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Barry V L Potter - One of the best experts on this subject based on the ideXlab platform.

  • Article pubs.acs.org/est Determination of neo- and D-chiro-Inositol Hexakisphosphate in Soils by Solution 31 P NMR Spectroscopy
    2013
    Co-Authors: Benjamin L. Turner, Andrew M. Riley, Yasmin H Godage, Er W. Cheesman, Barry V L Potter
    Abstract:

    *S Supporting Information ABSTRACT: The inositol phosphates are an abundant but poorly understood group of organic phosphorus compounds found widely in the environment. Four stereoisomers of inositol hexakisphosphate (IP6) occur, although for three of these (scyllo, neo, and D-chiro) the origins, dynamics, and biological function remain unknown, due in large part to analytical limitations in their measurement in environmental samples. We synthesized authentic neo- and D-chiro-IP6 and used them to identify signals from these compounds in three soils from the Falkland Islands. Both compounds resisted hypobromite oxidation and gave quantifiable 31P NMR signals at δ = 6.67 ppm (equatorial phosphate groups of the 4-equatorial/2-axial conformer of neo-IP6) and δ = 6.48 ppm (equatorial phosphate groups of the 2-equatorial/4-axial conformer of D-chiro-IP6) in soil extracts. Inositol hexakisphosphate accounted for 46−54 % of the soil organic phosphorus, of which the four stereoisomers constituted, on average, 55.9 % (myo), 32.8 % (scyllo), 6.1 % (neo), and 5.2 % (D-chiro). Reappraisal of the literature based on the new signal assignments revealed that neo- and D-chiro-IP6 occur widely in both terrestrial and aquatic ecosystems. These results confirm that the inositol phosphates can constitute a considerabl

  • determination of neo and d chiro inositol hexakisphosphate in soils by solution 31p nmr spectroscopy
    Environmental Science & Technology, 2012
    Co-Authors: Benjamin L. Turner, Andrew M. Riley, Alexander W Cheesman, Yasmin H Godage, Barry V L Potter
    Abstract:

    The inositol phosphates are an abundant but poorly understood group of organic phosphorus compounds found widely in the environment. Four stereoisomers of inositol hexakisphosphate (IP6) occur, although for three of these (scyllo, neo, and d-chiro) the origins, dynamics, and biological function remain unknown, due in large part to analytical limitations in their measurement in environmental samples. We synthesized authentic neo- and d-chiro-IP6 and used them to identify signals from these compounds in three soils from the Falkland Islands. Both compounds resisted hypobromite oxidation and gave quantifiable 31P NMR signals at δ = 6.67 ppm (equatorial phosphate groups of the 4-equatorial/2-axial conformer of neo-IP6) and δ = 6.48 ppm (equatorial phosphate groups of the 2-equatorial/4-axial conformer of d-chiro-IP6) in soil extracts. Inositol hexakisphosphate accounted for 46–54% of the soil organic phosphorus, of which the four stereoisomers constituted, on average, 55.9% (myo), 32.8% (scyllo), 6.1% (neo), ...

  • Scyllo-Inositol Pentakisphosphate as an Analogue of myo-Inositol 1,3,4,5,6-Pentakisphosphate: Chemical Synthesis, Physicochemistry and Biological Applications
    Chembiochem : a European journal of chemical biology, 2006
    Co-Authors: Andrew M. Riley, Bernard Spiess, Melanie Trusselle, Paul Kuad, Michal Borkovec, Jaiesoon Cho, Jae H. Choi, Xun Qian, Stephen B. Shears, Barry V L Potter
    Abstract:

    myo-Inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P(5)), an inositol polyphosphate of emerging significance in cellular signalling, and its C-2 epimer Scyllo-Inositol pentakisphosphate (scyllo-InsP(5)) were synthesised from the same myo-inositol-based precursor. Potentiometric and NMR titrations show that both pentakisphosphates undergo a conformational ring-flip at higher pH, beginning at pH 8 for scyllo-InsP(5) and pH 9 for Ins(1,3,4,5,6)P(5). Over the physiological pH range, however, the conformation of the inositol rings and the microprotonation patterns of the phosphate groups in Ins(1,3,4,5,6)P(5) and scyllo-InsP(5) are similar. Thus, scyllo-InsP(5) should be a useful tool for identifying biologically relevant actions of Ins(1,3,4,5,6)P(5), mediated by specific binding sites, and distinguishing them from nonspecific electrostatic effects. We also demonstrate that, although scyllo-InsP(5) and Ins(1,3,4,5,6)P(5) are both hydrolysed by multiple inositol polyphosphate phosphatase (MINPP), scyllo-InsP(5) is not dephosphorylated by PTEN or phosphorylated by Ins(1,3,4,5,6)P(5) 2-kinases. This finding both reinforces the value of scyllo-InsP(5) as a biological control and shows that the axial 2-OH group of Ins(1,3,4,5,6)P(5) plays a part in substrate recognition by PTEN and the Ins(1,3,4,5,6)P(5) 2-kinases.

  • synthesis of l scyllo inositol 1 2 4 trisphosphate scyllo inositol 1 2 4 5 tetrakisphosphate and phosphorothioate and dl 2 deoxy 2 fluoro myo inositol 1 4 5 trisphosphate optical resolution of dl 1 o allyl 3 6 di o benzyl 4 5 o isopropylidene scyllo
    Journal of The Chemical Society-perkin Transactions 1, 1996
    Co-Authors: Dethard Lampe, Changsheng Liu, Mary F Mahon, Barry V L Potter
    Abstract:

    Routes for the synthesis of Scyllo-Inositol tris-and tetrakis-phosphates and 2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate from myo-inositol have been devised. For DL-Scyllo-Inositol 1,2,4-trisphosphate, DL-1-O-allyl 1–3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was prepared from the triflate of DL-1-O-allyl-3,6-di-O-benzyl-4–5-O-isopropylidene-myo-inositol by inversion at C-2. Removal of the isopropylidene group and phosphorylation gave the protected trisphosphate. Deblocking with sodium in liquid ammonia afforded racemic Scyllo-Inositol 1,2,4-trisphosphate. DL-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was resolved into its enantiomers by means of the crystalline 2-O-camphanate ester. The structure of one diastereoisomer, 1D-O-allyl-3,6-di-O-benzyl-2-O-[(–)-camphanate]-4,5–0-isopropylidene-Scyllo-Inositol was determined by single-crystal X-ray crystallography. 1D-(+)-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was used to prepare 1L(–)-Scyllo-Inositol 1,2,4-trisphosphate in a fashion analogous to the racemic modification. DL-1-O-Allyl-3,6-di-O-benzyl-Scyllo-Inositol was isomerised to the (Z)-prop-1-enyl derivative. The propenyl group was then removed to give the meso-1,4-di-O-benzyScyllo-Inositol. Phosphitylation followed by oxidation or sulfoxidation gave the fully protected tetrakis-phosphate or -phosphorothioate, respectively. After deblocking and purification, Scyllo-Inositol 1,2,4,5-tetrakisphosphate and scyllo inositol 1,2,4,5-tetrakisphosphorothioate were obtained. DL-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was isomerised to the 1-O-[(Z)-prop-1-enyl] derivative which was converted into the 2-O-triflate. Displacement of the triflate using tetrabutylammonium fluoride proceeded with inversion of configuration to give DL-3,6-di-O-beflzyl-2-deoxy-2-fluoro-4,5-O-isopropylidene-1-O-([(Z)-prop-1-eny]-myo-inositol. Removal of propenyl and isopropylidene groups afforded DL-3,6-di-O-benzyl-2-deoxy-2-fluoro-myo-inositol, which was phosphitylated and the product oxidised to give the fully protected 2-fluoro trisphosphate. Deprotection furnished DL-2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate. These compounds will be useful probes for investigation of the polyphosphoinositide pathway of cellular signalling.

