Sarsasapogenin

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Sarsasapogenin
Sarsasapogenin.png
IUPAC name (5β,25S)-spirostan-3β-ol
Identifiers
InChI InChI=1/C27H44O3/c1-16-7-12-27 (29-15-16)17(2)24-23(30-27)14- 22-20-6-5-18-13-19(28)8-10-25( 18,3)21(20)9-11-26(22,24)4/h16 -24,28H,5-15H2,1-4H3/t16-,17-, 18+,19-,20+,21-,22-,23-,24-,25 -,26-,27+/m0/s1
InChIKey GMBQZIIUCVWOCD-WWASVFFGBR
Standard InChI InChI=1S/C27H44O3/c1-16-7-12-2 7(29-15-16)17(2)24-23(30-27)14 -22-20-6-5-18-13-19(28)8-10-25 (18,3)21(20)9-11-26(22,24)4/h1 6-24,28H,5-15H2,1-4H3/t16-,17- ,18+,19-,20+,21-,22-,23-,24-,2 5-,26-,27+/m0/s1
Standard InChIKey GMBQZIIUCVWOCD-WWASVFFGSA-N
CAS number [126-19-2]
EC number 204-776-3
ChemSpider 83145
Properties[1]
Chemical formula C27H44O3
Molar mass 416.64 g/mol
Melting point

199–199.5 °C

Solubility in ethanol soluble
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Sarsasapogenin is a steroidal sapogenin, that is the aglycosidic portion of a plant saponin. It is named after sarsaparilla (Smilax sp.),[2] a family of climbing plants found in subtropical regions. It was one of the first sapogenins to be identified,[2] and the first spirostan steroid to be identified as such.[3] The identification of the spirostan structure, with its ketone spiro acetal functionality, was fundamental in the development of the Marker degradation, which allowed the industrial production of progesterone and other sex hormones from plant steroids.

Sarsasapogenin is unusual in that it has a cis-linkage between rings A and B of the steroid nucleus, as opposed to the more usual trans-linkage found in other saturated steroids. This 5β configuration is biologically significant, as a specific enzyme – sarsasapogenin 3β-glucosyltransferase – is found in several plants for the glycosylation of sarsasapogenin.[4] The (S)-configuration at C-25 is also in contrast to other spirostan sapogenins: the epimer with a (25R)-configuration is known as smilagenin.

Sarsasapogenin has been used as a starting material for the synthesis of other steroids.[5] It has also attracted pharmaceutical interest in its own right,[6][7][8] and is found in the rhizome of Anemarrhena asphodeloides, used in Chinese tradition medicine (知母, zhī mǔ), from which it is extracted commercially.[9]

Occurrence and isolation

Sarsasapogenin is found as a glycoside – with one or more sugar units attached to the hydroxyl group, known as a saponin – in the roots of many species of monocotyledonous plant, in particular:[7]

Smilacaceae

Asparagaceae

Agavaceae

The sarsasapogenin saponin can be extracted from the dried powdered root with 95% ethanol. After removal of the fat from the resulting gum, the glycosidic linkage is hydrolyzed with hydrochloric acid (approx. 2 M) and the resulting crude steroid is recrystallized from anhydrous acetone. The yield of pure sarsasapogenin from 225 kg of Smilax root is reported to be about 450 grams.[1]

History

Sarsasapogenin was first isolated in 1914 from Sarsapilla root.[2] Although it was known to have three oxygen atoms, of which only one is a hydroxyl group, the structure of the side chain remained unclear for many years. Tschesche and Hagedorn proposed an unreactive double tetrahydrofuran structure based on degradation studies which indicated an ether oxygen atom attached to C-16.[10] The true nature of the side chain – a ketone spiro acetal – was discovered by Russell Marker in 1939, when he succeeded in opening the six-membered pyran ring with acetic anhydride.[3] Marker found that almost the entire side chain could be cleaved in three steps, a process now known as the Marker degradation.

