Send Orders for Reprints to [email protected] 56 Mini-Reviews in Medicinal Chemistry, 2014, 14, 56-63 Naturally Occurring Methyl Salicylate Glycosides 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 steroids anti-inflammation drug (NSAIDs), salicylate has developed from natural substance salicylic acid to natrium salicylicum, to aspirin. Now, methyl salicylate glycoside, a new derivative of salicylic acid, is modified with a -COOH group integrated one methyl radical into formic ether, and a -OH linked with a monosaccharide, a disaccharide or a trisaccharide unit by glycosidic linkage. It has the similar pharmacological activities, anti-inflammatory, analgesic, 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 “willow bark biological metabolism superiority, those derivative forms can relieve pain” to this day, salicylates especially aspirin, including chemical functional groups, the ester bond and the had played a critical role in treating cold, fever, headache, glycosidic bond 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 plants. 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 Gaultheria, Camellia, Polygala, long time to use aspirin have been discovered, gastrointestinal Filipendula and Passiflora. 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 arthritis, swelling pain, trauma, chronic cyclooxygenase (COX) resulted in loss of the cytoprotective tracheitis, cold and vertigo [7]. Tea leaves of Camellia are effects of prostaglandins (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 sugar special metabolism in vivo and the corresponding biological molecules 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 enzyme 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 phytochemical constituents and physic, it has been expounded that salicylic acid was abundantly distributed in THE STRUCTURAL FEATURES OF METHYL plant species. However, salicylic acid has not been widely SALICYLATE GLYCOSIDES used because of its bitter taste 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 carboxylic acid 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, rhamnose, apiose and glucose. 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-platelet 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, liver and kidney injury, together with ototoxicity. On the basis of current study, methyl salicylate 2-O--D- The most common symptoms are gastrointestinal irritation glucoside (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 arachidonic acid [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.