The synthesis of a series of highly luminescent, functional dithienophospholes via a click reacti... more The synthesis of a series of highly luminescent, functional dithienophospholes via a click reaction is reported. Slight modification of the lateral aromatic substituents leads to a significant difference in their solid-state organization. In addition, a novel water-soluble β-cyclodextrin hybrid is demonstrated to be an effective sensor for picric acid.
The modified α-cyclodextrin system having four nicotinate groups with an ABDE symmetry presents t... more The modified α-cyclodextrin system having four nicotinate groups with an ABDE symmetry presents two pairs of preferentially cis-coordinating pyridyl ligands. The molecule in dmso-d has been shown by H NMR to complex two cis-PtCl2 moieties. The observed non-equivalence of the pyridyl ligands may be explained by a molecular graphics study which places the metal above and outside the rim of
ABSTRACT Oligo/polymerisation of known mesogens constitutes a highly efficient strategy in liquid... more ABSTRACT Oligo/polymerisation of known mesogens constitutes a highly efficient strategy in liquid crystal research due to its potential to generate novel liquid crystal materials with intriguing mesomorphic properties. Here we report the synthesis and comparative studies of a synthetic liquid crystal dimer and two of its monomer analogues. By incorporating cholesterol as the mesogenic group, we designed a flexible scaffold consisting of a hybrid of non-polar hydrophobic chain and polar tetraethylene glycol appended to the cholesteryl mesogens. Detailed studies showed that the two classes of mesogens exhibit the same type of liquid crystal phases with similar dimensions but their transition temperatures varied which can be effectively rationalised by the particular chemical functionalities present in each class of materials. Graphical Abstract
OBJECTIVE: To assess the preclinical efficacy of a fluorinated analog of acetylated N-acetylgluco... more OBJECTIVE: To assess the preclinical efficacy of a fluorinated analog of acetylated N-acetylglucosamine as a therapy to promote myelin repair in multiple sclerosis by normalizing the expression of inhibitory chondroitin sulfate proteoglycan barrier molecules. BACKGROUND: Remyelination, the generation of new myelin after CNS insult, is impeded largely by the inhibitory nature of the extracellular lesion microenvironment. Our group recently established that the chondroitin sulfate proteoglycans (CSPGs), which are upregulated in CNS conditions such as multiple sclerosis, are potent inhibitors of myelin repair by oligodendrocyte precursor cells (OPCs) (Lau et al., Ann Neurol 72:419-432, 2012). We aimed to reduce this aberrant CSPG with a fluorinated analog of acetylated N-acetylglucosamine (Ac-4-F-GlcNAc), a synthesis inhibitor. DESIGN/METHODS: Murine astrocytes, which produce CSPGs when stimulated, were cultured in the presence of Ac-4-F-GlcNAc. Treated media was analyzed for CSPG content as well as functional effects on OPCs in culture. Ac-4-F-GlcNAc was administered following dorsal column microinjections of the demyelinating detergent lysolecithin in mice, and the content of spinal cord CSPGs was later assessed. Ac-4-F-GlcNAc was also administered to mice afflicted with experimental autoimmune encephalomyelitis (EAE) to assess the effects on an inflammatory model of MS. RESULTS: Murine OPCs are potently inhibited in terms of cell adhesion and process outgrowth in the presence of CSPGs. Ac-4-F-GlcNAc dramatically reduces the CSPG content of astrocytes in culture without evidence of toxicity, and OPCs appear less inhibited in the presence of this media. In vivo, Ac-4-F-GlcNAc reduces the CSPG content of mouse spinal cords following lysolecithin, and reduces the severity of EAE. CONCLUSIONS: Ac-4-F-GlcNAc appears to be a safe, systemic approach to reduce CSPGs following demyelination as well as mitigate the inflammatory component of EAE. We are currently addressing whether Ac-4-F-GlcNAc results in improved OPC recruitment and maturation in the lesion environment, and ultimately the impact on remyelination. Study Supported by: Multiple Sclerosis Society of Canada Disclosure: Dr. Keough has nothing to disclose. Dr. Rogers has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Plemel has nothing to disclose. Dr. Ling has nothing to disclose. Dr. Yong has received personal compensation for activities with Teva Neuroscience as a speaker. Dr. Yong has received research support from Teva Neuroscience and Novartis.
