The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mario B Pinto - One of the best experts on this subject based on the ideXlab platform.
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studies directed toward the stereochemical structure determination of the naturally occurring glucosidase Inhibitor kotalanol synthesis and Inhibitory activities against human maltase glucoamylase of seven carbon chain extended homologues of salacino
Journal of Organic Chemistry, 2008Co-Authors: Ravindranath Nasi, David R Rose, Brian O Patrick, Mario B PintoAbstract:The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio-d-arabinitol, analogues of the naturally occurring Glycosidase Inhibitor salacinol, are described. These compounds were designed on the basis of the structure activity data of chain-extended analogues of salacinol, with the intention of determining the hitherto unknown stereochemical structure of kotalanol, the naturally occurring seven-carbon chain-extended analogue of salacinol. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-thio-d-arabinitols at the least hindered carbon atom of two 1,3-cyclic sulfates differing in stereochemistry at only one stereogenic center. The desired cyclic sulfates were synthesized starting from d-glucose via Wittig olefination and Sharpless asymmetric dihydroxylation. Deprotection of the coupled products by using a two-step sequence afforded two sulfonium sulfates. Optical rotation data for one of our compounds indicated...
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synthesis of 2 amido 2 amino and 2 azido derivatives of the nitrogen analogue of the naturally occurring Glycosidase Inhibitor salacinol and their Inhibitory activities against o glcnacase and nagz enzymes
Carbohydrate Research, 2008Co-Authors: Niloufar Choubdar, Ramakrishna G Bhat, Keith A Stubbs, Scott A Yuzwa, Mario B PintoAbstract:Seven 2-substituted derivatives of the nitrogen analogue of salacinol, a naturally occurring Glycosidase Inhibitor, were synthesized for structure-activity studies with hexosaminidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the 2-azido-1,4-dideoxy-1,4-imino-D-arabinitol at the least hindered carbon atom of 2,4-O-benzylidene-L-erythritol-1,3-cyclic sulfate. Hydrogenation of the azido zwitterionic compound in methanol resulted in the reduction of the azide and subsequent methylation of the resulting amine in one pot. A similar reaction, with ethanol as the solvent, gave the N-ethyl derivative. The 2-amino analogues were finally obtained by the reduction of the azide function using triphenylphosphine. Acylation of the amine using acetic, propionic, or valeric anhydride afforded the corresponding 2-amido derivatives. Deprotection of the acylated, coupled products using 80% trifluoroacetic acid proceeded smoothly. Unlike their sulfonium ion counterparts, these compounds were stable and did not undergo ring opening. We also report the synthesis of the parent nitrogen heterocycles, N-Boc-1,2,4-trideoxy-2-amino-1,4-imino-D-arabinitol, and 1,2,4-trideoxy-2-acetamido-1,4-imino-D-arabinitol and its corresponding N-Boc protected compound. The 2-substituted analogues and the parent iminoalditol showed marginal activity (<33% at 250 microM) against human O-GlcNAcase and Vibrio cholerae NagZ enzymes.
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binding of sulfonium ion analogues of di epi swainsonine and 8 epi lentiginosine to drosophila golgi alpha mannosidase ii the role of water in Inhibitor binding
Proteins, 2007Co-Authors: Nag S. Kumar, David R Rose, Mario B Pinto, Douglas A Kuntz, Xin WenAbstract:Retaining Glycosidases operate by a two-step catalytic mechanism in which the transition states are characterized by buildup of a partial positive charge at the anomeric center. Sulfonium-ion analogues of the naturally occurring Glycosidase Inhibitors, swainsonine and 8-epi-lentiginosine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, were synthesized in order to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor. Initial prediction based on computational docking indicated three plausible binding modes to Drosophila Golgi α-mannosidase II (dGMII), the most likely being close to that of swainsonine. Observation of the binding of di-epi-thioswainsonine and 8-epi-thiolentiginosine to dGMII from crystallographic data, however, revealed an orientation different from swainsonine in the active site. Screening these two compounds against dGMII shows that they are Inhibitors with IC50 values of 2.0 and 0.014 mM, respectively. This dramatic difference in affinity between the two compounds, which differ by only one hydroxyl group, is rationalized in terms of bound water molecules and the water molecule substructure in the active site, as identified by comparison of high resolution X-ray crystal structures of several dGMII-Inhibitor complexes. Proteins 2008. © 2007 Wiley-Liss, Inc.
