Review Paper Chemistry and in Vivo Profile of Ent-Kaurene Glycosides Of
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Natural Product Radiance, Vol. 8(2), 2009, pp.181-189 Review Paper Chemistry and in vivo profile of ent-kaurene glycosides of Stevia rebaudiana Bertoni—An overview Manishika Sharma1, Naveen Kr Thakral2 and Seema Thakral3* 1G.V.M. College of Pharmacy, Sonipat-131 001, Haryana, India 2Laborate Pharmaceutical India Ltd., Poanta Sahib-173 025, Himachal Pradesh, India 3PDM College of Pharmacy, Bahadurgarh-124 507, Haryana *Correspondent author, E-mail: [email protected] Received 17 January 2008; Accepted 16 December 2008 structures are constituted by a Abstract The ent-kaurene type of diterpenoid glycosides are typically the characteristics of leaves perhydrophenanthrene unit (A, B and C of Stevia rebaudiana Bertoni, the plant with sweet leaves. Relative to sucrose, the potent rings) fused with a cyclopentane unit (D sweetness intensities of these glycosides have projected them as cost effective sucrose substitute. In ring) formed by a bridge of two carbons the present paper, the structural and physicochemical features of ent-kaurene glycosides of Stevia between C-8 and C-13 (Fig. 1 a). Various along with an insight into the structure-sweetness relationship are presented. Despite their age-old criteria are employed for the widespread use in several parts of the world, there still remains certain concern regarding safety profile of these glycosides. Henceforth, the pharmacokinetic, pharmacological and toxicological nomenclature of the kaurene diterpenes, evaluation of ent-kaurene glycosides is reviewed. the most prevalent being the inversion of Keywords: ent-kaurene glycosides, Stevia, Stevia rebaudiana, Structure-sweetness relationship, the conventional description of Sweeteners. stereochemistry when the name is IPC code; Int. cl.8 — A23L 1/09, A61K 36/28, A61K 127/00 preceded by the prefix “ent-”. The nomenclature, numbering and stereochemistry of the ent-kaurene Introduction concentrated liquid, crushed leaf or skeleton (Fig. 1a) have already been ent concentrated white powder. The greenish- The -kaurene type of established by IUPAC recommendations 4. black concentrated liquid is 70 times diterpenoid glycosides are typically the All ent-kaurenoic glycosides are Stevia while the crushed leaf form is about 30 characteristics of leaves of derived from a common moiety, rebaudiana times as sweet as sugar. With reference to Bertoni (Family— kaurenoic acid (Fig. 1b). Kaurenoic acid its sweetening power, it is estimated that Asteraceae), the plant with sweet leaves. is one of the intermediate compounds 30 ml (1 oz) of Stevia extract is equivalent Owing to presence of these sweet-tasting involved in the biosynthesis of diverse to 3 Kg (6.6 lbs) of sucrose3. glycosides, the plant is also known as sweet kaurene diterpenes, including Caa-he-é The structural and herb, honey leaf, or sweet gibberellins, which represent the chrysanthemum. It is also regarded as the physicochemical features of ent-kaurene glycosides of Stevia along with an insight important group of growth “sweet herb of Paraguay”, as its leaves have phytohormones. However, in plant, this been traditionally used for hundreds of into the structure-sweetness relationship and pharmacokinetic, pharmacological kaurenoic acid moiety diverts toward the years by natives of Paraguay and Brazil to ent- and toxicological evaluation of ent- formation of kaurene glycosides sweeten local teas, medicines and as a through steviol, which is the aglycone for ‘sweet treat’. In addition, the leaves are kaurene glycosides are reviewed in the present paper. all the Stevia glycosides. also used for their medicinal benefits in The ent-kaurene type of high blood pressure, obesity, topical glycosides present in Stevia are referred dressing for wounds and other skin Chemistry of ent-kaurene to as steviol glycosides, though steviol is 1-2. disorders Glycosides not the glycoside but the aglycone moiety As an alternative to the Kaurenes represent an important of all these glycosides. Chemically steviol conventional sugar, it is available as a group of tetracyclic diterpenes. Their is ent-13-hydroxy kaur-16-en-19-oic acid Vol 8(2) March-April 2009 181 Review Paper 12 12 11 13 CH 20 2 13 17 20 11 CH C 16 2 14 C 16 D 14 1 1 D 2 10 8 15 2 10 8 15 A H A B H 3 5 B 7 3 5 7 4 6 4 6 H H 18 18 19 (a)COOH (b) Fig. 1 (a-b): Structure of ent-kaurene (a) and ent-kaurenoic acid (b) glucose in total, with the middle glucose rebaudioside A present in Stevia is the of the triplet connected to the central main determinant of taste quality. When steviol structure. The aqueous extract from steviol glycosides are more than 50% of Stevia rebaudiana leaves leaves is known to contain about ~ the total glycosides, the taste is common/ 10-70% of stevioside