The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is ... more The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is very remarkable, owing to the unique, multifaceted structural features that have been combined into one molecule, which include (1) the rare ido-configuration, (2) the unusual 7-carbon backbone, and (3) the challenging β-(1→2)-cis-anomeric configuration. Two distinct strategies toward the total synthesis of this interesting target are reported. The first involved establishment of the β-d-idopyranosyl configuration from β-d-galactopyranosides, prior to a C-6-homologation extending the d-hexose to the desired 6-deoxy-d-heptose. However, this approach encountered difficulties due to the significantly reduced reactivity of the 6-position of the β-d-idopyranosides, so instead a second strategy was employed, which involved first carrying out a 6-homologation on the less flexible d-galactopyranose, followed by a very successful conversion to the desired β-d-ido-configuration found in the target heptopyranoside (2). This report is the first successful synthesis of the 6-deoxy-β-d-ido-heptopyranoside, which could possess interesting immunological properties.
Tetratritylation of alpha-cyclodextrin (CD) and subsequent peracetylation of the partially trityl... more Tetratritylation of alpha-cyclodextrin (CD) and subsequent peracetylation of the partially tritylated mixture allowed the preparation and isolation of the symmetrical 6(A),6(B),6(D),6(E)-tetratritylated alpha-CD in pure form. The (1)H NMR spectra of the compound showed abnormal behaviour with the anomeric proton of one of the glycopyranosyl systems resonating below 3.0 ppm, which is exceptionally unusual. To understand this anomaly in the (1)H NMR data, we performed a complete NMR analysis and using molecular modelling as a tool, we were able to obtain a conformation that can explain the observed NMR phenomenon.
Treatment of per-2-O-tosyl-cyclodextrins with K2CO3 allows the synthesis of cyclomannoepoxides 2a... more Treatment of per-2-O-tosyl-cyclodextrins with K2CO3 allows the synthesis of cyclomannoepoxides 2a, 2b, 2c in high yields (>90%). The glucopyranose structure of 2a, 2b, 2c, is assigned from the H coupling pattern (J1,2 = 0 Hz, J2,3 = 3.5 Hz, J3,4 = 0 Hz), as a half chair conformation. 2b shows surfactant properties in water. Full analysis of the NMR spectra
Substitution of the primary hydroxyl groups of α-cyclodextrin by nicotinate groups in an ABDE con... more Substitution of the primary hydroxyl groups of α-cyclodextrin by nicotinate groups in an ABDE conformation yields a molecule having two pairs of pyridyl ligands. The compound complexes CoCl2 and CuBr2 in methanol or acetone to yield 1:2 complexes which are soluble in chloroform. The electronic spectrum of the blue CoCl2 complex is almost identical to that of Co(Py)2Cl2, implying a
The synthesis of a series of highly luminescent, functional dithienophospholes via a click reacti... more The synthesis of a series of highly luminescent, functional dithienophospholes via a click reaction is reported. Slight modification of the lateral aromatic substituents leads to a significant difference in their solid-state organization. In addition, a novel water-soluble β-cyclodextrin hybrid is demonstrated to be an effective sensor for picric acid.
The modified α-cyclodextrin system having four nicotinate groups with an ABDE symmetry presents t... more The modified α-cyclodextrin system having four nicotinate groups with an ABDE symmetry presents two pairs of preferentially cis-coordinating pyridyl ligands. The molecule in dmso-d has been shown by H NMR to complex two cis-PtCl2 moieties. The observed non-equivalence of the pyridyl ligands may be explained by a molecular graphics study which places the metal above and outside the rim of
ABSTRACT Oligo/polymerisation of known mesogens constitutes a highly efficient strategy in liquid... more ABSTRACT Oligo/polymerisation of known mesogens constitutes a highly efficient strategy in liquid crystal research due to its potential to generate novel liquid crystal materials with intriguing mesomorphic properties. Here we report the synthesis and comparative studies of a synthetic liquid crystal dimer and two of its monomer analogues. By incorporating cholesterol as the mesogenic group, we designed a flexible scaffold consisting of a hybrid of non-polar hydrophobic chain and polar tetraethylene glycol appended to the cholesteryl mesogens. Detailed studies showed that the two classes of mesogens exhibit the same type of liquid crystal phases with similar dimensions but their transition temperatures varied which can be effectively rationalised by the particular chemical functionalities present in each class of materials. Graphical Abstract
