis of current study, methyl salicylate 2-O--D- The most common symptoms are gastrointestinal irritation (MeSAG) is the only monoglycoside. It is also the with indigestion, gastric ulcers, bleeding and perforation [1]. structural foundation of all, one methyl-salicylate group The pharmacological mechanism of salicylates has linked with the -OH of a glucopyranosyl unit. The rest already been taken a great deal of researches. In 1971, John naturally occurring methyl salicylate glycosides have this Vane et al. put forward the theory of COX, which had got structural unit and are completely based on it. MeSAG also broad approval. It was said that salicylates were inhibitors is the most widely distributed among all of them, including towards COX which is the key enzyme of the biosynthesis of Gaultheria, Passiflora, Camellia, Pluchea, two species PGs from [11]. This was a common Holmskioldia sanguine and Verbena brasiliensis in the mechanism of their many actions. The inhibition of PGs Verbenaceae family (Table 1). synthesis was not only responsible for the anti-inflammatory

HO O O OCH O HO O OCH CH OH 3 HO OCH3 HO 3 2 OH OH HO O O HO O O O HO O O O O HO HO HO OH OH OH 1 2 3 OH O O OH OCH OCH3 CH OH HO OCH3 HO O O 3 CH OH 2 3 O O O O OH HO O O O O O HO O O HO HO HO HO OH OH OH HO OH OH 4 5 6

O O HO O HO O HO OCH3 HO OCH3 CH OH OH OH 2 O O HO O HO O O HO O O O OCH HO HO HO 3 HOH2C OH O O O O HO O HO HO O O HO HO HO OH OH OH 7 8 9

Fig. (1). Chemical Structure of Compounds 1-9. 58 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Mao et al.

Table 1. Methyl Salicylate Glycosides.

No. Name Common Name Resource Activities

1 methyl salicylate 2-O--D-glucoside MeSAG P. edulis [13] P. edulis f flavicarpa [13] P. ligularis [13] P. molissima [13] G. yunnanensis [14] H. sanguine [15] Saccharum officinarum [16] Mallotus metcalfianus [17] Poacynum hendersonii [18] Arabidopsis thaliana [19] V. brasiliensis [20] Streblus asper [21] C. sinensis var. sinensis cv. Benihomare [22] C. sinensis var. sinensis cv. Chin-Shin-Oolong and Chinhsuan-Oolong [23] P. indica [24] Panax [25]

2 methyl salicylate 2-O--L-arabinopyranosyl(16)-- Paeonovicinoside; Paeonia anomala [26] D-glucopyranoside Violutoside; Cladogynos orientalis [27] methyl salicylate vicianoside Salacia chinensis [28] Viola tricolor [29] V. cornuta [30] P. sibirica [31] P. arillata [32]

3 methyl salicylate 2-O--D-xylopyranosyl (16) -D- Gaultherin; G. yunnanensis [5] Anti-inflammatory glucopyranoside Monotropitoside; G. procumbens [33] [5, 46, 48] methyl salicylate G. cumingiana [33] Analgetic [5, 48] primeveroside G. pyroloides [33] C. sinensis var. sinensis cv. Benihomare [22] C. sinensis var. sinensis cv. Chin-Shin-Oolong and cv. Chinhsuan-Oolong [23] C. sinensis var. sinensis cv. Yabukita [34] C. sinensis var. sinensis cv. Maoxie [35] S. asper [21] Schisandra propinqua [36] F. glaberrima [37] F. ulmaria [38] Vaccinium myrtillus [39] P. hendersonii [18]

4 methyl salicylate 2-O--L-Rhamnopyranosyl(16)- methyl salicylate P. edulis [13] -D-glucopyranoside rutinoside P. edulis f flavicarpa [13] P. ligularis [13] P. molissima [13] Methyl Salicylate Glycosides Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 59

(Table 1) Contd….

