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	{{DISPLAYTITLE:''scyllo''-Inositol}}		{{DISPLAYTITLE:''scyllo''-Inositol}}
	{{Chembox		{{Chembox
			\| Verifiedfields = changed
	\| verifiedrevid = 428259682
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	\| ImageFile = Scyllo-inositol.svg		\| ImageFile = Scyllo-inositol.svg
	\| ImageSize = ~~200px~~		\| ImageSize =
	\| Name = ''scyllo''-Inositol		\| Name = ''scyllo''-Inositol
			\| IUPACName = ''scyllo''-inositol<ref name=iupac2013/>
	\| IUPACName = (1''R'',2''R'',3''R'',4''R'',5''R'',6''R'')-Cyclohexane-1,2,3,4,5,6-hexaol
			\| SystematicName = (1''R'',2''R'',3''R'',4''R'',5''R'',6''R'')-cyclohexane-1,2,3,4,5,6-hexol
	\| OtherNames = Scyllitol; Cocositol; Quercinitol; AZD 103; 1,3,5/2,4,6-Hexahydroxycyclohexane; ''scyllo''-Cyclohexanehexol
			\| OtherNames = scyllitol; cocositol; quercinitol; 1,3,5/2,4,6-hexahydroxycyclohexane; ''scyllo''-cyclohexanehexol; ELND005; AZD-103
	\| Section1 = {{Chembox Identifiers
			\|Section1={{Chembox Identifiers
			\| IUPHAR_ligand = 4649
			\| CASNo_Ref = {{cascite\|correct\|??}}
	\| CASNo = 488-59-5		\| CASNo = 488-59-5
			\| EINECS = 610-437-4
			\| UNII_Ref = {{fdacite\|correct\|FDA}}
			\| UNII = 1VS4X81277
	\| PubChem =		\| PubChem =
	\| SMILES = O1(O)(O)(O)(O)1O		\| SMILES = O1(O)(O)(O)(O)1O
			\| ChemSpiderID_Ref = {{chemspidercite\|changed\|chemspider}}
			\| ChemSpiderID = 10254646
			\| InChI = 1/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3+,4+,5-,6-
			\| InChIKey = CDAISMWEOUEBRE-CDRYSYESBJ
			\| StdInChI_Ref = {{stdinchicite\|changed\|chemspider}}
			\| StdInChI = 1S/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3+,4+,5-,6-
			\| StdInChIKey_Ref = {{stdinchicite\|changed\|chemspider}}
			\| StdInChIKey = CDAISMWEOUEBRE-CDRYSYESSA-N
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	\| Section2 = {{Chembox Properties		\|Section2={{Chembox Properties
	\| C=6\|H=12\|O=6		\| C=6 \| H=12 \| O=6
	\| Appearance = White crystalline solid		\| Appearance = White crystalline solid
	\| Density =		\| Density = 1.57 (A), 1.66 (B) g/ml,<ref name=beko2014/>
	\| MeltingPt = ~~348.5-350~~ °C		\| MeltingPt = 358 °C (A),<ref name=beko2014/> 360 °C (B)<ref name=yeon2001/>
			\| MeltingPt_notes = decomposes
	\| BoilingPt =		\| BoilingPt =
	\| Solubility = }}		\| Solubility = }}
	\| Section3 = {{Chembox Hazards		\|Section3={{Chembox Hazards
	\| MainHazards =		\| MainHazards =
	\| FlashPt =		\| FlashPt =
	\| ~~Autoignition~~ = }}		\| AutoignitionPt =
			}}
	}}		}}

			'''''scyllo''-Inositol''', also called '''scyllitol''', '''cocositol''', or '''quercinitol''', is a ] with ] {{chem2\|C6H12O6}}, one of the nine ]s, the ]s of ]. The molecule has a ring of six ] atoms, each bound to one ] atom and one ] group (–OH); if the ring is assumed horizontal, the hydroxyls lie alternately above and below the respective hydrogens.
	'''''scyllo''-Inositol''' is one of the ]s of ]. It is also known as scyllitol, cocositol, quercinitol, and 1,3,5/2,4,6-hexahydroxycyclohexane. ''scyllo''-Inositol is a naturally occurring plant sugar ] found most abundantly in the ].<ref>, Dr. Duke's Phytochemical and Ethnobotanical Databases</ref>