  • 6-Deoxy-6-hydroxymethyl Scyllo-Inositol 1,2,4-trisphosphate: A potent agonist at the inositol 1,4,5-trisphosphate receptor
    Bioorganic & Medicinal Chemistry Letters, 1996
    Co-Authors: Andrew M. Riley, Christine T. Murphy, C. J. Lindley, John Westwick, Barry V L Potter
    Abstract:

    Abstract The synthesis of racemic 6-deoxy-6-hydroxymethyl scyllo -inositol 1,2,4-trisphosphate is described. This compound is a highly potent agonist at the platelet d - myo -inositol 1,4,5-trisphosphate receptor, and it binds to the rat cerebellar receptor with an affinity equal to that of the natural ligand. These results suggest that the 5″-hydroxymethyl group of adenophostin A may contribute to its unusual potency.

Jo Anne Mclaurin - One of the best experts on this subject based on the ideXlab platform.

  • Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer’s disease
    Brain research, 2017
    Co-Authors: Mingzhe Liu, Stefan Jevtic, Kelly Markham-coultes, Nicholas Ellens, Meaghan A. O'reilly, Kullervo Hynynen, Isabelle Aubert, Jo Anne Mclaurin
    Abstract:

    Abstract Amyloid-beta peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Here, we explored the use of a combination treatment to reduce amyloid load through microglial phagocytosis in a mouse model of AD. We hypothesized that using an initial treatment of magnetic resonance image guided focused ultrasound (MRIgFUS) to transiently increase the blood–brain barrier (BBB) permeability and enhance the delivery of an Aβ-antibody (BAM-10), followed by Scyllo-Inositol treatment would result in accelerated clearance. TgCRND8 mice expressing both Swedish (KM670/671NL) and Indiana (V717F) APP mutations under the hamster prion (PrP) promoter at 5 months of age were either treated with Scyllo-Inositol or received an initial MRIgFUS treatment delivering BAM-10 prior to Scyllo-Inositol treatment for one month. Treated animals and untreated TgCRND8 littermates were then sacrificed at 6 months of age, and their brains were processed for immunohistochemistry and immunofluorescence. Amyloid load was quantified and analyzed through immunohistochemical staining. Astrocyte and microglial activation were quantified and analyzed through immunofluorescent staining. We found that both the Scyllo-Inositol treatment and combination treatment, MRIgFUS/BAM10+Scyllo-Inositol, significantly reduced amyloid load and astrocyte activation in the hippocampus and the cortex. Furthermore, in both treatment paradigms microglial activation and phagocytosis was increased in comparison to the untreated mice. There were no differences detected between the two treatment paradigms. We propose that the 30-day Scyllo-Inositol treatment saturated the early benefit of the MRIgFUS/BAM-10 treatment. In the future, multiple FUS treatments combined with BAM-10 throughout the duration of Scyllo-Inositol treatment may lead to more effective amyloid clearance.

  • Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease.
    PloS one, 2016
    Co-Authors: Christopher D. Morrone, Isabelle Aubert, Mary E. Brown, Lynsie A.m. Thomason, Jo Anne Mclaurin
    Abstract:

    Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer's disease (AD)-like pathology, specifically Aβ-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aβ pathology with Scyllo-Inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of Scyllo-Inositol treatment. The prolonged exposure to Aβ-pathology leads to deficits in the neurogenic niche, thus targeting Aβ alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined Scyllo-Inositol treatment with leteprinim potassium (neotrofin), the latter of which stimulates neurotrophin expression. We show that the combination treatment of Scyllo-Inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Aβ-pathology and neurotrophin deficits as a potential treatment for AD.

