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scyllo-Inositol

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scyllo-Inositol
Names
IUPAC name
scyllo-inositol[1]
Systematic IUPAC name
(1R,2R,3R,4R,5R,6R)-cyclohexane-1,2,3,4,5,6-hexol
Other names
scyllitol; cocositol; quercinitol; 1,3,5/2,4,6-hexahydroxycyclohexane; scyllo-cyclohexanehexol; ELND005; AZD-103
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.113.358 Edit this at Wikidata
EC Number
  • 610-437-4
UNII
  • InChI=1S/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3+,4+,5-,6- ☒N
    Key: CDAISMWEOUEBRE-CDRYSYESSA-N ☒N
  • InChI=1/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3+,4+,5-,6-
    Key: CDAISMWEOUEBRE-CDRYSYESBJ
  • O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Properties
C6H12O6
Molar mass 180.156 g·mol−1
Appearance White crystalline solid
Density 1.57 (A), 1.66 (B) g/ml,[2]
Melting point 358 °C (A),[2] 360 °C (B)[3] decomposes
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

scyllo-Inositol, also called scyllitol, cocositol, or quercinitol, is a chemical compound with formula C6H12O6, one of the nine inositols, the stereoisomers of cyclohexane-1,2,3,4,5,6-hexol. The molecule has a ring of six carbon atoms, each bound to one hydrogen atom and one hydroxyl group (–OH); if the ring is assumed horizontal, the hydroxyls lie alternatively above and below the respective hydrogens.

scyllo-Inositol is a naturally occurring carbohydrate, specifically a sugar alcohol. It occurs in small amounts in the tissues of humans and other animals,[4] certain bacteria,[5] and more abundantly in some plants.[5][6]

Around 2000, scyllo-inositol attracted attention as a possible treatment for neurodegenerative disorders such as Alzheimer's. For this use it received the codes AZD-103 and ELND005.[7]

Chemical and physical properties

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Crystal structure

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Anhydrous scyllo-inositol exists in at least two polymorphs (crystal forms).[8] In both forms the molecules have symmetry and are in the chair conformation,[3] that puts all the hydroxyls in nearly equatorial positions.[9]

The "A" form readily crystallizes from water. It has a lower density 1.57 g/ml and decomposes at 358 °C.[2] It crystallizes in the monoclinic system with group is . The cell parameters are a = 508.9 pm, b = 664.5 pm, c = 1194.8 pm, β = 116.98°, Z = 2. The ring puckering parameter Q is 58.1 pm.[3]

The "B" form is hard to obtain in pure form, as it often crystallizes mixed with the "A" form. Its density is 1.66 g/ml[2] and decomposes at about 360 °C. Its crystal system is triclinic with group . The cell parameters are a = 672.5 pm, b = 679.7 pm, c = 863.5 pm, α = 95.45°, β = 99.49°, γ = 99.19°, Z = 2. The puckering Q is 56.6 pm.[3]

The density of the "A" form is similar to that of myo-inositol but about 0.05 to 0.10 g/mL lower than that of the other inositol stereoisomers, and of the "B" form. The melting (decomposition) point of both forms is the highest among all inositols. Like all of them, the crystals feature infinite chains of hydrogen bonds.[10]

Synthesis

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Scyllitol and other stereo isomers can be synthesized from para-benzoquinone via a conduritol intermediate.[11] It can also be obtained from myo-inositol by the Mitsunobu reaction.[9]

Various animals, plants, insects, and bacteria have been found to convert myo-inositol to scyllo-inositol,[5] including Streptomyces griseus, where that conversion is part of the synthesis of streptomycin.[12]

Scyllitol was known to be a facultative intermediate in the metabolism of myo-inositol by the bacterium Bacillus subtilis.[13] In 2011 a genetically engineered strain of this organism was developed which interrupted that pathway and converted part of the myo-inositol in the medium to scyllo-inositol in 48 hours.[14] Eventually the process was able to produce 27.6 g/L of scyllo-inositol in the medium, from 50 g/L of myo-inositol, in 48 h.[15]

In 2021 another process was developed using the bacterium Corynebacterium glutamicum, producing 1.8 g/L of scyllitol from 20 g/L glucose and 4.4 g/L from 20 g/L sucrose in 72 h. The conversion involves NAD+-dependent oxidation of myo-inositol to 2-keto-myo-inositol (scyllo-inosose), followed by NADPH-dependent reduction to scyllitol.[16]