No. Name Common Name Resource Activities

5 methyl salicylate 2-O--D-galactopyranosyl(14)-- methyl salicylate G. yunnanensis [40] Anti-inflammatory D- glucopyranoside lactoside [40, 52, 53, 54] Analgetic [52]

6 methyl salicylate 2-O--D-apiofuranosyl(16)--D- Canthoside A P. sibirica [31] glucopyranoside Canthium berberidifolium [41] C. sinensis var. sinensis cv. Zhuye [42] Croton Oblongifolius [43] Chenopodium quinoa [44] American cranberry v. macrocarpon [45]

7 methyl salicylate 2-O--D-glucopyranosyl(16)-O- methyl salicylate P. Ginseng [25] -D-glucopyranoside gentiobioside

8 methyl salicylate 2-O--D-xylopyranosyl (12)[O-- MSTG-A G. yunnanensis [46] Anti-inflammatory D-xylopyranosyl(16)]-O--D-glucopyranoside [46, 48] Analgetic [48]

9 methyl salicylate 2-O--D-glucopyranosyl ( 12)[O- MSTG-B Lycopersicon esculentum [47] Anti-inflammatory [48] -D-xylopyranosyl(16)]-O--D-glucopyranoside G. yunnanensis [48] Analgetic [48]

Methyl Salicylate Diglycosides glycosides. But for the type of the glycosyl groups, they have not been completely clear [49]. Six of the nine compounds are diglycosides. They have the structural unit of MeSAG mentioned above. As for the Among those plants, G. yunnanensis is perhaps the glucopyranosyl unit, some other monosaccharide units are biggest concerned-given species, and there has been a connected to it. Among those , apiose is the tremendous amount of work on the active compounds, methyl only furanose of all in the Compound 6, canthoside A. The salicylate glycosides. Up to now, five kinds of this class of others are pyranose, including arabinose, xylose, rhamnose, compounds have been found in it, including MeSAG (1), galactose, and glucose corresponded to the compounds 2, 3, Gaultherin (3), methyl salicylate lactoside (5), MSTG-A (8) 4, 5 and 7, respectively. As far as the location, except for the and MSTG-B (9). The G. yunnanensis plant in the Ericaceae compound 5, one monosaccharide unit linked with the - family mainly growing in the southwest and southern regions OH(4) in the glucopyranosyl unit, the other compounds are of China, is a kind of folk herbal medicine used for the at -OH(6) instead. Gaultherin (3) and methyl salicylate lactoside treatments of rheumatoid arthritis, swelling pain, trauma, (5) have significant pharmacologic activities, which we will chronic tracheitis, cold and vertigo. Modern researches also discuss later. exhibited its anti-inflammatory and analgesia activities, and Methyl Salicylate Triglycosides methyl salicylate glycosides in it are considered as characteristic target ingredient in this genus to explain There are two methyl salicylate triglycosides, MSTG-A traditional effects [40, 46, 48]. (8) and MSTG-B (9). Their structures are similar, except for the type of one monosaccharide. On the basis of Gaultherin The Camellia species belongs to the Thecae family also (3), there is a xylose and glucosyl connected to -OH(2) of the contains those active compounds. Via the manufacturing glucopyranosyl unit in MSTG-A (8) and MSTG-B (9), process, the flesh leave become tea, which is one of the most respectively, isolated from G. yunnanensis. Those compounds, popular natural drinks. Ancient records, tea is bitter and cold, including MeSAG (1) are considered as characteristic target used for heat syndrome and headache. Maybe those effects ingredient in this genus, which may provides a new owe to the methyl salicylate glycosides. Modern research mechanism to explain its anti-rheumatic effect [48]. also found tea has anti-inflammatory effect, and the function of the methyl salicylate glycosides in it is worth studying THE DISTRIBUTION OF METHYL SALICYLATE [50]. GLYCOSIDES P. sibirica L. is a member of the Polygalaceae family, Those methyl salicylate glycosides are distributed in and the root is one of the authorized sources of “Yuan Zhi” various plants in genus Gaultheria, Camellia, Polygala, in TCM. It’s worth mentioning that “Yuan Zhi” can cure Filipendula, Viola, and Passiflora (Table 1). In addition, for sore and ulcer. Paeonovicinoside (2) and canthoside A (6) in some plants, such as (Raphanus sativus L.), we only it maybe provide a new mechanism to explain this efficacy knew it contained O- glycosidically bound methyl salicylate [31]. 60 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Mao et al.