OBJECTIVE: To assess the preclinical efficacy of a fluorinated analog of acetylated N-acetylgluco... more OBJECTIVE: To assess the preclinical efficacy of a fluorinated analog of acetylated N-acetylglucosamine as a therapy to promote myelin repair in multiple sclerosis by normalizing the expression of inhibitory chondroitin sulfate proteoglycan barrier molecules. BACKGROUND: Remyelination, the generation of new myelin after CNS insult, is impeded largely by the inhibitory nature of the extracellular lesion microenvironment. Our group recently established that the chondroitin sulfate proteoglycans (CSPGs), which are upregulated in CNS conditions such as multiple sclerosis, are potent inhibitors of myelin repair by oligodendrocyte precursor cells (OPCs) (Lau et al., Ann Neurol 72:419-432, 2012). We aimed to reduce this aberrant CSPG with a fluorinated analog of acetylated N-acetylglucosamine (Ac-4-F-GlcNAc), a synthesis inhibitor. DESIGN/METHODS: Murine astrocytes, which produce CSPGs when stimulated, were cultured in the presence of Ac-4-F-GlcNAc. Treated media was analyzed for CSPG content as well as functional effects on OPCs in culture. Ac-4-F-GlcNAc was administered following dorsal column microinjections of the demyelinating detergent lysolecithin in mice, and the content of spinal cord CSPGs was later assessed. Ac-4-F-GlcNAc was also administered to mice afflicted with experimental autoimmune encephalomyelitis (EAE) to assess the effects on an inflammatory model of MS. RESULTS: Murine OPCs are potently inhibited in terms of cell adhesion and process outgrowth in the presence of CSPGs. Ac-4-F-GlcNAc dramatically reduces the CSPG content of astrocytes in culture without evidence of toxicity, and OPCs appear less inhibited in the presence of this media. In vivo, Ac-4-F-GlcNAc reduces the CSPG content of mouse spinal cords following lysolecithin, and reduces the severity of EAE. CONCLUSIONS: Ac-4-F-GlcNAc appears to be a safe, systemic approach to reduce CSPGs following demyelination as well as mitigate the inflammatory component of EAE. We are currently addressing whether Ac-4-F-GlcNAc results in improved OPC recruitment and maturation in the lesion environment, and ultimately the impact on remyelination. Study Supported by: Multiple Sclerosis Society of Canada Disclosure: Dr. Keough has nothing to disclose. Dr. Rogers has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Plemel has nothing to disclose. Dr. Ling has nothing to disclose. Dr. Yong has received personal compensation for activities with Teva Neuroscience as a speaker. Dr. Yong has received research support from Teva Neuroscience and Novartis.
The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is ... more The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is very remarkable, owing to the unique, multifaceted structural features that have been combined into one molecule, which include (1) the rare ido-configuration, (2) the unusual 7-carbon backbone, and (3) the challenging β-(1→2)-cis-anomeric configuration. Two distinct strategies toward the total synthesis of this interesting target are reported. The first involved establishment of the β-d-idopyranosyl configuration from β-d-galactopyranosides, prior to a C-6-homologation extending the d-hexose to the desired 6-deoxy-d-heptose. However, this approach encountered difficulties due to the significantly reduced reactivity of the 6-position of the β-d-idopyranosides, so instead a second strategy was employed, which involved first carrying out a 6-homologation on the less flexible d-galactopyranose, followed by a very successful conversion to the desired β-d-ido-configuration found in the target heptopyranoside (2). This report is the first successful synthesis of the 6-deoxy-β-d-ido-heptopyranoside, which could possess interesting immunological properties.
Tetratritylation of alpha-cyclodextrin (CD) and subsequent peracetylation of the partially trityl... more Tetratritylation of alpha-cyclodextrin (CD) and subsequent peracetylation of the partially tritylated mixture allowed the preparation and isolation of the symmetrical 6(A),6(B),6(D),6(E)-tetratritylated alpha-CD in pure form. The (1)H NMR spectra of the compound showed abnormal behaviour with the anomeric proton of one of the glycopyranosyl systems resonating below 3.0 ppm, which is exceptionally unusual. To understand this anomaly in the (1)H NMR data, we performed a complete NMR analysis and using molecular modelling as a tool, we were able to obtain a conformation that can explain the observed NMR phenomenon.
Treatment of per-2-O-tosyl-cyclodextrins with K2CO3 allows the synthesis of cyclomannoepoxides 2a... more Treatment of per-2-O-tosyl-cyclodextrins with K2CO3 allows the synthesis of cyclomannoepoxides 2a, 2b, 2c in high yields (>90%). The glucopyranose structure of 2a, 2b, 2c, is assigned from the H coupling pattern (J1,2 = 0 Hz, J2,3 = 3.5 Hz, J3,4 = 0 Hz), as a half chair conformation. 2b shows surfactant properties in water. Full analysis of the NMR spectra
Substitution of the primary hydroxyl groups of α-cyclodextrin by nicotinate groups in an ABDE con... more Substitution of the primary hydroxyl groups of α-cyclodextrin by nicotinate groups in an ABDE conformation yields a molecule having two pairs of pyridyl ligands. The compound complexes CoCl2 and CuBr2 in methanol or acetone to yield 1:2 complexes which are soluble in chloroform. The electronic spectrum of the blue CoCl2 complex is almost identical to that of Co(Py)2Cl2, implying a
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