  • Scyllo-Inositol promotes robust mutant Huntingtin protein degradation.
    The Journal of biological chemistry, 2013
    Co-Authors: Aaron Y. Lai, Mary E. Brown, Cynthia P. Lan, Salwa M. Hasan, Jo Anne Mclaurin
    Abstract:

    Abstract Huntington disease is characterized by neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein and peptide fragments (polyQ-Htt). We have used an established cell-based assay employing a PC12 cell line overexpressing truncated exon 1 of Htt with a 103-residue polyQ expansion that yields polyQ-Htt aggregates to investigate the fate of polyQ-Htt-drug complexes. Scyllo-Inositol is an endogenous inositol stereoisomer known to inhibit accumulation and toxicity of the amyloid-β peptide and α-synuclein. In light of these properties, we investigated the effect of Scyllo-Inositol on polyQ-Htt accumulation. We show that Scyllo-Inositol lowered the number of visible polyQ-Htt aggregates and robustly decreased polyQ-Htt protein abundance without concomitant cellular toxicity. We found that Scyllo-Inositol-induced polyQ-Htt reduction was by rescue of degradation pathways mediated by the lysosome and by the proteasome but not autophagosomes. The rescue of degradation pathways was not a direct result of Scyllo-Inositol on the lysosome or proteasome but due to Scyllo-Inositol-induced reduction in mutant polyQ-Htt protein levels.

  • Scyllo-Inositol, preclinical, and clinical data for Alzheimer's disease.
    Advances in pharmacology (San Diego Calif.), 2012
    Co-Authors: Lynsie A.m. Thomason, Jo Anne Mclaurin
    Abstract:

    Abstract Preclinical development of scyllo- inositol for the treatment of Alzheimer’s disease (AD) has been investigated in both in vitro and in vivo models with positive results. scyllo- Inositol stabilized a small conformer of Aβ42 in vitro , neutralized cell derived Aβ trimers and promoted low molecular weight Aβ species in vivo . These interactions resulted in decreased neuronal toxicity, increased long-term potentiation (LTP) and ablation of cognitive deficits in multiple mouse models of AD. scyllo- Inositol bioavailability, pharmacokinetics, and small animal toxicology studies demonstrated the potential for translation to human patients. The results of Phase I and Phase II clinical trials for AD are presented. Furthermore, the use of this compound for imaging and other amyloid related disorders is discussed.

  • Comparisons of [18F]-1-deoxy-1-fluoro-Scyllo-Inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice
    Nuclear medicine and biology, 2011
    Co-Authors: Kristin Mclarty, Jo Anne Mclaurin, Mark Nitz, Matthew D. Moran, Deborah A. Scollard, Conrad Chan, Nesrin Sabha, Joydeep Mukherjee, Abhijit Guha, Sylvain Houle
    Abstract:

    Abstract Introduction The aim of the study was to evaluate the uptake of [ 18 F]-1-deoxy-1-fluoro- scyllo -inositol ([ 18 F]- scyllo -inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [ 18 F]-2-fluoro-2-deoxy-d-glucose ([ 18 F]-FDG) under the same conditions were also performed. Methods Radiosynthesis of [ 18 F]- scyllo -inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [ 18 F]- scyllo -inositol and [ 18 F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results The radiosynthesis of [ 18 F]- scyllo -inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n =5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [ 18 F]- scyllo -inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [ 18 F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P =.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [ 18 F]- scyllo -inositol in inflammation was lower than [ 18 F]-FDG. While uptake of [ 18 F]- scyllo -inositol in intracranial U-87 MG xenografts was significantly lower than [ 18 F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P =.001). Conclusions Consistent with biodistribution studies, uptake of [ 18 F]- scyllo -inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [ 18 F]-FDG. The tumour-to-brain ratio of [ 18 F]- scyllo -inositol was also significantly higher than that of [ 18 F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast.

Mark Nitz - One of the best experts on this subject based on the ideXlab platform.