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synthesis of phosphate derivatives related to the Glycosidase Inhibitor salacinol
Carbohydrate Research, 2007Co-Authors: Ramakrishna G Bhat, Nag S. Kumar, Mario B PintoAbstract:Abstract The syntheses of polyhydroxylated imino- and anhydro thio-alditol compounds related to the naturally occurring Glycosidase Inhibitor, salacinol, containing a phosphate group in the side chain are described. The compounds lack hydroxyl groups on the acyclic side chain and are prototypes of the exact salacinol analogue. The synthetic strategy relies on the Mitsunobu reaction of N- and S-hydroxyalkyl derivatives of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino- d -arabinitol and 1,4-anhydro-2,3,5-tri-O-benzyl-1-thio- d -arabinitol with dibenzyl phosphate to yield the corresponding protected heteroalditol phosphates. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective Inhibitors of MGA and demonstrates the importance of the hydroxyl and/or sulfate substituents present on the side chain for effective inhibition. The attempted synthesis of the exact analogue of salacinol by opening of cyclic phosphates is also described.
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synthesis of analogues of salacinol containing a carboxylate inner salt and their Inhibitory activities against human maltase glucoamylase
Carbohydrate Research, 2007Co-Authors: Wang Chen, David R Rose, Mario B PintoAbstract:Abstract The syntheses of analogues of the naturally occurring Glycosidase Inhibitor, salacinol, containing a carboxylate inner salt are described. Salacinol is a sulfonium ion with an internal sulfate counterion. The synthetic strategy relies on the nucleophilic attack of 1,4-anhydro-2,3,5-tri- O -benzyl-4-thio- d - or l -arabinitol at the least hindered carbon of 4,5-anhydro-2,3- O -isopropylidene- d -ribonic acid benzyl ester to yield coupled adducts. Deprotection of the coupled products gives the target compounds. The compound derived from d -arabinitol inhibits recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with a K i value of 10 ± 1 μM.
B. Mario Pinto - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of 2-deoxy-2-fluoro and 1,2-ene derivatives of the naturally occurring Glycosidase Inhibitor, salacinol, and their Inhibitory activities against recombinant human maltase glucoamylase
Carbohydrate Research, 2008Co-Authors: Niloufar Choubdar, David R Rose, B. Mario PintoAbstract:Abstract 2-Deoxy-2-fluorosalacinol and a 1,2-ene derivative of the naturally occurring Glycosidase Inhibitor salacinol were synthesized for structure activity studies with human maltase glucoamylase (MGA). 2-Deoxy-2-fluorosalacinol was synthesized through the coupling reaction of 2-deoxy-2-fluoro-3,5-di- O - p -methoxybenzyl-1,4-anhydro-4-thio- d -arabinitol with 2,4- O -benzylidene- l -erythritol-1,3-cyclic sulfate in hexafluoroisopropanol (HFIP) containing 0.3 equiv of K 2 CO 3 . Excess of K 2 CO 3 resulted in the elimination of HF from the coupled product, and the formation of an alkene derivative of salacinol. Nucleophilic attack of the 1,4-anhydro-4-thio- d -arabinitol moiety on the cyclic sulfate did not proceed in the absence of K 2 CO 3 . No reaction was observed in acetonitrile containing K 2 CO 3 . The target compounds were obtained by deprotection with TFA. The 2-deoxy-1-ene derivative of salacinol and 2-deoxy-2-fluorosalacinol inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose, with an IC 50 value of 150 μM and a K i value of 6 ± 1 μM, respectively.
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Synthesis of thioswainsonine as a potential Glycosidase Inhibitor
Carbohydrate Research, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:Abstract The synthesis of a bicyclic sulfonium-ion analogue of a naturally occurring Glycosidase Inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multi-step synthesis starting from 1,4-anhydro-2,3-di- O -benzyl-4-thio- d -lyxitol. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt will serve as a candidate to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor.