Derivatives

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Several derivatives of scyllo-inositol have been synthesized and studied in the laboratory, such as phosphates (variants of phytic acid)[9] and orthoformates with an adamantane structure.[17]

Biochemistry

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Natural occurrence

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Scyllitol is widely distributed in nature in fish, insects, mammalian tissues and urine, certain bacteria, and plants[5][14] such as Calycanthus occidentalis.[5] It is particularly abundant in coconut milk.[6]

The scyllitol derivative O-methyl-scyllo-inositol is one of the predominant soluble carbohydrate derivatives in the root nodules of the pea plant created bythe bacterium Rhizobium leguminosarum, together with the isomer ononitol (4-O-methyl-myo-inositol), which are not found elsewhere in the plant.[18]

Scyllitol hexakis dihydrogenphosphate, the scyllo isomer of phytic acid (but not lower phosphates) has been detected in pasture soils from England and Wales at concentrations up to 130 mg of phosphorus per kg of soil, accounting for up to 15% of the soil organic phosphorus. The ratio of the scyllo isomer to the myo isomer ranged between 0.29 and 0.79.[19][20]

The concentration of scyllo-inositol in coconut milk (the fluid inside the fruit of Cocos nucifera) is 0.5 g/L, five times that of myo-inositol.[6]

Physiology

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The concentration of scyllo-inositol in human brain can be measured by NMR; typical values are 0.35 mM for white matter, 0.4 mM for grey matter and 0.5 mM for cerebellum[21] Another study compared the concentrations of myo and scyllo-inositol in brains of 24 healthy volunteers. Averages were about 0.36 mM for scyllo and 4.31 mM for myo, with large deviations. The study found a significant increase of both isomers in the older 14 (46-71 yrs) compared to the younger 10 (26-29 yrs), namely about 40% for scyllo, 20% for myo; and a weak correlation between the two values.[22] However a concentration of scyllo-inositol 300% higher than normal was measured in a healthy volunteer, without a corresponding increase in myo-inositol; suggesting that metabolism of the two isomers are independently regulated.[23]

Researchers at the Harvard Medical School-affiliated McLean Hospital found that chronic users of anabolic steroids had lower levels of brain scyllo-inositol levels than non-users.[24]

Brain concentration of scyllo-inositol was found to be about 75% lower than average in patients with hepatic encephalopathy, which also lowers the levels of myo-inositol.[25]

Scyllitol was found to inhibit in vitro the aggregation of α-synuclein into fibrils, a phenomenon implicated in Parkinson's disease.[26]

Previous intravenous administration of either myo- or scyllo-inositol was found to reduce the duration and intensity of chemically-induced seizures in rats.[27]

Since the 1940s, 5–20% of coconut milk has been used as a growth-promoting agent in formulations of plant cell culture medium. Part of its effectiveness in this application is due to its myo- and scyllo-inositol contents.[6]

Clinical evaluation

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Alzheimer's disease

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In the early 2000s it was reported that scyllo–inositol crossed blood-brain barrier and, when given to mice (TgCRND8) that were genetically engineered to exhibit Alzheimers-like symptoms, it inhibited cognitive deficits and significantly improved the disease pathology.[28] The compound was found to decrease the amount of insoluble amyloid proteins Aβ40, Aβ42 and amyloid plaque accumulation in the brain, without interfering with the synthesis of phosphatidylinositol lipids from myo-inositol.[29][30] More recently, it has also been found to inhibit the binding of Aβ oligomers to plasma membranes and interfering with synaptic function.[31]

Motivated by these and other results, in about 2008 Transition Therapeutics set to investigate scyllo-inositol as a disease-modifying therapy for Alzheimer's disease, under the designation AZD-103. Transition partnered with Elan Corporation for the development of the compound, relabeled ELND005, and a patent for this use (U.S. patent 7,521,481) was issued on April 21, 2009. In 2014, ELND005 reverted to Transition Therapeutics, which was acquired by OPKO Health in 2016.[32]