  • Aβ(1-42) assembly in the presence of Scyllo-Inositol derivatives: identification of an oxime linkage as important for the development of assembly inhibitors.
    ACS chemical neuroscience, 2011
    Co-Authors: James E. Shaw, J Chio, Somnath Dasgupta, A Y Lai, F Pang, L A M Thomason, A J Yang, C M Yip, Mark Nitz
    Abstract:

    To identify a lead skeleton structure for optimization of Scyllo-Inositol-based inhibitors of amyloid-beta peptide (Aβ) aggregation, we have synthesized aldoxime, hydroxamate, carbamate, and amide linked Scyllo-Inositol derivatives. These structures represent backbones that can be readily expanded into a wide array of derivatives. They also provide conservative modifications of the Scyllo-Inositol backbone, as they maintain the display of the equatorial polar atoms, preserving the stereochemical requirement necessary for maximum inhibition of Aβ(1-42) fiber formation. In addition, a reliable work plan for screening derivatives was developed in order to preferentially identify a backbone(s) structure that prevents fibrillogenesis and stabilizes nontoxic small molecular weight oligomers, as we have previously reported for Scyllo-Inositol. In the present studies, we have adapted a high throughput ELISA-based oligomerization assay followed by atomic force microscopy to validate the results screen compounds. The lead compounds were then tested for toxicity and ability to rescue Aβ(1-42) induced toxicity in vitro and the affinity of the compounds for Aβ(1-42) compared by mass spectrometry. The data to suggest that compounds must maintain a planar conformation to exhibit activity similar to Scyllo-Inositol and that the oxime derivative represents the lead backbone for future development.

  • Comparisons of [18F]-1-deoxy-1-fluoro-Scyllo-Inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice
    Nuclear medicine and biology, 2011
    Co-Authors: Kristin Mclarty, Jo Anne Mclaurin, Mark Nitz, Matthew D. Moran, Deborah A. Scollard, Conrad Chan, Nesrin Sabha, Joydeep Mukherjee, Abhijit Guha, Sylvain Houle
    Abstract:

    Abstract Introduction The aim of the study was to evaluate the uptake of [ 18 F]-1-deoxy-1-fluoro- scyllo -inositol ([ 18 F]- scyllo -inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [ 18 F]-2-fluoro-2-deoxy-d-glucose ([ 18 F]-FDG) under the same conditions were also performed. Methods Radiosynthesis of [ 18 F]- scyllo -inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [ 18 F]- scyllo -inositol and [ 18 F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results The radiosynthesis of [ 18 F]- scyllo -inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n =5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [ 18 F]- scyllo -inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [ 18 F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P =.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [ 18 F]- scyllo -inositol in inflammation was lower than [ 18 F]-FDG. While uptake of [ 18 F]- scyllo -inositol in intracranial U-87 MG xenografts was significantly lower than [ 18 F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P =.001). Conclusions Consistent with biodistribution studies, uptake of [ 18 F]- scyllo -inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [ 18 F]-FDG. The tumour-to-brain ratio of [ 18 F]- scyllo -inositol was also significantly higher than that of [ 18 F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast.

  • Small molecule β-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease
    The European journal of neuroscience, 2010
    Co-Authors: Cheryl A. Hawkes, James E. Shaw, Mark Nitz, Le Hua Deng, Jo Anne Mclaurin
    Abstract:

    β-Amyloid (Aβ) peptides are thought to play a major role in the pathogenesis of Alzheimer’s disease. Compounds that disrupt the kinetic pathways of Aβ aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar Aβ in the etiology of the disease. We have previously reported that Scyllo-Inositol inhibits Aβ42 fibril formation but the mechanism(s) by which this occurs has not been investigated in detail. Using a series of Scyllo-Inositol derivatives in which one or two hydroxyl groups were replaced with hydrogen, chlorine or methoxy substituents, we examined the role of hydrogen bonding and hydrophobicity in the structure–function relationship of Scyllo-Inositol–Aβ binding. We report here that all Scyllo-Inositol derivatives demonstrated reduced effectiveness in preventing Aβ42 fibrillization compared with Scyllo-Inositol, suggesting that Scyllo-Inositol interacts with Aβ42 via key hydrogen bonds that are formed by all hydroxyl groups. Increasing the hydrophobicity of Scyllo-Inositol by the addition of two methoxy groups (1,4-di-O-methyl-Scyllo-Inositol) produced a derivative that stabilized Aβ42 protofibrils in vitro. Prophylactic administration of 1,4-di-O-methyl-Scyllo-Inositol to TgCRND8 mice attenuated spatial memory impairments and significantly decreased cerebral amyloid pathology. These results suggest that Aβ aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer’s disease-like pathology.

  • Synthesis and preliminary biological evaluations of [18F]-1-deoxy-1-fluoro-Scyllo-Inositol.
    Chemical communications (Cambridge England), 2009
    Co-Authors: Neil Vasdev, Jo Anne Mclaurin, Mark Nitz, Sylvain Houle, Jason Chio, Erik M. Van Oosten, Douglass Vines, Raymond M. Reilly, Alan A. Wilson
    Abstract:

    A novel PET radiotracer, [18F]-1-deoxy-1-fluoro-Scyllo-Inositol, was synthesized via a one-pot reaction in 16 ± 3% uncorrected radiochemical yield within 80 minutes; although this compound revealed low brain penetration it shows promise in rodent tumour models for breast cancer imaging.

  • Synthesis of scyllo -inositol derivatives and their effects on amyloid beta peptide aggregation
    Bioorganic & medicinal chemistry, 2008
    Co-Authors: Yedi Sun, Guohua Zhang, Cheryl A. Hawkes, James E. Shaw, Jo Anne Mclaurin, Mark Nitz
    Abstract:

    Scyllo-Inositol has shown promise as a potential therapeutic for Alzheimer’s disease, by directly interacting with the amyloid β (Aβ) peptide to inhibit Aβ42 fiber formation. To explore the molecular details of the inositol-Aβ42 interaction, a series of Scyllo-Inositol derivatives have been synthesized which contain deoxy, fluoro, chloro, and methoxy substitutions. The effects of these compounds on the aggregation cascade of Aβ42 have been investigated using electron microscopy (EM). EM analyses revealed that the 1-deoxy-1-fluoro- and 1,4-dimethyl-Scyllo-Inositols significantly inhibit the formation of Aβ42 fibers. The other derivatives showed some alterations in the morphology of the Aβ42 fibers produced. These findings indicate the importance of all of the hydroxyl groups of Scyllo-Inositol for complete inhibition of Aβ aggregation.

Marcia A Kaetzel - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of d 1 2 dideoxy 1 2 difluoro myo inositol 3 4 5 6 tetrakisphosphate and its enantiomer as analogues of myo inositol 3 4 5 6 tetrakisphosphate
    Carbohydrate Research, 1998
    Co-Authors: Kevin R H Solomons, Stephen B. Shears, Sally Freeman, Carl H Schwalbe, Deborah J Nelson, Weiwen Xie, Karol S Bruzik, Marcia A Kaetzel
    Abstract:

    Abstract dl -3,4,5,6-Tetra-O-benzyl-1-deoxy-1-fluoro-Scyllo-Inositol was resolved using (−)-(1S, 4R)-camphanyl chloride. The diastereoisomers formed were separated and the structure of d -3,4,5,6-tetra-O-benzyl-2-(1S,4R)-camphanyl-1-deoxy-1-fluoro-Scyllo-Inositol was solved by X-ray crystallography to an R-factor of 4.2%. A series of manipulations led to the preparation of d -1,2-dideoxy-1,2-difluoro-myo-inositol 3,4,5,6-tetrakisphosphate and its enantiomer. The d -1,2-difluoro enantiomer stereospecifically inhibited CaMK II-activated Cl− current, but with low potency; however, efficacy of this compound was greatly enhanced by myo-inositol 3,4,5,6-tetrakisphosphate itself.