PHARMACOLOGY OF METHYL SALICYLATE the methyl salicylate lactoside (5) had the similar effect to GLYCOSIDES the aspirin’s (200 mg/kg body wt.) at doses of 400 mg/kg body wt. [5, 52]. The SDF also significantly decreased the Metabolism of Methyl Salicylate Glycosides carrageenan-induced oedema in 6 h measurements at doses In experimental given gaultherin (3) orally, the of 200 and 400 mg/kg body wt., and the later was the most parent compound was not detected in plasma, while the only effective and close to indomethacin (10 mg/kg body wt., metabolic product, salicylic acid, was demonstrated to be in p.o.) [48]. Aspirin and indomethacin are both well known animals by HPLC. The study also showed that the time to PGs inhibitor. reach the maximum plasma concentration (C ) of salicylic max The further findings demonstrated that, Gaultherin (3), acid was over 5 hours. Compared to aspirin whose peak MSTG-A (8) and methyl salicylate lactoside (5) could all reached within 1 h before declining rapidly, gaultherin (3) significantly suppress the production of pro-inflammatory was slower at converting to the active metabolite salicylic produced by the macrophages, such as mediators, nitric acid and drug elimination. oxide (NO), reactive oxygen species (ROS) and cytokines. A deeper look at this converting in vitro proved that, Cytokines included tumor necrosis factor- (TNF-), orally administered gaultherin (3) was hydrolyzed to product interleukin-1 (IL-1), and interleukin-6 (IL-6). Those pro- methyl salicylate owing to the glycosidase from intestinal inflammatory factors and cytokines all performed important bacteria. Then the methyl salicylate was absorbed in plasma roles in the pathogenesis of chronic inflammatory diseases which contained plenty of esterase. With the action of that [40, 46, 53]. esterase in intestine, and liver, the ester linkage could In the experience of carrageenan-induced pleurisy in rat, be hydrolyzed to the final salicylic acid metabolite to Chao Huang et al. also found methyl salicylate lactoside (5) produce the efficacy [5]. extracted from G. yunnanensis could lower the content of The compounds that have pharmacological effects after TNF-, IL-1 and NO. Compared to the model group, the conversion in vivo were called precursor drugs. The concept rats injected methyl salicylate lactoside (5) could suppress of precursor drug was put forward by Albert in 1958 [51]. the increase of exudates volume, the amount of leukocytes, The precursor drug itself was inactive or displayed very low protein concentration, PGE2, (MDA), and activity. After being metabolized in the body, it converted to improve the activity of supeoxide dismutase (SOD). According active form. This proceeding was attended to improve its to the analysis of this study, the decrease of PGE2 relied on bioavailability, strengthen targeting, and reduce drug toxicity the inhibitory activities of COX-2 by methyl salicylate and side effects. As stated above, methyl salicylate glycosides glycoside. ROS could assail monounsaturated fatty on can be considered as natural precursor drugs, and they also biomembrane to produce MDA, and the content of MDA have some advantages of this kind of drugs. On the one could reflect the damage degree of the biomembrane. SOD hand, for the lack of the corresponding hydrolytic could eliminate oxygen free radicals, so the content of SOD in stomach, methyl salicylate glycosides don’t convert to could evaluate anti-inflammatory activities [54]. active form salicylic acid until reaching intestine. Just like a To go further, nuclear factor-kappaB (NF-B) is a critical natural enteric-coated drug, which can protect the stomach regulator for the expression of pro-inflammatory cytokines, from irritation, or rather, the active salicylic acid is not inducible nitric oxide synthase (iNOS), COX-1 and COX-2. released to inhibit the protecting stomach enzyme COX-1 in Methyl salicylate lactoside (5) prevented the nuclear gastric epithelium. Thus, the most concerned side effect can translocation and DNA binding activity of NF-B by be reduced. On the other hand, those compounds are also suppressing (LPS) induction of having the advantages of released-slow drugs. From methyl phosphorylated IB kinase (pIKK) and NF-B-p65 activities, salicylate glycosides to methyl salicylate, to salicylic acid, as well as by inhibiting LPS-induced degradation of inhibitor the biological enzyme speed is slow, which can of NF-B (IB). In recent years, that aspirin having not only reduce the high concentrations of salicylic acid that protective effect against Alzheimer’s disease (AD) was may lead to various side effects, but also can prolong the believed. The mechanism might be its anti-aggregation time of effective concentrations. activity for beta amyloid peptide (A) by blocking the NF- The Bioactivities of Methyl Salicylate Glycosides B signaling pathway, and A was related to the pathological process of AD. Thus, it was suspected that Anti-inflammatory methyl salicylate lactoside (5) may be effective in the Since methyl salicylate glycosides have the metabolic treatment of neuroinflammatory disorders and AD [40, 53]. product salicylic acid, which is a classical anti-inflammatory Analgesic agent as a COX-2 inhibitor, methyl salicylate glycosides have the active in anti-inflammatory without question. Bin The main acting site of salicylates is in peripheral region, Zhang et al. isolated a salicylate derivatives fraction (SDF) when tissue injury and inflammation, algogenic substance primarily consisting of Gaultherin (3), MSTG-A (8) and auch as PGs, 5-hydroxytryptamine (5-HT) and Kinins (pro- MSTG-B (9) from G. yunnanensis. They found that strong inflammatory factors) are released, stimulated the pain inhibitory activity of SDF (800 mg/kg body wt.) on croton receptors to pain. What’s more, PGs can increase sensitivity oil-induced ear oedema in mice was comparable to aspirin of pain receptors to algogenic substance. Methyl salicylate (200 mg/kg body wt.) [48]. Meanwhile, more croton oil- glycosides can inhibit the synthesis of PGs, so they have induced ear oedema tests showed that the Gaultherin (3) and effect to enduring dull pain, especially inflammatory pain. Methyl Salicylate Glycosides Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 61