			''scyllo''-Inositol is a naturally occurring ], specifically a ]. It occurs in small amounts in the tissues of humans and other animals,<ref name=sher1968/> certain ],<ref name=horn1968/> and more abundantly in some plants.<ref name=horn1968/><ref name=thor2008/>
	== Biological effects ==

	Researchers at the ] have found that ''scyllo''-inositol can block the development of ] (Aβ) plaques in the brains of transgenic mice.<ref></ref> ''scyllo''-Inositol also reversed memory deficits, reduced the formation of Aβ ], and alleviated other symptoms that are associated with the accumulation of Aβ proteins in these mice.<ref>{{cite journal \| pmid = 16767098 \| doi=10.1038/nm1423 \| volume=12 \| issue=7 \| title=Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model \| year=2006 \| month=July \| pages=801–8}}</ref>
			Around 2000, ''scyllo''-inositol attracted attention as a possible treatment for ]s such as ]. For this use it received the codes '''AZD-103''' and '''ELND005'''.<ref name=make2012/>

			== Chemical and physical properties ==

			=== Crystal structure ===

			Anhydrous ''scyllo''-inositol exists in at least two ]s (crystal forms).<ref name=dayg2006/> In both forms the molecules have symmetry <math>\bar 1</math> and are in the ],<ref name=yeon2001/> that puts all the hydroxyls in nearly equatorial positions.<ref name=kees1999/>

			The "A" form readily crystallizes from water. It has a lower density 1.57 ]/] and decomposes at 358 ].<ref name=beko2014/> It crystallizes in the ] system with ] is <math>P2_1/c</math>. The cell parameters are ''a'' = 508.9 ], ''b'' = 664.5 pm, ''c'' = 1194.8 pm, β = 116.98], ''Z'' = 2. The ring puckering parameter ''Q'' is 58.1 pm.<ref name=yeon2001/>

			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<ref name=beko2014/> and decomposes at about 360 °C. Its crystal system is ] with group <math>P\bar 1</math>. 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.<ref name=yeon2001/>

			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 ]s.<ref name=simp2006/>

			=== Synthesis ===

			Scyllitol and other stereo isomers can be synthesized from ''para''-benzoquinone via a ] intermediate.<ref name=pode2003/> It can also be obtained from ''myo''-inositol by the ].<ref name=kees1999/>

			Various animals, plants, insects, and bacteria have been found to convert ''myo''-inositol to ''scyllo''-inositol,<ref name=horn1968/> including '']'', where that conversion is part of the synthesis of ].<ref name=brut1967/>

			Scyllitol was known to be a facultative intermediate in the metabolism of ''myo''-inositol by the bacterium '']''.<ref name=mori2010/> In 2011 a ] strain of this organism was developed which interrupted that pathway and converted part of the ''myo''-inositol in the ] to ''scyllo''-inositol in 48 hours.<ref name=yama2011/> Eventually the process was able to produce 27.6 ]/] of ''scyllo''-inositol in the medium, from 50 g/L of ''myo''-inositol, in 48 h.<ref name=tana2017/>

			In 2021 another process was developed using the bacterium '']'', producing 1.8 g/L of scyllitol from 20 g/L ] and 4.4 g/L from 20 g/L ] in 72 h. The conversion involves ]-dependent oxidation of ''myo''-inositol to ] (]), followed by ]-dependent reduction to scyllitol.<ref name=ramp2021/>

			===Derivatives===

			Several derivatives of ''scyllo''-inositol have been synthesized and studied in the laboratory, such as ]s (variants of ])<ref name=kees1999/> and ]s with an ] structure.<ref name=leeh1985/>

			== Biochemistry ==

			===Natural occurrence===

			Scyllitol is widely distributed in nature in fish, insects, mammalian tissues and urine, certain bacteria, and plants<ref name=horn1968/><ref name=yama2011/> such as '']''.<ref name=horn1968/> It is particularly abundant in ].<ref name=thor2008/>

			The scyllitol derivative ] is one of the predominant soluble carbohydrate derivatives in the ]s of the ] plant created bythe bacterium '']'', together with the isomer ] (4-O-methyl-''myo''-inositol), which are not found elsewhere in the plant.<ref name=skot1984/>