Marker was able to convert sarsasapogenin into pregane-3,20-diol[11] (a progesterone analogue) and testosterone.[12] However, for large scale production of steroid hormones, it proved more convenient to use diosgenin (extracted from the Mexican yam Dioscorea mexicana) as the starting material, as it contains a double bond in the steroid nucleus.[13]

Pharmacological interest

Sarsasapogenin and its C-25 epimer smilagenin lowered blood sugar and reversed diabetic weight gain in experiments with in mice with a mutant diabetes gene (db).[6] Both steroids also halted the decline in muscarinic acetylcholine receptors (mAChRs) in animal models of Alzheimer's disease.[7][8] In both cases, the effects seem to be specific to the 5β-configuration, the cis-linkage between rings A and B, as diosgenin (with a Δ5 double bond which can be hydrogenated in the body) had much lower anti-diabetic activity[6] (and no significant effect on mAChRs[7]) while tigogenin (the 5α-epimer of smilagenin) showed no effect at all in either study.[6][7]

References

  1. ↑ 1.0 1.1 Jacobs, Walter A.; Simpson, James C. E. On Sarsasapogenin and Gitogenin. J. Biol. Chem. 1934, 105 (3), 501–10, <http://www.jbc.org/content/105/3/501.full.pdf>.
  2. ↑ 2.0 2.1 2.2 Power, Frederick Belding; Salway, Arthur Henry Chemical examination of sarsaparilla root. J. Chem. Soc., Trans. 1914, 105, 201–19. DOI: 10.1039/CT9140500201.
  3. ↑ 3.0 3.1 Marker, Russell E.; Rohrmann, Ewald Sterols. LIII. The Structure of the Side Chain of Sarsasapogenin. J. Am. Chem. Soc. 1939, 61 (4), 846–51. DOI: 10.1021/ja01873a020.
  4. ↑ Paczkowski, Cezary; Wojciechowski, Zdzisław A. The occurrence of UDPG-dependent glucosyltransferase specific for sarsasapogenin in Asparagus officinalis. Phytochemistry 1988, 27 (9), 2743–47. DOI: 10.1016/0031-9422(88)80654-X.
  5. ↑ Dryden, Jr., Hugh L.; Markos, Charles S. (Searle & Co.) Process for the preparation of 17β-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone. US Patent 4057543, published 8 November 1977.
  6. ↑ 6.0 6.1 6.2 6.3 Applezweig, Norman (Progenics Inc.) Treatment of obesity and diabetes using sapogenins. US Patent 4680289, published 14 July 1987.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Xia, Zongqin; Hu, Yaer; Rubin, Ian, et al. (Phytopharm plc) Steroidal sapogenins and their derivatives for treating alzheimer's disease. US Patent 6812213, published 19 December 2002.
  8. ↑ 8.0 8.1 Hu, Yaer; Xia, Zongqin; Sun, Qixiang; Orsi, Antonia; Rees, Daryl A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Research 2005, 1060 (1–2), 26–39. DOI: 10.1016/j.brainres.2005.08.019.
  9. ↑ Sarsasapogenin; Wilshire Technologies, <http://www.wilshiretechnologies.com/steroidal_saponins_and_sapogenins_pdf/sarsasapogenin.pdf>. (accessed 7 March 2010).
  10. ↑ Tschesche, R.; Hagedorn, A. Über neutrale Saponine, II. Mitteil.: Abbau eines Genins der neutralen Sapogenine zu einem Gallensäure-Derivat. Ber. Dtsch. Chem. Ges. 1935, 68, 1412–20. DOI: 10.1002/cber.19350680736.
  11. ↑ Marker, Russell E.; Rohrmann, Ewald Sterols. LXXXI. Conversion of Sarsasapogenin to Pregnanediol-3(α),20(α). J. Am. Chem. Soc. 1939, 61. DOI: 10.1021/ja01267a513. Marker, Russell E.; Rohrmann, Ewald Sterols. LXXXVIII. Pregnanediols from Sarsasapogenin. J. Am. Chem. Soc. 1940, 62 (3), 518–20. DOI: 10.1021/ja01860a017.
  12. ↑ Marker, Russell E. Sterols. CV. The Preparation of Testosterone and Related Compounds from Sarsasapogenin and Diosgenin. J. Am. Chem. Soc. 1940, 62 (9), 2543–47. DOI: 10.1021/ja01866a077.
  13. ↑ Marker, Russell E.; Tsukamoto, Takeo; Turner, D. L. Sterols. C. Diosgenin. J. Am. Chem. Soc. 1940, 62 (9), 2525–32. DOI: 10.1021/ja01866a072.
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