Animal studies showed that, SDF (3, 8, 9) and methyl revealed when methyl salicylate glycosides went through the salicylate lactoside (5) (200, 400, 800 mg/kg body wt.) stomach. It was very likely to owing to both the special considerably reduced the number of writhing and stretching structure (ester linkage and glycosidic linkage) and the induced by the . The effect of them offered by 800 distribution of corresponding enzyme in the body. Those mg/kg body wt. respectively was close to that of aspirin (200 structural features protected gastric mucosa from acid group, mg/kg body wt.) [48, 52]. Taking aspirin with this concentration and gastric ulcer and other sides effect could be under control. as a reference, another study showed, Gaultherin (3) could Furthermore, the active group was not exposed in gastric, achieve the same effect in the number of writhing at doses of and gastrointestinal COX-1 was not inhibited. This metabolism 400 mg/kg body wt. [5]. While, the SDF (400, 800 mg/kg characteristic was taken as a proof that methyl salicylate body wt.) have comparable efficacy to aspirin (200 mg/kg glycosides had relatively large advantage on reducing side body wt.) on the inhibition to licking times in the second effects, especially attenuating gastric mucosal injury. phase (20-30 mins) on Formalin-Induced Pain. In hot plate CONCLUSIONS test, SDF didn’t change latency of reaction to the thermal stimulus, which also excluded central acting analgesic With so much bioactivity, methyl salicylate glycosides properties of SDF [48]. have been observed in various plants commonly available, and there may be much more to be discovered in the broaden Antifungal resource. We can find them according to the treatment Now, there are few reports on the antifungal effect of experience of herb usage in TCM and the genetic relationship methyl salicylate glycosides. While methyl salicylate, has with some plants has already been discovered. As a natural attracted some people's attentions on this activity. Methyl pro-drug of salicylic acid, methyl salicylate glycosides have salicylate is a volatile constituent, known as oil. the same therapeutic effect as aspirin, with fewer side effects. Based on the study, methyl salicylate stored in the flesh tea Those findings can relieve the suffering of the patients and leaves was mainly in the form of glycosides, and those offer treatment for more people. It also can be a huge glycosides were easy to be hydrolyzed by the actions of both advantage to the NSAIDs frequently used and even can be an the endogenous and the exogenous glycosidase [5]. After evidence for methyl salicylate glycosides to replace them. hydrolysis, methyl salicylate released the aglycone methyl Although the theory of COX as pharmacological salicylate having antifungal effect. As this study proved, mechanism of aspirin-like drugs has been commonly accepted, methyl salicylate exhibited remarkable antifungal activities people found that it was not enough to elucidate the anti- against Colletorichum Camelliae Massea [42]. inflammatory and analgesic effects of aspirin completely Antipyretic after several years of detailed studies. Rueff et al. discovered that afferent sensory fiber was not excited with high Fever was believed to be the result, defence mechanism concentrations of PG in models [57], and Ballon et of body against a variety of pyrogens, including bacteria, al. displayed that aspirin still has marked analgesic effect to viruses, fungi, endotoxin, inflammatory factors, etc. Those the mice lack of COX-1 and COX-2 [58]. More recent pyrogens caused a rise in synthesis and release of PG that research showed new mechanism into the