A clinical investigation of ELND005 with approximately 353 patients, planned to take 18 months, was started in 2008 and received fast track designation from the U.S. Food and Drug Administration.[7] The study initially used daily doses of 500, 2000, and 4000 mg; however, the last two were discontinued by December 2009, due to suspected adverse effects, including 9 deaths.[29] Results of this trial were not positive but considered inconclusive.[33][34] A new 12-week fast-track trial with 296 moderate to advanced Alzheimer's was started in November 2012, to investigate the effect of a single dose of ELND005 on the NPI-C agitation and aggression scores. In June 2015, the results of this trial were reported as negative, and the company abandoned plans to extend the trial further.[35]

Bipolar disorder

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In 2012, Elan started a Phase 2 study of AZD-103 as an add-on therapy in 400 patients with bipolar disorder; this program was discontinued in 2014.[35]

Down's syndrome

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In 2013, a four-week Phase 2 trial began evaluating 250 and 500 mg daily of AZD-103 in 23 young adults with Down's syndrome. This trial was completed in November 2014, without significant positive results, and was considered inconclusive.[36][37]

See also

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References

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  1. ^ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 1415. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
  2. ^ a b c d Sándor L. Bekö, Edith Alig, Martin U. Schmidt, Jacco van de Streek (2014): "On the correlation between hydrogen bonding and melting points in the inositols". International Union of Crystallography Journal (IUCrJ), volume 1, part 1, pages 61-73. doi:10.1107/S2052252513026511
  3. ^ a b c d Younghee Yeon (2001): "The crystal and molecular structures of neo-inositol and two forms of scyllo-inositol". Korean Journal of Crystallography, volume 12, issue 3, pages 150-156.
  4. ^ William R. Sherman, Mark A. Stewart, Mary M. Kurien, Sally L. Goodwin (1968): "The measurement of myo-inositol, myo-inosose-2 and scyllo-inositol in mammalian tissues". Biochimica et Biophysica Acta (BBA), volume 158, issue 2, pages 197-205 doi:10.1016/0304-4165(68)90131-1
  5. ^ a b c d e William H. Horner, I.H. Thaker (1968): "The metabolism of scyllo-inositol in Streptomyces griseus". Biochimica et Biophysica Acta (BBA), volume 165, issue 2, pages 306-308 doi:10.1016/0304-4165(68)90064-0
  6. ^ a b c d Trevor A Thorpe, C Stasolla, Edward Yeung, Geert-Jan De Klerk, A. Roberts, E.F. George (2008): "The components of plant tissue culture media II. Organic additions, osmotic and pH effects, and support systems". In Plant Propagation by Tissue Culture, 3rd edition, pages 115–173. doi:10.1007/978-1-4020-5005-3_4
  7. ^ a b Keran Ma, Lynsie A.M. Thomason, JoAnne McLaurin (2012): "scyllo-Inositol, preclinical, and clinical data for Alzheimer's disease". Chapter of Advances in Pharmacology, volume 64, pages 177–212. doi:10.1016/B978-0-12-394816-8.00006-4 PMID 22840748 ISBN 9780123948168
  8. ^ Graeme M. Day, Jacco van de Streek, Arnaud Bonnet, Jonathan C. Burley, William Jones, and W. D. Sam Motherwell (2006): "Polymorphism of scyllo-inositol:  Joining crystal structure prediction with experiment to elucidate the structures of two polymorphs". Crystal Growth & Design, volume 6, issue 10, pages 2301-2307. doi:10.1021/cg060179a
  9. ^ a b c Sung-Kee Chung, Yong-Uk Kwon, Young-Tae Chang, Kwang-Hoon Sohn, Jung-Han Shin, Kyu-Hwan Park, Bong-Jin Hong, In-Hee Chung (1999): "Synthesis of all possible regioisomers of scyllo-Inositol phosphate". Bioorganic & Medicinal Chemistry, volume 7, issue 11, pages 2577-2589 doi:10.1016/S0968-0896(99)00183-2