and ~ 20-70% of traditional, with a metallic or liquorice (Table 1), a diterpenoidic carboxylic rebaudioside A, with a total glycoside after-taste, whereas when rebaudioside A alcohol5. contents of more than 90%. The remaining makes up more than 50% of the glycosidal A total of eight ent-kaurene glycosides are present in lesser amounts11, 12. contents, the taste is improved with a diterpene glycosides have been isolated In addition to these glycosides, it also reduced after-taste15. from S. rebaudiana namely: stevioside, contains a diverse mixture of labdane steviolbioside, dulcoside A and diterpenes, triterpenes, stigmasterol, Aqueous solubility: All the ent-kaurene rebaudiosides A, B, C, D and E6. tannins as well as volatile oils13. glycosides possess good aqueous solubility S. rebaudiana is an anomaly in the and can be easily extracted with aqueous genus Stevia, as it has been reported that General features solvents16. none of the other 230 species belonging All the ent-kaurene glycosides of to this genus has ever been found to Stevia have been demonstrated to possess Thermostability: Contrary to sugar produce these compounds at high certain common features; some of the which starts to caramalize at about 150- concentration levels7. The yield of important ones are as follows: 160°C, ent-kaurene glycosides can withstand temperatures up to 200°C. The stevioside is the highest (2-10%), Sweetness: These glycosides are about 200 sweetness property of aqueous solution of rebaudioside follows next (about 1%) and times sweeter than sucrose. In addition stevioside does not change when heated the other constituents are the minor quality is superior to sugar in mildness 8-10 to 95°C for two hours17. components . The basic chemical and refreshment2. These tend to produce structures along with important a sweet taste less instantly than sucrose Stability towards extreme pH: These physicochemical properties of these but the taste lasts for a longer period. glycosides are exemplified in Table 1. glycosides are exceptionally stable towards As evident from Table 1, ent- Relative sweetness: Rebaudioside A is pH ranging between 2 to 10. A 0.02% kaurene glycosides are formed by sweeter than other steviol glycosides (300 stevioside solution at pH 3 maintained at times compared with sucrose) and also 95°C for 1 h shows no significant replacing the substituents R1 with glucose has a more palatable taste profile, having degradation while a 12% solution of and R2 with combinations of glucose and rhamnose. Glycoside stevioside differs less of the metallic/liquorice taste often stevioside at pH 2 under these conditions from rebaudioside in the feature that the associated with steviol glycosides14. decomposes17. former is composed of glucose, sophorose Index of taste: Ratio of Stevioside and and steviol while, the latter has four No calorie sweeteners: These 182 Natural Product Radiance Review Paper glycosides have zero glycemic index, zero Flavour enhancement: In conjugation of providing oral health benefits by glycemic load and no calories effects8. with other flavours, ent-kaurene interference with cell surface functions of glycosides act as a flavour enhancer cariogenic bacteria. Taste enhancement: These glycosides producing a stronger flavour, allowing a As these glycosides are heat and produce synergistic effect on taste when smaller quantity of the flavour to be pH stable, non-fermentable and do not used in conjunction with other incorporated. darken upon cooking, these have been sweeteners, e.g. glycerrhizin, aspartame, exploited in a wide range of applications acesulfame and cyclamate (but not with Oral hygiene: Steviol, isosteviol and in food products since ages. saccharin)18. It was found that sweetness rebaudioside B, C and E have been found property of stevioside gets improved along to inhibit the glucan–induced aggregation Synthesis of ent-kaurene glycosides with reduction in aftertaste on of cariogenic organism, Streptococcus The in vivo biosynthetic combination with sucrose and fructose14. mutans19. Thus, they have the potential pathway for ent-kaurene glycosides has Table 1: Structure and properties of eight ent-kaurene glycosides of Stevia OR2 12 13 20 11 CH2 C 16 14 D 1 2 10 8 15 A H B 3 5 7 4 6 H 18 COOR1 Steviol: the aglycone of ent-kaurene glycosides (R1 and R2=H) Compound R R Mol.Wt. M.P. (°C) Solubility (%) Sweetness RS QT 1 2 Stevioside β-Glc β-Glc-β-Glc(2→1) 804 196-198 0.13 100-270 143 0 Steviolbioside H β-Glc-β-Glc(2→1) 642 188-192 0.03 10-15 NA NA Rebaudioside A β-Glc β-Glc-β-Glc(2→1) 966 242-244 0.80 150-320 242 +2 β-Glc(3→1) Rebaudioside B H β-Glc-β-Glc(2→1) 804 193-195 0.10 10-15 NA NA β-Glc(3→1) Rebaudioside C β-Glc β-Glc-α-Rha(2→1) 958 215-217 0.21 40-60 NA -1 (Dulcoside B) β-Glc(3→1) Rebaudioside D β-Glc- β-Glc-β-Glc(2→1) 1128 283-286 1.00 200-250 221 +3