anti-inflammatory acted on body’s thermostat in the hypothalamus, making the actions of aspirin induction of NO through the generation of set point over 37 degrees Celsius and leading to febrile epi- can’t apply to other salicylates [59]. All of these responses [55]. Methyl salicylate had the function of reducing researches indicated that, in addition to COX, aspirin-like fever [56]. We believed it was based on inhibition of PG drugs had other targets of drug action. It is an urgent task to (COX) and some other pyrogens (like fungi, inflammatory be studied to find better structural modification of salicylate, factors), resulted in the body’s thermostat dropping back to and maybe it can explain the superiority of methyl salicylate normal level. Thus, it was speculated that antipyretic had glycosides on side effects from another point of view. some connections to the antifungal and anti-inflammatory. Furthermore, we could also deduce that methyl salicylate Almost every time the emergence of a new major glycosides may have antipyretic effect because it could break disease, aspirin can be discovered a new role, like Prostate down into methyl salicylate easily in the body. cancer and Parkinson's disease, osteoporosis and other disease prevention. For methyl salicylate glycosides, having the Effect of Methyl Salicylate Glycosides on Gastric Mucosa same mother nucleus with aspirin, a rudimentary knowledge The lesion in the stomach, such as indigestion, gastric of it with fewer side effects, those new effects have almost ulcers, bleeding and perforation, were always the most troubling not been explored. Maybe there are some valuable effects in concerns to the patients taken salicylates. According to the them. contrast experiments on rats between gaultherin (3) and According to the metabolic and pharmacological aspirin, gaultherin (3) (100 mM; 330 mg/kg) does no damage mechanism of methyl salicylate glycosides, some other to stomach, while lesion was observed in the gastric mucosa, of salicylic acids and their glycosides also can be good aspirin (100 mM; 135 mg/kg) given. And the average lesion 2 for the same structural features, like score was 20.3 ± 4.1 mm . Pretreatment of the animals with glycosides, phenyl salicylate glycosides and those two drugs, the lesion score produced by water immersion so on. They have not yet been found in plants, but they may restraint stress in the presence of gaultherin (3) was significantly have the same pharmacological superiority with methyl less than that observed with aspirin [5]. Carboxylate radical salicylate glycosides. So the study of this kind of compound of salicylates was a major factor in the gastric ulcerogenic is important to the developments in contemporary medicine, activities of these drugs [6]. The carboxylate radical was not 62 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Mao et al. including a serious improvement to the quality of life and [19] Song, J.T.; Koo, Y.J.; Seo, H.S.; Kim, M.C.; Choi, Y.D.; Kim, improving longevity for patients. J.H. Overexpression of AtSGT1, an Arabidopsis salicylic acid glucosyltransferase, leads to increased susceptibility to CONFLICT OF INTEREST Pseudomonas syringae. , 2008, 69(5), 1128-1134. [20] Ono, M.; Oishi, K.; Abe, H.; Masuoka, C.; Okawa, M.; Ikeda, T.; The authors confirm that this article content has no Nohara, T. New from the aerial parts of Verbena conflicts of interest. brasiliensis. Chem. Pharm. Bull., 2006, 54(10), 1421-1424. [21] Li, J. 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Received: September 22, 2013 Revised: November 18, 2013 Accepted: November 18, 2013

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PMID: 24329991