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Synthesis of a sulfonium ion analogue of the Glycosidase Inhibitor swainsonine.
The Journal of organic chemistry, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-thiolane. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt provides a candidate with which to further probe the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor.
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Synthesis and conformational analysis of bicyclic sulfonium salts. Structures related to the Glycosidase Inhibitor australine.
The Journal of Organic Chemistry, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, are described. The synthetic strategy relies on the intramolecular attack of a cyclic thioether across a terminal double bond in the presence of a suitable electrophile. We postulate that these compounds, having a permanent positive charge on the sulfur atom, will mimic the highly unstable oxacarbenium ion transition state in a Glycosidase-catalyzed hydrolysis reaction. The conformational preferences of these compounds, based on analysis of 1H−1H vicinal coupling constants and 1D-NOESY data, are attributed to both steric and electrostatic interactions. These compounds will be used in the study of structure−activity relationships with Glycosidase enzymes.
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Synthesis of D-lyxitol and D-ribitol analogues of the naturally occurring Glycosidase Inhibitor salacinol.
Carbohydrate research, 2005Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:Abstract The synthesis of analogues of the naturally occurring Glycosidase Inhibitor, salacinol, in which the d -arabinitol ring has been replaced by d -lyxitol or d -ribitol, is described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata , which are traditionally used in India and Sri Lanka for the treatment of Type II diabetes. The synthetic strategy relies on the nucleophilic attack of 1,4-anhydro-2,3,5-tri- O - p -methoxybenzyl-4-thio- d -lyxitol or 1,4-anhydro-2,3,5-tri- O - p -methoxybenzyl-4-thio- d -ribitol at the least hindered carbon of the benzylidene-protected l -cyclic sulfate derived from l -erythritol. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective Inhibitors of MGA and demonstrates the importance of the d -arabinitol configuration in the heterocyclic ring for effective inhibition.
David R Rose - One of the best experts on this subject based on the ideXlab platform.
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structural analysis of golgi alpha mannosidase ii Inhibitors identified from a focused Glycosidase Inhibitor screen
Biochemistry, 2008Co-Authors: Douglas A Kuntz, Stephen G Withers, Chris A. Tarling, David R RoseAbstract:The N-glycosylation pathway is a target for pharmaceutical intervention in a number of pathological conditions including cancer. Golgi α-mannosidase II (GMII) is the final glycoside hydrolase in the pathway and has been the target for a number of synthetic efforts aimed at providing more selective and effective Inhibitors. Drosophila GMII (dGMII) has been extensively studied due to the ease of obtaining high resolution structural data, allowing the observation of substrate distortion upon binding and after formation of a trapped covalent reaction intermediate. However, attempts to find new Inhibitor leads by high-throughput screening of large commercial libraries or through in silico docking were unsuccessful. In this paper we provide a kinetic and structural analysis of five Inhibitors derived from a small Glycosidase-focused library. Surprisingly, four of these were known Inhibitors of β-glucosidases. X-ray crystallographic analysis of the dGMII:Inhibitor complexes highlights the ability of the zinc-con...
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studies directed toward the stereochemical structure determination of the naturally occurring glucosidase Inhibitor kotalanol synthesis and Inhibitory activities against human maltase glucoamylase of seven carbon chain extended homologues of salacino
Journal of Organic Chemistry, 2008Co-Authors: Ravindranath Nasi, David R Rose, Brian O Patrick, Mario B PintoAbstract:The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio-d-arabinitol, analogues of the naturally occurring Glycosidase Inhibitor salacinol, are described. These compounds were designed on the basis of the structure activity data of chain-extended analogues of salacinol, with the intention of determining the hitherto unknown stereochemical structure of kotalanol, the naturally occurring seven-carbon chain-extended analogue of salacinol. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-thio-d-arabinitols at the least hindered carbon atom of two 1,3-cyclic sulfates differing in stereochemistry at only one stereogenic center. The desired cyclic sulfates were synthesized starting from d-glucose via Wittig olefination and Sharpless asymmetric dihydroxylation. Deprotection of the coupled products by using a two-step sequence afforded two sulfonium sulfates. Optical rotation data for one of our compounds indicated...
