<ref name=pode2003>Michael Podeschwa, Oliver Plettenburg, Jochen vom Brocke, Oliver Block, Stephan Adelt, Hans-Josef Altenbach (2003): "Stereoselective synthesis of ''myo''-, ''neo''-, <small>L</small>-''chiro'', <small>D</small>-''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}}<!--Found that scyllo–inositol inhibits cognitive deficits in genetically engineered mice (TgCRND8) and significantly ameliorates disease pathology. Decreases in insoluble Aβ40, Aβ42, and plaque accumulation. Crosses the bllod-brain barrier.  Does not incorporate into the phosphatidylinositol family of lipids.--></ref>

<ref name=alzf2019>Alzforum (2019): "[https://www.alzforum.org/therapeutics/elnd005 ELND005]". ''Therapeutics'' section of [https://www.alzforum.org Alzforum website]. Last updated 2019-06-14 [https://web.archive.org/web/20231226004006/https://www.alzforum.org/therapeutics/elnd005?id=130 archived]; accessed 2024-06-31. </ref>

<ref name=alzf2014>Alzforum (2014): "[https://www.alzforum.org/news/conference-coverage/new-treatments-alzheimers-behavioral-symptoms-horizon New Treatments for Alzheimer’s Behavioral Symptoms on Horizon]". ''[https://www.alzforum.org/news/conference-coverage/clinical-trials-alzheimers-disease-2014 Clinicat Trials 2014''  section of the [https://www.alzforum.org Alzforum website] dated 2014-12-23, accessed on 2024-06-31.</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". Chapter 4 of ''Plant Propagation by Tissue Culture'', 3rd edition, pages 115–173.  {{doi|10.1007/978-1-4020-5005-3_4}}</ref>

<ref name=yeon2001>Younghee Yeon (2001): "[https://koreascience.kr/article/JAKO200111920935778.pdf 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.</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}}<!--Within 48 h of cultivation, the engineered strain was able to convert almost half of 10 g/L myo-inositol to scyllo-inositol that accumulated in the culture medium.--></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=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}}<!--The stereoinversion of myo-inositol into scyllo-inositol was accomplished by Mitsunobu reaction of the vicinal cis-diol.--></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}}<!--''Streptomyces griseus''' converts ''myo''-inositol to ''scyllo''-inositol and then that to streptomycin --></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}}<!--Nice symmetrical esters of ''scyllo''-inositol with orthoformic acid.--></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}}<!--Brain concentration of ''scyllo''-inositol decreases by about 75% in patients with hepatic encephalopathy.--></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}}<!--Metabolism pathway of scyllitol in ''Bacillus subtilis''--></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}}<!--in vitro scyllo-inositol inhibits aggregation of fibers of  a protein implicated in Parkinson's disease.</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}}<!--''scyllo''-inositol inhibits binding of Aβ oligomers to plasma membranes and interfering with synaptic function.--></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>

Abstract: Background: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

<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}}<!--Ononitol (4-O-methyl-myo-inositol) and O-methyl-scyllo-inositol were identified in pea (''Pisum sativum'' L.) root nodules formed by two ''Rhizobium leguminosarum'' strains. Ononitol was the major soluble carbohydrate in nodules formed by strain 1045 while O-methyl-scyllo-inositol and two unidentified components were dominant in the carbohydrate pattern of the nodules formed by strain 1 a. The cyclitols were also present in the denodulated roots, but to a much smaller extent; in the above-ground plant parts only traces were found. The identification of ononitol and O-methyl-scyllo-inositol was established by gas chromatography and gas chromatography-mass spectrometry utilizing trimethylsilyl- and acetyl-derivatives.--></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}}<!--Metabolism of ''myo''-inostol involves NAD+-dependent oxidation to 2-keto-myo-inositol followed by NADPH-dependent reduction to scyllo-inositol.</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}}<!--Detects scyllitol ''hexakis''-phosphate, but not lower phosphates.</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}}<!--Concentrations of scyllo-inositol hexakisphosphate in 29 temperate pasture soils from England and Wales ranged between 11 and 130 mg of phosphorus per kg soil and accounted for between 4 and 15% of the soil organic phosphorus. The ratio of scyllo-inositol hexakisphosphate to myo-inositol hexakisphosphate ranged between 0.29 and 0.79.--></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}},<!--Improves previous B.subtilis factory to produce 27.6 g/l in 48 h.<ref name=tana2017/>--></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}}<!--Previous intravenous administration of either ''myo''- or ''scyllo''-inositol was found to reduce the duration and intensity of chemically-induced seizures in rats.--></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}}<!--Measured 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.  Found significant increase of both in the older 14 (46-71 yrs) and younger 10 (26-29 yrs), namely about 40% for ''scyllo'', 20% for ''myo''; and a weak correlation between the two values.<ref name=kais2005/>--></ref>


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The metabolism of scyllo-inositol in Streptomyces griseus<ref name=horn1968/>

scyllo-Inositol, is widely distributed in nature in fish, mammalian urines, rat
tissue and plants 1. More recently it has been detected in Streptomyces griseus 2, insects a
and mammalian nerve and kidney 4.
Although the biological function of scyllo-inositol remains unknown, recent
progress has been made in elucidating the metabolism of this cyclitol. POSTERNAK
et al. 5 administered 2-14C-labeled myo-inositol and ~4C-labeled scyllo-inositol, to rats
and isolated labeled sqvllo-inositol and labeled myo-inositol, respectively, from the
carcasses. Administration of [2-14CJmyo-inosose-2 resulted in isotope incorporation
into both cyclitols isolated from rat carcass. Based on these findings, myo-inosose-2
was suggested as an intermediate in the interconversion of these cyclitols.
SCHOLDA et al. 6 using both z~C-labeled myo-inositol and myo-inosose-2 showed
that the plant Calycanthus occidentalis converted myo-inositol to scyllo-inositol, and
myo-inosose-2 to both cyclitols. BRUTON, HORNER AND Russ 2 detected interconversion
of these inositols by Streptomyces griseus with uniformly l~C-labeled myo-inositol
and [aHJscyllo-inositol. CANDY ~ found that fat body extracts of the locust, Schistocerca
gregaria, converted uniformly ~4C-labeled myo-inositol to II~C~scyllo-inositol provided
NAD + was present. Evidence was also obtained that myo-inosose-2 was converted
predominantly to myo-inosit01 when NADH was present and to scyllo-inositol upon
NADPH supplementation. Finally, the reactions of the two cyclitols and myoinosose-2 were followed by observing the oxidation and reduction of NAD and
NADP spectrophotometrically. Based on these results the following pathway for
epimerization was proposed by CANDY3:
NAD+ NADP+
"~ myo-inosose-2 ~ ~ scyllo-inositol myo-Inositol .. NADH NADPH
No direct evidence for the formation of myo-inosose-2 as an intermediate in the
interconversion of myo-inositol and scyllo-inositol was provided by these experiments.
It should be noted, however, that myo-inosose-2 is a product of myo-inositol
oxidation in Acetobactersuboxydans 7 and Aerobacter aerogenes s and has been detected
in mammalian nerve and brain ~.
In this communication we report the formation of labeled myo-inosose-2 from
either [2-~4Clmyo-inositol or FaH~scyllo-inositol and the conversion of uniformly zaClabeled myo-inosose-2 to both cyclitols by S. griseus.