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  11. ^ Michael Podeschwa, Oliver Plettenburg, Jochen vom Brocke, Oliver Block, Stephan Adelt, Hans-Josef Altenbach (2003): "Stereoselective synthesis of myo-, neo-, L-chiro, D-chiro, allo-, scyllo-, and epi-inositol systems via conduritols prepared from p-benzoquinone". European Journal of Organic Chemistry, volume 2003, issue 10, pages 1958-1972. doi:10.1002/ejoc.200200572
  12. ^ Joseph Bruton, William H. Horner, Gerald A. Russ (1967): "Biosynthesis of streptomycin: IV. Further studies on the biosynthesis of streptidine and N-methyl-L-glucosamine". Journal of Biological Chemistry, volume 242, issue 5, 10 March, pages 813-818 doi:10.1016/S0021-9258(18)96198-3
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  14. ^ a b Masaru Yamaoka, Shin Osawa, Tetsuro Morinaga, Shinji Takenaka, Ken-ichi Yoshida (2011): "A cell factory of Bacillus subtilis engineered for the simple bioconversion of myo-inositol to scyllo-inositol, a potential therapeutic agent for Alzheimer's disease". Microbial Cell Factories, volume 10, article number 69. doi:10.1186/1475-2859-10-69
  15. ^ Kosei Tanaka, Ayane Natsume, Shu Ishikawa, Shinji Takenaka, Ken-ichi Yoshida (2017): "A new-generation of Bacillus subtilis cell factory for further elevated scyllo-inositol production". Microbial Cell Factories, volume 16, article number 67. doi:10.1186/s12934-017-0682-0,
  16. ^ Paul Ramp, Alexander Lehnert, Susana Matamouros, Astrid Wirtz, Meike Baumgart, Michael Bott (2021): "Metabolic engineering of Corynebacterium glutamicum for production of scyllo-inositol, a drug candidate against Alzheimer's disease". Metabolic Engineering, volume 67, pages 173-185 doi:10.1016/j.ymben.2021.06.011
  17. ^ Hyo Won Lee and Yoshito Kishi (1985): "Synthesis of mono- and unsymmetrical bis-orthoesters of scyllo-inositol". Journal of Organic Chemistry, volume 50, issue 22, pages 4402–4404 doi:10.1021/jo00222a046
  18. ^ Lief Skøt, Helge Egsgaard (1984): "Identification of ononitol and O-methyl-scyllo-inositol in pea root nodules". Planta, volume 161, pages 32–36. doi:10.1007/BF00951457
  19. ^ Benjamin L. Turner, Alan E. Richardson (2004): "Identification of scyllo-inositol phosphates in soil by solution phosphorus-31 nuclear magnetic resonance spectroscopy". Soil Science Society of America Journal, division S-2 Soil Chemistry, volume 68, issue 3 pages 802-808. doi:10.2136/sssaj2004.8020
  20. ^ Benjamin L. Turner, Nathalie Mahieu, Leo M. Condron, C. R. Chen (2005): "Quantification and bioavailability of scyllo-inositol hexakisphosphate in pasture soils". Soil Biology and Biochemistry, volume 37, issue 11, pages 2155-2158 doi:10.1016/j.soilbio.2005.03.005
  21. ^ Thomas Michaelis, Gunther Helms, Klaus-Dietmar Merboldt, Wolfgang Hänicke, Harald Bruhn, Jens Frahm (1993): "Identification of scyllo-inositol in proton NMR spectra of human brain in vivo". NMR in Biomedicine, volume 6, issue 1, pages 105-109. doi:10.1002/nbm.1940060116
  22. ^ Lana G. Kaiser, Norbert Schuff, Nathan Cashdollar, Michael W. Weiner (2005): "Scyllo-inositol in normal aging human brain: 1H magnetic resonance spectroscopy study at 4 Tesla". NMR in Biomedicine, volume 18, issue 1, pages 51-55. doi:10.1002/nbm.927
  23. ^ Elizabeth R. Seaquist, Rolf Gruetter (1998): "Identification of a high concentration of scyllo-inositol in the brain of a healthy human subject using 1H- and 13C-NMR". Magnetic Resonance in Medicine, volume 39, issue 2, pages 313-316. doi:10.1002/mrm.1910390220
