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Richard A Bartsch - One of the best experts on this subject based on the ideXlab platform.
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Calixarenes with Dansyl Groups as potential chemosensors
Inorganica Chimica Acta, 2012Co-Authors: Ümmühan Ocak, Miraç Ocak, Richard A BartschAbstract:Abstract This short review describes the use of Dansyl Groups attached to calixarene scaffolds for the spectrofluorimetric detection of ionic and neutral analytes by complexation. References from the last decade are discussed and data on complex formation and analytical merits, such as the detection limit and the effect of competing ions for cation determination, are presented. Effects of the calixarene conformation and substituents on the lower and/or upper rims on the mechanism for guest-induced changes in the Dansyl-Group fluorescence are discussed.
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Effect of Pendant Group Length Upon Metal Ion Complexation in Acetonitrile by Di-Ionized Calix[4]Arenes Bearing Two Dansyl Fluorophores
Journal of Fluorescence, 2009Co-Authors: Ümmühan Ocak, Miraç Ocak, Xin Shen, Kazimierz Surowiec, Richard A BartschAbstract:A series of three di-ionizable calix[4]arenes with two pendant Dansyl (1-dimethylaminonaphthalene-5-sulfonyl) Groups linked to the lower rims was synthesized. Structures of the three ligands were identical except for the length of the spacers which connected the two Dansyl Groups to the calix[4]arene scaffold. Following conversion of the ligands into their di-ionized di(tetramethylammonium) salts, absorption and emission spectrophotometry were utilized to probe the influence of metal cation (Li^+, Na^+, K^+, Rb^+, Cs^+, Mg^2+, Ca^2+, Sr^2+, Ba^2+, Ag^+, Cd^2+, Co^2+, Fe^2+, Hg^2+, Mn^2+, Pb^2+, Zn^2+ and Fe^3+) complexation in acetonitrile. Upon complexation with these metal cations, emission spectra underwent marked red shifts and quenching of the Dansyl Group fluorescence for the di-ionized ligand with the shortest spacer. A similar effect was noted for the di-ionized ligand with an intermediate spacer for all of the metal ions, except Ba^2+. For the di-ionized ligand with the longest spacer, the metal cations showed different effects on the emission spectrum. Li^+, Mg^2+, Ca^2+ and Ba^2+ caused enhancement of emission intensity with a red shift. Other metal cations produce quenching with red shifts in the emission spectra. Transition metal cations interacted strongly with all three di-ionized ligands. In particular, Fe^3+ and Hg^2+ caused greater than 99% quenching of the Dansyl fluorescence in the di-ionized ligands.
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optical determination of thallium i and cesium i with a fluorogenic calix 4 arenebis crown 6 ether containing one pendent Dansyl Group
Analytical Chemistry, 2007Co-Authors: Ebony D Roper, Vladimir S Talanov, Maryna G Gorbunova, Richard A Bartsch, Galina G TalanovaAbstract:A fluorogenic derivative of 1,3-alternate calix[4]arenebis(crown-6) (1) containing a Dansyl Group in the proton-ionizable side arm has been employed in selective sensing of Tl+ and Cs+ at low concentration levels in MeCN−H2O (1:1) mixed solvent. Optical recognition of these two metal cations by 1 occurs in contrasting modes. On the basis of the results of fluorescence, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 1H NMR studies, Tl+ and Cs+ react with 1 via formation of 1:1 complexes that differ in coordination arrangement around the metal ion.
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Novel fluorogenic calix[4]arene-bis(crown-6-ether) for selective recognition of thallium(I)
Chemical Communications, 2005Co-Authors: Galina G Talanova, Ebony D Roper, Maryna G Gorbunova, Richard A Bartsch, Nicole M. Buie, Vladimir S TalanovAbstract:A new fluorogenic, Dansyl Group-containing derivative of 1,3-alternate calix[4]arene-bis(crown-6-ether) provides optical recognition of Tl+ with selectivity over many other metal cations, including Na+, K+, Ca2+, Ag+, Hg2+ and Pb2+, and embodies the first example of a calixarene-based fluorescent Tl+-chemosensor.
Kazuyuki Horie - One of the best experts on this subject based on the ideXlab platform.