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Synthesis of 2-deoxy-2-fluoro and 1,2-ene derivatives of the naturally occurring Glycosidase Inhibitor, salacinol, and their Inhibitory activities against recombinant human maltase glucoamylase
Carbohydrate Research, 2008Co-Authors: Niloufar Choubdar, David R Rose, B. Mario PintoAbstract:Abstract 2-Deoxy-2-fluorosalacinol and a 1,2-ene derivative of the naturally occurring Glycosidase Inhibitor salacinol were synthesized for structure activity studies with human maltase glucoamylase (MGA). 2-Deoxy-2-fluorosalacinol was synthesized through the coupling reaction of 2-deoxy-2-fluoro-3,5-di- O - p -methoxybenzyl-1,4-anhydro-4-thio- d -arabinitol with 2,4- O -benzylidene- l -erythritol-1,3-cyclic sulfate in hexafluoroisopropanol (HFIP) containing 0.3 equiv of K 2 CO 3 . Excess of K 2 CO 3 resulted in the elimination of HF from the coupled product, and the formation of an alkene derivative of salacinol. Nucleophilic attack of the 1,4-anhydro-4-thio- d -arabinitol moiety on the cyclic sulfate did not proceed in the absence of K 2 CO 3 . No reaction was observed in acetonitrile containing K 2 CO 3 . The target compounds were obtained by deprotection with TFA. The 2-deoxy-1-ene derivative of salacinol and 2-deoxy-2-fluorosalacinol inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose, with an IC 50 value of 150 μM and a K i value of 6 ± 1 μM, respectively.
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binding of sulfonium ion analogues of di epi swainsonine and 8 epi lentiginosine to drosophila golgi alpha mannosidase ii the role of water in Inhibitor binding
Proteins, 2007Co-Authors: Nag S. Kumar, David R Rose, Mario B Pinto, Douglas A Kuntz, Xin WenAbstract:Retaining Glycosidases operate by a two-step catalytic mechanism in which the transition states are characterized by buildup of a partial positive charge at the anomeric center. Sulfonium-ion analogues of the naturally occurring Glycosidase Inhibitors, swainsonine and 8-epi-lentiginosine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, were synthesized in order to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor. Initial prediction based on computational docking indicated three plausible binding modes to Drosophila Golgi α-mannosidase II (dGMII), the most likely being close to that of swainsonine. Observation of the binding of di-epi-thioswainsonine and 8-epi-thiolentiginosine to dGMII from crystallographic data, however, revealed an orientation different from swainsonine in the active site. Screening these two compounds against dGMII shows that they are Inhibitors with IC50 values of 2.0 and 0.014 mM, respectively. This dramatic difference in affinity between the two compounds, which differ by only one hydroxyl group, is rationalized in terms of bound water molecules and the water molecule substructure in the active site, as identified by comparison of high resolution X-ray crystal structures of several dGMII-Inhibitor complexes. Proteins 2008. © 2007 Wiley-Liss, Inc.
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synthesis of analogues of salacinol containing a carboxylate inner salt and their Inhibitory activities against human maltase glucoamylase
Carbohydrate Research, 2007Co-Authors: Wang Chen, David R Rose, Mario B PintoAbstract:Abstract The syntheses of analogues of the naturally occurring Glycosidase Inhibitor, salacinol, containing a carboxylate inner salt are described. Salacinol is a sulfonium ion with an internal sulfate counterion. The synthetic strategy relies on the nucleophilic attack of 1,4-anhydro-2,3,5-tri- O -benzyl-4-thio- d - or l -arabinitol at the least hindered carbon of 4,5-anhydro-2,3- O -isopropylidene- d -ribonic acid benzyl ester to yield coupled adducts. Deprotection of the coupled products gives the target compounds. The compound derived from d -arabinitol inhibits recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with a K i value of 10 ± 1 μM.
Nag S. Kumar - One of the best experts on this subject based on the ideXlab platform.