  24. ^ Kaufman, Marc J.; Janes, Amy C.; Hudson, James I.; Brennan, Brian P.; Kanayama, Gen; Kerrigan, Andrew R.; Jensen, J. Eric; Pope, Harrison G. (2015-07-01). "Brain and cognition abnormalities in long-term anabolic-androgenic steroid users". Drug and Alcohol Dependence. 152: 47–56. doi:10.1016/j.drugalcdep.2015.04.023. ISSN 1879-0046. PMC 4458166. PMID 25986964.
  25. ^ Yeong-Hau H. Lien, Thomas Michaelis, Rex A. Moats, Brian D. Ross (1994): "Scyllo-inositol depletion in hepatic encephalopathy". Life Sciences, volume 54, issue 20, pages 1507-1512 doi:10.1016/0024-3205(94)90018-3
  26. ^ Tarek Ibrahim, JoAnne McLaurin (2016): "α-Synuclein aggregation, seeding and inhibition by scyllo-inositol". Biochemical and Biophysical Research Communications, volume 469, issue 3, pages 529-534. doi:10.1016/j.bbrc.2015.12.043
  27. ^ M. Nozadze, E. Mikautadze, E. Lepsveridze, E. Mikeladze, N. Kuchiashvili, T. Kiguradze, M. Kikvidze, R. Solomonia (2011): "Anticonvulsant activities of myo-inositol and scyllo-inositol on pentylenetetrazol induced seizures". Seizure, Volume 20, Issue 2, March, Pages 173-176 doi:10.1016/j.seizure.2010.10.008
  28. ^ McLaurin, Joanne; Kierstead, Meredith E.; Brown, Mary E.; Hawkes, Cheryl A.; Lambermon, Mark H L.; Phinney, Amie L.; Darabie, Audrey A.; Cousins, Julian E.; French, Janet E.; Lan, Melissa F.; Chen, Fusheng; Wong, Sydney S N.; Mount, Howard T J.; Fraser, Paul E.; Westaway, David; George-Hyslop, Peter St (July 2006). "Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model". Nature Medicine. 12 (7): 801–8. doi:10.1038/nm1423. PMID 16767098. S2CID 24478093.
  29. ^ a b Daniela Fenili, Mary Brown, Rebecca Rappaport, JoAnne McLaurin (2007): "Properties of scyllo–inositol as a therapeutic treatment of AD-like pathology". Journal of Molecular Medicine, volume 85, pages 603–611. doi:10.1007/s00109-007-0156-7
  30. ^ Daniela Fenili, Keran Ma, JoAnne McLaurin (2010): "scyllo-Inositol: A potential therapeutic for Alzheimer's disease". Chapter 5 of Emerging Drugs and Targets for Alzheimer's Disease, Volume 1: Beta-Amyloid, Tau Protein and Glucose Metabolism, pages 94-116 doi:10.1039/9781849731065-00094
  31. ^ Ming Jin, Dennis J. Selkoe (2015): "Systematic analysis of time-dependent neural effects of soluble amyloid β oligomers in culture and in vivo: Prevention by scyllo-inositol". Neurobiology of Disease, volume 82, pages 152-163 doi:10.1016/j.nbd.2015.05.020
  32. ^ Elan and Transition Therapeutics Receive Key Patent for Alzheimer's Disease Treatment with ELND005 Archived 2013-01-22 at archive.today
  33. ^ S. Salloway, R. Sperling, R. Keren, A.P. Porsteinsson, C.H. van Dyck, P.N. Tariot, S. Gilman, D. Arnold, S. Abushakra, C. Hernandez, G. Crans, E. Liang, G. Quinn, M. Bairu, A. Pastrak, and J.M. Cedarbaum (2011): "A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease" (ELND005-AD201 trial). Neurology, volume 77, issue 13, pages 1253-1262. Quote: "The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL." doi:10.1212/WNL.0b013e3182309fa5
  34. ^ https://clinicaltrials.gov/study/NCT00934050?tab=results>
  35. ^ a b Alzforum (2019): "ELND005". Therapeutics section of Alzforum website. Last updated 2019-06-14 archived; accessed 2024-06-31.
  36. ^ Alzforum (2014): "New Treatments for Alzheimer’s Behavioral Symptoms on Horizon". Clinical Trials 2014 section of the [https://www.alzforum.org Alzforum website dated 2014-12-23, accessed on 2024-06-30.
  37. ^ Michael S. Rafii, Brian G. Skotko, Mary Ellen McDonough, Margaret Pulsifer, Caseye Evans, Eric Doran, Gabriel Muranevici, Patrick Kesslak, Susan Abushakra, Ira T. Lott, for the ELND005-DS Study Group (2017): "A randomized, double-blind, placebo-controlled, Phase II study of oral ELND005 (scyllo-inositol) in young adults with Down syndrome without dementia". Journal of Alzheimer's Disease, volume 58, issue 2, pages 401-411 doi:10.3233/JAD-160965
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