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Fluorescence study on the conformational change of an amino Group-containing polymer chain grafted onto a polyethylene microfiltration membrane
Macromolecules, 1998Co-Authors: Satoshi Tsuneda, Kazuyuki Horie, Toshihiro Endo, Kyoichi Saito, Kazuyuki Sugita, Takashi Yamashita, Takanobu SugoAbstract:The fluorescence probe technique was used to investigate the characteristics of an amino Group-containing polymer chain grafted onto a polyethylene microfiltration (MF) membrane. The amino Group-containing polymer chain labeled with a Dansyl Group that served as a fluorescence probe was grafted onto a polyethylene MF membrane by radiation-induced graft polymerization. The conformational changes of the grafted polymer chain (graft chain) in various solvents were monitored by considering that the steady-state fluorescence emission spectrum of the Dansyl Group was affected by the polarity of the solvent, the polyethylene, and the graft chain itself. The shift of the emission peak wavelength of graft chains with different lengths demonstrated that the graft chain containing amino Groups stretched in water and methanol and shrank in dimethylformamide, acetone, and benzene. These results corresponded to changes in solvent permeability through the membrane pore to which the amino Group-containing polymer chains were grafted.
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fluorescence studies of the volume phase transition in methanol water mixed solvent of poly n isopropylacrylamide gels labeled with Dansyl Group
Polymer Gels and Networks, 1995Co-Authors: Makoto Asano, Kazuyuki Horie, Takashi YamashitaAbstract:Abstract The volume phase transition of poly(N-isopropylacrylamide) gels was studied by fluorescence techniques by using gels labeled with a side chain Dansyl fluorescent Group. The gels undergo re-entrant volume phase transition in a mixed solvent of methanol/water at 20 °C. The existence of two transition points in the PNIPA gels has been observed. From the measurement of steady-state fluorescence spectra, fluorescence lifetimes, and fluorescence anisotropy ratios, the changes in the microenvironment around the Dansyl probe and the changes in the rotational diffusion motion of the Dansyl probe accompanying the phase transition were characterized. The fluorescence peak shifts to a shorter wavelength and the lifetimes increase, when the gel undergoes a change from the swollen to the collapsed state. The rotational diffusion coefficients of the probe were calculated from the values of the lifetime and the anisotropy. They decrease as the gels shrink and increase as the gels swell.
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change in mobility of side chains due to neutralization of charged poly l lysine with Dansyl Group
Biopolymers, 1994Co-Authors: Toshinori Torii, Takashi Yamashita, Kazuyuki HorieAbstract:Poly(L-lysine) having Dansyl (5-dimethylamino-1-naphthalene-sulfonyl) Groups to its side chains was prepared. The fluorescence spectra and fluorescence anisotropy ratios of the Dansyl (DNS) Group were measured in various conditions. In aqueous solution the increase in emission intensity was observed reflecting the alkali-induced coil-to-helix transition. In aqueous-methanolic solutions with methanol content above 60 wt %, the poly(L-lysine) with DNS Group (DNS-PLL) was probed to show α-helical conformation from CD spectra. With addition of alkali, the increase in fluorescence intensity of α-helical DNS-PLL and the drastic change in fluorescence anisotropy ratio were observed. In this case the rotational mobility of DNS probe decreases, gives a minimum at a certain concentration of added alkali, and then increases again up to approximately the initial level. At the concentration where the rotational mobility gives the minimum, intensity of scattered light gives a maximum. This shows that suppression of the mobility of DNS side chains is caused by the intermolecular aggregation of α-helical DNS-PLL. This concentration of added alkali corresponds to the midpoint of neutralization to charged side chains of the DNS-PLL. The interaction that causes aggregate of α-helical DNS-PLL is suggested to be the intermolecular hydrogen bonding between neutralized and unneutralized side chains. © 1994 John Wiley & Sons, Inc.