Dethard Lampe - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of l scyllo inositol 1 2 4 trisphosphate scyllo inositol 1 2 4 5 tetrakisphosphate and phosphorothioate and dl 2 deoxy 2 fluoro myo inositol 1 4 5 trisphosphate optical resolution of dl 1 o allyl 3 6 di o benzyl 4 5 o isopropylidene scyllo
    Journal of The Chemical Society-perkin Transactions 1, 1996
    Co-Authors: Dethard Lampe, Changsheng Liu, Mary F Mahon, Barry V L Potter
    Abstract:

    Routes for the synthesis of Scyllo-Inositol tris-and tetrakis-phosphates and 2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate from myo-inositol have been devised. For DL-Scyllo-Inositol 1,2,4-trisphosphate, DL-1-O-allyl 1–3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was prepared from the triflate of DL-1-O-allyl-3,6-di-O-benzyl-4–5-O-isopropylidene-myo-inositol by inversion at C-2. Removal of the isopropylidene group and phosphorylation gave the protected trisphosphate. Deblocking with sodium in liquid ammonia afforded racemic Scyllo-Inositol 1,2,4-trisphosphate. DL-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was resolved into its enantiomers by means of the crystalline 2-O-camphanate ester. The structure of one diastereoisomer, 1D-O-allyl-3,6-di-O-benzyl-2-O-[(–)-camphanate]-4,5–0-isopropylidene-Scyllo-Inositol was determined by single-crystal X-ray crystallography. 1D-(+)-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was used to prepare 1L(–)-Scyllo-Inositol 1,2,4-trisphosphate in a fashion analogous to the racemic modification. DL-1-O-Allyl-3,6-di-O-benzyl-Scyllo-Inositol was isomerised to the (Z)-prop-1-enyl derivative. The propenyl group was then removed to give the meso-1,4-di-O-benzyScyllo-Inositol. Phosphitylation followed by oxidation or sulfoxidation gave the fully protected tetrakis-phosphate or -phosphorothioate, respectively. After deblocking and purification, Scyllo-Inositol 1,2,4,5-tetrakisphosphate and scyllo inositol 1,2,4,5-tetrakisphosphorothioate were obtained. DL-1-O-Allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-Scyllo-Inositol was isomerised to the 1-O-[(Z)-prop-1-enyl] derivative which was converted into the 2-O-triflate. Displacement of the triflate using tetrabutylammonium fluoride proceeded with inversion of configuration to give DL-3,6-di-O-beflzyl-2-deoxy-2-fluoro-4,5-O-isopropylidene-1-O-([(Z)-prop-1-eny]-myo-inositol. Removal of propenyl and isopropylidene groups afforded DL-3,6-di-O-benzyl-2-deoxy-2-fluoro-myo-inositol, which was phosphitylated and the product oxidised to give the fully protected 2-fluoro trisphosphate. Deprotection furnished DL-2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate. These compounds will be useful probes for investigation of the polyphosphoinositide pathway of cellular signalling.

  • Synthesis of 2-fluoro-2-deoxy-myo-inositol 1,4,5-trisphosphate and Scyllo-Inositol 1,2,4-trisphosphate, novel analogues of the second messenger myo-inositol 1,4,5-trisphosphate
    Tetrahedron Letters, 1993
    Co-Authors: Dethard Lampe, Barry V L Potter
    Abstract:

    Abstract The novel myo -inositol 1,4,5-triphosphate receptor agonists, 2-flouro-2-deoxy- myo -inositol 1,4,5-triphosphate and scyllo -inositol 1,2,4-triphosphate, were synthesised in racemic form from suitably protected inositol precursors.