			Scyllitol hexakis ], the ''scyllo'' isomer of ] (but not lower phosphates) has been detected in pasture soils from England and Wales at concentrations up to 130 mg of ] 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.<ref name=turn2004/><ref name=turn2005/>

			The concentration of ''scyllo''-inositol in coconut milk (the fluid inside the fruit of '']'') is 0.5 g/L, five times that of ''myo''-inositol.<ref name=thor2008/>

			===Physiology===

			The concentration of ''scyllo''-inositol in human brain can be measured by ]; typical values are 0.35 ] for ], 0.4 mM for ] and 0.5 mM for ]<ref name=mich1993/> 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.<ref name=kais2005/> 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.<ref name=seaq1998/>

			Researchers at the ]-affiliated ] found that chronic users of ]s had lower levels of brain ''scyllo''-inositol levels than non-users.<ref name=kauf2015/>

			Brain concentration of ''scyllo''-inositol was found to be about 75% lower than average in patients with ], which also lowers the levels of ''myo''-inositol.<ref name=lien1994/>

			Scyllitol was found to inhibit ] the aggregation of ] into ]s, a phenomenon implicated in ].<ref name=ibra2016/>

			Previous intravenous administration of either ''myo''- or ''scyllo''-inositol was found to reduce the duration and intensity of chemically-induced ]s in rats.<ref name=noza2011/>

			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.<ref name=thor2008/>

	== Clinical evaluation ==		== Clinical evaluation ==
	''scyllo''-Inositol is under investigation by ] as a disease-modifying therapy for ] under the designation AZD-103. A patent was issued on April 21, 2009 (US patent number 7,521,481) claiming the use of ''scyllo''-inositol for treating Alzheimer's disease.<ref></ref> ''scyllo''-Inositol is undergoing clinical investigation as an orally-administered therapeutic agent for the treatment of mild to moderate Alzheimer's disease. It has received ] from the ]. Transition has partnered with ] on the development of the compound under the designation ELND005. ELND005 is currently in a Phase 2 clinical study, which completed enrollment in October 2008. The study is a randomized, double-blind, placebo-controlled, dose-ranging, safety and efficacy study in approximately 353 patients with mild to moderate Alzheimer's disease. The planned treatment period for each patient is approximately 18 months.

			===Alzheimer's disease===
	In December 2009, Elan and Transition jointly reported that the study has been modified so that only the 250 mg twice daily dose will be continued because of greater rates of adverse events, including 9 deaths, in the higher dose groups (1000 mg and 2000 mg dosed twice daily).<ref></ref>
			In the early 2000s it was reported that ''scyllo''–inositol crossed ] and, when given to ] (TgCRND8) that were genetically engineered to exhibit Alzheimers-like symptoms, it inhibited cognitive deficits and significantly improved the disease pathology.<ref name=mcla2006/> The compound was found to decrease the amount of insoluble ]s Aβ40, Aβ42 and ] accumulation in the brain, without interfering with the synthesis of ] lipids from ''myo''-inositol.<ref name=feni2007/><ref name=feni2010/> More recently, it has also been found to inhibit the binding of Aβ ]s to ]s and interfering with ] function.<ref name=jinm2015/>

			Motivated by these and other results, in about 2008 ] set to investigate ''scyllo''-inositol as a disease-modifying therapy for ], under the designation AZD-103. Transition partnered with ] for the development of the compound, relabeled ELND005, and a patent for this use ({{US patent\|7521481}}) was issued on April 21, 2009. In 2014, ELND005 reverted to Transition Therapeutics, which was acquired by ] in 2016.<ref name=elan2009/>
	== External Links ==


			A clinical investigation of ELND005 with approximately 353 patients, planned to take 18 months, was started in 2008 and received ] from the ].<ref name=make2012/> 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.<ref name=feni2007/> Results of this trial were not positive but considered inconclusive.<ref name=sall2011/><ref name=opko2019/> 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 ] 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.<ref name=alzf2019/>

			===Bipolar disorder===
			In 2012, Elan started a Phase 2 study of AZD-103 as an add-on therapy in 400 patients with ]; this program was discontinued in 2014.<ref name=alzf2019/>