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fluorescence studies of the volume phase transition and dynamic fluctuation in polyacrylamide gels with a Dansyl Group induced by the composition change in an acetone water mixed solvent
Macromolecules, 1992Co-Authors: Yuxin Hu, Kazuyuki Horie, Hideharu Ushiki, Fumiaki Tsunomori, Takashi YamashitaAbstract:Fluorescence studies have been made on the ionic poly(acrylamide) gels and linear poly(acrylamide) having a side-chain Dansyl fluorescent probe. The gels undergo a discontinuous first-order volume phase transition at 60% acetone volume content in the mixed solvent of acetone/water at 20°C. According to fluorescence data, the phase transition from the swollen to collapsed state is accompanied by the change in hydrophobic interaction of the main chains of the gel. The rotational diffusion coefficient becomes infinite and shows a sharp peak at the phase transition point due to the dynamic fluctuation of the network of the gel
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fluorescence studies of the volume phase transition of poly acrylamide gels with a Dansyl Group
Macromolecules, 1992Co-Authors: Yuxin Hu, Kazuyuki Horie, Hideharu UshikiAbstract:The changes in microenvironments during a pH-induced volume transition of poly(acrylamide) (PAAm) gels with a Dansyl Group as a fluorescent probe in an acetone/water (9/11) mixed solvent have been studied. Irrespective of the presence or absence of fluorescence probe Groups labeled on the network of PAAm gels, the gels are in the collapsed state at pH=1.0-5.0. They show a discontinuous volume phase transition (DVPT) at pH=5.1 and remain swollen up to pH=9.6. The fluorescence anisotropy ratio also changes at pH= 5.1 for the Dansyl Group, but the peak shift of the fluorescence spectra of the Dansyl Group takes place at pH= 3.8, i.e. before the DVPT
Rosangela Marchelli - One of the best experts on this subject based on the ideXlab platform.
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Enantioselective Fluorescence Sensing of Amino Acids by Modified Cyclodextrins: Role of the Cavity and Sensing Mechanism
Chemistry: A European Journal, 2004Co-Authors: Sara Pagliari, Roberto Corradini, Arnaldo Dossena, Gianni Galaverna, Stefano Sforza, Marco Montalti, Luca Prodi, Nelsi Zaccheroni, Rosangela MarchelliAbstract:Two selectors based on modified cyclodextrins containing a metal binding site and a Dansyl fluorophore-4-deoxy-6-N-(N α -[(5-dimethyl-amino-1-naphthalenesulfonyl)amino-ethyl]phenylalanylamino-β-cyclodextrin-containing D-Phe (3) and L-Phe (4) moieties were synthesized. The conformations of the two selectors were studied by circular dichroism, two-dimensional NMR spectroscopy and time-resolved fluorescence spectroscopy. Cyclodextrin 4 was found to have a predominant conformation in which the Dansyl Group is self-included in the cyclodextrin cavity, while 3 showed a larger proportion of the conformation with the Dansyl Group outside the cavity. As a consequence, the two cyclodextrins were found to bind copper(II) with different affinities, as revealed by fluorescence quenching in competitive binding measurements. Addition of D- or L-amino acids induced increases in fluorescence intensity, which were dependent on the amino acid used and in some cases on its absolute configuration. The cyclodextrin 4 was found to be more enantioselective than 3, suggesting that the self-inclusion in the cyclodextrin cavity strongly increases the chiral discrimination ability of the copper(II) complex. Accordingly, a linear fluorescent ligand N α -[(5-dimethylamino-1-naphthalene-sulfonyl)aminoethyl]-N 1 -propyl-phenyl-alaninamide, which has the same binding site and absolute configuration as 4, showed very low chiral discrimination ability. The enantioselectivity in fluorescence response was found to be due to the formation of diastereomeric ternary complexes, which were detected by ESI-MS and by circular dichroism. Time-resolved fluorescence studies showed that the fluorescence of the Dansyl Group was completely quenched in the ternary complexes formed, and that the residual fluorescence was due to uncomplexed ligand.