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binding of sulfonium ion analogues of di epi swainsonine and 8 epi lentiginosine to drosophila golgi alpha mannosidase ii the role of water in Inhibitor binding
Proteins, 2007Co-Authors: Nag S. Kumar, David R Rose, Mario B Pinto, Douglas A Kuntz, Xin WenAbstract:Retaining Glycosidases operate by a two-step catalytic mechanism in which the transition states are characterized by buildup of a partial positive charge at the anomeric center. Sulfonium-ion analogues of the naturally occurring Glycosidase Inhibitors, swainsonine and 8-epi-lentiginosine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, were synthesized in order to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor. Initial prediction based on computational docking indicated three plausible binding modes to Drosophila Golgi α-mannosidase II (dGMII), the most likely being close to that of swainsonine. Observation of the binding of di-epi-thioswainsonine and 8-epi-thiolentiginosine to dGMII from crystallographic data, however, revealed an orientation different from swainsonine in the active site. Screening these two compounds against dGMII shows that they are Inhibitors with IC50 values of 2.0 and 0.014 mM, respectively. This dramatic difference in affinity between the two compounds, which differ by only one hydroxyl group, is rationalized in terms of bound water molecules and the water molecule substructure in the active site, as identified by comparison of high resolution X-ray crystal structures of several dGMII-Inhibitor complexes. Proteins 2008. © 2007 Wiley-Liss, Inc.
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synthesis of phosphate derivatives related to the Glycosidase Inhibitor salacinol
Carbohydrate Research, 2007Co-Authors: Ramakrishna G Bhat, Nag S. Kumar, Mario B PintoAbstract:Abstract The syntheses of polyhydroxylated imino- and anhydro thio-alditol compounds related to the naturally occurring Glycosidase Inhibitor, salacinol, containing a phosphate group in the side chain are described. The compounds lack hydroxyl groups on the acyclic side chain and are prototypes of the exact salacinol analogue. The synthetic strategy relies on the Mitsunobu reaction of N- and S-hydroxyalkyl derivatives of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino- d -arabinitol and 1,4-anhydro-2,3,5-tri-O-benzyl-1-thio- d -arabinitol with dibenzyl phosphate to yield the corresponding protected heteroalditol phosphates. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective Inhibitors of MGA and demonstrates the importance of the hydroxyl and/or sulfate substituents present on the side chain for effective inhibition. The attempted synthesis of the exact analogue of salacinol by opening of cyclic phosphates is also described.
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Synthesis of thioswainsonine as a potential Glycosidase Inhibitor
Carbohydrate Research, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:Abstract The synthesis of a bicyclic sulfonium-ion analogue of a naturally occurring Glycosidase Inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multi-step synthesis starting from 1,4-anhydro-2,3-di- O -benzyl-4-thio- d -lyxitol. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt will serve as a candidate to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor.
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Synthesis of a sulfonium ion analogue of the Glycosidase Inhibitor swainsonine.
The Journal of organic chemistry, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-thiolane. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt provides a candidate with which to further probe the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective Glycosidase Inhibitor.
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Synthesis and conformational analysis of bicyclic sulfonium salts. Structures related to the Glycosidase Inhibitor australine.
The Journal of Organic Chemistry, 2006Co-Authors: Nag S. Kumar, B. Mario PintoAbstract:The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, are described. The synthetic strategy relies on the intramolecular attack of a cyclic thioether across a terminal double bond in the presence of a suitable electrophile. We postulate that these compounds, having a permanent positive charge on the sulfur atom, will mimic the highly unstable oxacarbenium ion transition state in a Glycosidase-catalyzed hydrolysis reaction. The conformational preferences of these compounds, based on analysis of 1H−1H vicinal coupling constants and 1D-NOESY data, are attributed to both steric and electrostatic interactions. These compounds will be used in the study of structure−activity relationships with Glycosidase enzymes.
Blair D Johnston - One of the best experts on this subject based on the ideXlab platform.