			===Down's syndrome===
			In 2013, a four-week Phase 2 trial began evaluating 250 and 500 mg daily of AZD-103 in 23 young adults with ]. This trial was completed in November 2014, without significant positive results, and was considered inconclusive.<ref name=alzf2014/><ref name=rafi2017/>

			==See also==
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	==References==		==References==
			<references>
	{{reflist}}

			<ref name=iupac2013>{{cite book \|author=] \|date=2014 \|title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 \|publisher=] \|pages=1415 \|doi=10.1039/9781849733069 \|isbn=978-0-85404-182-4}}</ref>

			<ref name=pode2003>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}}</ref>

			<ref name=make2012>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}}</ref>

			<ref name=feni2007>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}}</ref>

			<ref name=feni2010>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}}</ref>

			<ref name=mcla2006>{{cite journal \| pmid = 16767098 \| doi=10.1038/nm1423 \| volume=12 \| issue=7 \| title=Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model \|date=July 2006 \| pages=801–8\| last1=McLaurin \| first1=Joanne \| last2=Kierstead \| first2=Meredith E. \| last3=Brown \| first3=Mary E. \| last4=Hawkes \| first4=Cheryl A. \| last5=Lambermon \| first5=Mark H L. \| last6=Phinney \| first6=Amie L. \| last7=Darabie \| first7=Audrey A. \| last8=Cousins \| first8=Julian E. \| last9=French \| first9=Janet E. \| last10=Lan \| first10=Melissa F. \| last11=Chen \| first11=Fusheng \| last12=Wong \| first12=Sydney S N. \| last13=Mount \| first13=Howard T J. \| last14=Fraser \| first14=Paul E. \| last15=Westaway \| first15=David \| last16=George-Hyslop \| first16=Peter St \| journal=Nature Medicine \| s2cid=24478093 }}</ref>

			<ref name=elan2009> {{webarchive\|url=https://archive.today/20130122001730/http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-newsArticle&ID=1279660&highlight=ELND005 \|date=2013-01-22 }}</ref>

			<ref name=opko2019>https://clinicaltrials.gov/study/NCT00934050?tab=results></ref>

			<ref name=alzf2019>Alzforum (2019): "". ''Therapeutics'' section of . Last updated 2019-06-14 ; accessed 2024-06-31.</ref>

			<ref name=alzf2014>Alzforum (2014): "". dated 2014-12-23, accessed on 2024-06-30.</ref>

			<ref name=thor2008>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}}</ref>

			<ref name=kauf2015>{{Cite journal \|last1=Kaufman \|first1=Marc J. \|last2=Janes \|first2=Amy C. \|last3=Hudson \|first3=James I. \|last4=Brennan \|first4=Brian P. \|last5=Kanayama \|first5=Gen \|last6=Kerrigan \|first6=Andrew R. \|last7=Jensen \|first7=J. Eric \|last8=Pope \|first8=Harrison G. \|date=2015-07-01 \|title=Brain and cognition abnormalities in long-term anabolic-androgenic steroid users \|journal=Drug and Alcohol Dependence \|volume=152 \|pages=47–56 \|doi=10.1016/j.drugalcdep.2015.04.023 \|issn=1879-0046 \|pmc=4458166 \|pmid=25986964}}</ref>

			<ref name=yeon2001>Younghee Yeon (2001): "". ''Korean Journal of Crystallography'', volume 12, issue 3, pages 150-156.</ref>

			<ref name=beko2014>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}}</ref>

			<ref name=dayg2006>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}}</ref>

			<ref name=sall2011>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}}</ref>

			<ref name=yama2011>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}}</ref>

			<ref name=sher1968>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}}</ref>

			<ref name=kees1999>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}}</ref>

			<ref name=horn1968>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}}</ref>

			<ref name=brut1967>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}}</ref>

			<ref name=mich1993>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}}</ref>

			<ref name=leeh1985>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}}</ref>

			<ref name=lien1994>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}}</ref>

			<ref name=mori2010>Tetsuro Morinaga, Hitoshi Ashida and Ken-ichi Yoshida (2010): "Identification of two ''scyllo''-inositol dehydrogenases in ''Bacillus subtilis''". ''Microbiology'', volume 156, issue 5, pages 1538–1546 {{doi\|10.1099/mic.0.037499-0}}</ref>

			<ref name=turn2004>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}}</ref>

			<ref name=ibra2016>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}}</ref>

			<ref name=jinm2015>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}}</ref>

			<ref name=rafi2017>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}}</ref>

			<ref name=skot1984>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}}</ref>

			<ref name=ramp2021>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}}</ref>

			<ref name=turn2005>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}}</ref>

			<ref name=tana2017>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}},</ref>

			<ref name=seaq1998>Elizabeth R. Seaquist, Rolf Gruetter (1998): "Identification of a high concentration of ''scyllo''-inositol in the brain of a healthy human subject using <sup>1</sup>H- and <sup>13</sup>C-NMR". ''Magnetic Resonance in Medicine'', volume 39, issue 2, pages 313-316. {{doi\|10.1002/mrm.1910390220}}</ref>

			<ref name=noza2011>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}}</ref>

			<ref name=simp2006>Alexandra Simperler, Stephen W. Watt, P. Arnaud Bonnet, William Jones, W. D. Samuel Motherwell (2006): "Correlation of melting points of inositols with hydrogen bonding patterns". ''CrystEngComm'', volume 8, pages 589-600 {{doi\|10.1039/B606107A}}</ref>

			<ref name=kais2005>Lana G. Kaiser, Norbert Schuff, Nathan Cashdollar, Michael W. Weiner (2005): "''Scyllo''-inositol in normal aging human brain: <sup>1</sup>H magnetic resonance spectroscopy study at 4 Tesla". ''NMR in Biomedicine'', volume 18, issue 1, pages 51-55. {{doi\|10.1002/nbm.927}}</ref>

			</references>

	{{DEFAULTSORT:Inositol, scyllo-}}		{{DEFAULTSORT:Inositol, scyllo-}}
	]		]

Latest revision as of 07:23, 3 January 2025

*scyllo*-Inositol
Names

IUPAC name scyllo-inositol
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
CAS Number	488-59-5
3D model (JSmol)	Interactive image
ChemSpider	10254646
ECHA InfoCard	100.113.358
EC Number	610-437-4
IUPHAR/BPS	4649
UNII	1VS4X81277
CompTox Dashboard (EPA)	DTXSID50905091
InChI InChI=1S/C6H12O6/c7-1-2(8)4(10)6(12)5(11)3(1)9/h1-12H/t1-,2-,3+,4+,5-,6-Key: CDAISMWEOUEBRE-CDRYSYESSA-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
SMILES O1(O)(O)(O)(O)1O
Properties
Chemical formula	C₆H₁₂O₆
Molar mass	180.156 g·mol
Appearance	White crystalline solid
Density	1.57 (A), 1.66 (B) g/ml,
Melting point	358 °C (A), 360 °C (B) decomposes
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). N verify (what is ?) Infobox references

Chemical compound

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 alternately 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, certain bacteria, and more abundantly in some plants.

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.

Chemical and physical properties

Crystal structure

Anhydrous scyllo-inositol exists in at least two polymorphs (crystal forms). In both forms the molecules have symmetry ${\bar {1}}$ and are in the chair conformation, that puts all the hydroxyls in nearly equatorial positions.

The "A" form readily crystallizes from water. It has a lower density 1.57 g/ml and decomposes at 358 °C. It crystallizes in the monoclinic system with group is $P2_{1}/c$ . 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.

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 and decomposes at about 360 °C. Its crystal system is triclinic with group $P{\bar {1}}$ . 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.

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.

Synthesis

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

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

Scyllitol was known to be a facultative intermediate in the metabolism of myo-inositol by the bacterium Bacillus subtilis. 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. 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.

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.

Derivatives

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

Biochemistry

Natural occurrence

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

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.

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.

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.

Physiology

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 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. 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.

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.

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.

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

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

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.

Clinical evaluation

Alzheimer's disease

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. 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. More recently, it has also been found to inhibit the binding of Aβ oligomers to plasma membranes and interfering with synaptic function.

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.

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. 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. Results of this trial were not positive but considered inconclusive. 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.

Bipolar disorder

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.

Down's syndrome

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.

References

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https://clinicaltrials.gov/study/NCT00934050?tab=results>
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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

Category:

Inositol