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improved syntheses of the naturally occurring Glycosidase Inhibitor salacinol
Synlett, 2003Co-Authors: Ahmad Ghavami, Kashinath Sadalapure, Blair D Johnston, Mercedes Lobera, Barry B Snider, Mario B PintoAbstract:Improved syntheses of the naturally occurring sulfonium ion, salacinol are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of Type 2 Diabetes. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl- or 2,3,5-tri-O-p-methoxybenzyl- 1 ,4-anhydro-4-thio-D-arabinitol at the least hindered carbon of benzylidene-protected L-erythritol-1,3-cyclic sulfate in 1,1,1,3,3,3-hexafluoro-2-propanol as solvent. The reactions are compared to those with the benzyl-protected L-erythritol-1.3-cyclic sulfate and also to those in acetone and 2-propanol. Excellent yields are obtained for the reactions with the benzylidene-protected cyclic sulfate. The synthetic route employing p-methoxybenzyl ether protecting groups is advantageous since all protecting groups in the adduct may be removed with trifluoroacetic acid to yield salacinol, thereby obviating the problematic deprotection of benzyl ethers by hydrogenolysis.
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synthesis of 1 4 anhydro d xylitol heteroanalogues of the naturally occurring Glycosidase Inhibitor salacinol and their evaluation as Glycosidase Inhibitors
Canadian Journal of Chemistry, 2002Co-Authors: Ahmad Ghavami, Morten T Jensen, Birte Svensson, Blair D Johnston, Matthew D Maddess, Sarah M Chinapoo, Mario B PintoAbstract:The syntheses of two 1,4-anhydro-D-xylitol heteroanalogues (8 and 9) of the naturally occurring sulfonium ion, salacinol (3), containing a sulfur or nitrogen atom in the ring are described. Salacin...
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synthesis of selenium analogues of the naturally occurring Glycosidase Inhibitor salacinol and their evaluation as Glycosidase Inhibitors
Journal of the American Chemical Society, 2002Co-Authors: Blair D Johnston, Morten T Jensen, Birte Svensson, Ahmad Ghavami, Mario B PintoAbstract:The syntheses of two selenium analogues (10 and 11) of the naturally occurring sulfonium ion, salacinol (3), are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 2,3,5-tri-O-benzyl-1,4-anhydro-4-seleno-D-arabinitol at the least hindered carbon of benzyl- or benzylidene-protected D- or L-erythritol-1,3-cyclic sulfate. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as a solvent in the coupling reaction proves to be beneficial. Enzyme inhibition assays indicate that 10 is a better Inhibitor (K(i) = 0.72 mM) of glucoamylase than 3, which has a K(i) value of 1.7 mM. In contrast, 11 showed no significant inhibition of glucoamylase. Compounds 10 and 11 showed no significant inhibition of barley-alpha-amylase or porcine pancreatic-alpha-amylase.
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a new class of Glycosidase Inhibitor synthesis of salacinol and its stereoisomers
Journal of Organic Chemistry, 2001Co-Authors: Ahmad Ghavami, Blair D Johnston, B M PintoAbstract:Salacinol (4) is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The syntheses of salacinol (4), the enantiomer of salacinol (5), and a diastereomer (7) are described. The synthetic strategy relies on the selective nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-D- or L-arabinitol at C-1 of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The work serves to resolve the ambiguity about the exact structure of salacinol and establishes conclusively the structure of the natural product.
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synthesis and conformational analysis of a sulfonium ion analogue of the Glycosidase Inhibitor castanospermine
Journal of the American Chemical Society, 2000Co-Authors: Lars Svansson, Blair D Johnston, And Brian O Patrick, Mario B PintoAbstract:The synthesis of a bridgehead sulfonium salt analogue (7) of the indolizidine alkaloid castanospermine has been achieved by a multistep procedure starting from 5-thio-d-glucopyranose pentaacetate. The compound was intended to test the theory that Glycosidase Inhibitory activity of the indolizidine alkaloids might be due to electrostatic stabilization of a positively charged species in the enzyme active site and that a sulfonium salt carrying a permanent positive charge might be advantageous. The structure of the bicylic sulfonium salt (7) [3(R),4(S),5(R),6(S)-3,4,5-trihydroxy-cis-1-thioniabicyclo[4.3.0]nonane perchlorate] was confirmed by X-ray crystallography. Analysis of the 1H NMR spectrum of compound 7 indicated that a similar conformation was adopted in solution. This conformational preference, with hydroxyl groups in the more sterically hindered axial orientations, has been attributed to the dominance of stabilizing electrostatic interactions between the oxygen atoms and the sulfonium center.