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Fluorescent Chemosensor for Organic Guests and Copper(II) Ion Based on Dansyldiethylenetriamine-Modified β-Cyclodextrin
Journal of Organic Chemistry, 1997Co-Authors: Roberto Corradini, Arnaldo Dossena, Rosangela Marchelli, Gianni Galaverna, And Anna Panagia, Giorgio SartorAbstract:A modified cyclodextrin containing a Dansyldiethylenetriamine metal-binding Group (6-deoxy-6-N-(N‘‘-Dansyldiethylenetriamino)-β-cyclodextrin, CD-dien-DNS) was synthesized. The conformation of CD-dien-DNS was studied by 2D NMR (ROESY spectra) in D2O, by circular dichroism, and by fluorescence. The results were compared with those previously obtained with the analogous 6-deoxy-6-N-(N‘-Dansylethylenediamino)-β-cyclodextrin (CD-en-DNS) and were consistent with the self-inclusion of the Dansyl Group within the macrocycle cavity. However, the orientation of the Dansyl Group for CD-dien-DNS was found to be equatorial, whereas for CD-en-DNS it was axial, suggesting a dependence of the orientation of the Dansyl Group upon the length of the linker. In the presence of lipophilic organic molecules, CD-dien-DNS showed sensing properties similar to those observed for CD-en-DNS, suggesting a similar “in-out” movement of the Dansyl Group, due to competitive inclusion of the guest. Unlike CD-en-DNS, CD-dien-DNS was found ...
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a modified cyclodextrin with a fully encapsulated Dansyl Group self inclusion in the solid state and in solution
Chemistry: A European Journal, 1996Co-Authors: Roberto Corradini, Arnaldo Dossena, Rosangela Marchelli, Anna Panagia, Giorgio Sartor, Michele Saviano, Angela Lombardi, Vincenzo PavoneAbstract:A monofunctionalized β-cyclodextrin containing a Dansyl moiety, 6- deoxy- 6 - N - ( N′- (5- dimethylamino - 1 - naphthalenesulfonyl)diaminoethane) - β-cyclodextrin (CD-en-DNS, 2), was synthesized and its crystal structure determined. It was shown that the Dansyl Group is fully encapsulated within the cyclodextrin cavity, with the dimethylamino and sulfonyl Groups emerging from opposite sides. The shape of the cavity is considerably flattened, since O(4)–O(4) distances parallel to the naphtalene ring were found to be longer than the others. The conformation of the diaminoethane linker was found to be determined by the inclusion of the Dansyl Group and by a hydrogen bond between the sulfonamide NH and one of the O(6)–H Groups on the cyclodextrin rim. The self-inclusion features of the aromatic moiety were found to be consistent with the solution data: 1H NMR ROESY spectra suggested that the orientation of the Dansyl moiety observed in the solid state was retained in aqueous solution; the circular dichroism spectrum was consistent with an axial complexation model. Fluorescence spectra showed that the inclusion of the Dansyl Group in the cyclodextrin cavity considerably increases the quantum yield: time-resolved fluorescence experiments showed the presence of a long-lifetime component (16.1 ns), which was attributed to the included fluorophore. The ability of 2 to act as a fluorescence sensor was evaluated by the addition of several guests of different shape: fluorescence intensity was lowered, especially upon addition of adamantanecarboxylic acid. All the data obtained were consistent with the model of the in-out movement of the Dansyl Group from the self-included conformation observed in the solid state to a position more exposed to the bulk solvent. Copper(II) was shown to enhance the difference in the fluorescence of 2 in the presence of guests by additional static quenching.
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A Modified Cyclodextrin with a Fully Encapsulated Dansyl Group: Self‐Inclusion in the Solid State and in Solution
Chemistry: A European Journal, 1996Co-Authors: Roberto Corradini, Arnaldo Dossena, Rosangela Marchelli, Anna Panagia, Giorgio Sartor, Michele Saviano, Angela Lombardi, Vincenzo PavoneAbstract:A monofunctionalized β-cyclodextrin containing a Dansyl moiety, 6- deoxy- 6 - N - ( N′- (5- dimethylamino - 1 - naphthalenesulfonyl)diaminoethane) - β-cyclodextrin (CD-en-DNS, 2), was synthesized and its crystal structure determined. It was shown that the Dansyl Group is fully encapsulated within the cyclodextrin cavity, with the dimethylamino and sulfonyl Groups emerging from opposite sides. The shape of the cavity is considerably flattened, since O(4)–O(4) distances parallel to the naphtalene ring were found to be longer than the others. The conformation of the diaminoethane linker was found to be determined by the inclusion of the Dansyl Group and by a hydrogen bond between the sulfonamide NH and one of the O(6)–H Groups on the cyclodextrin rim. The self-inclusion features of the aromatic moiety were found to be consistent with the solution data: 1H NMR ROESY spectra suggested that the orientation of the Dansyl moiety observed in the solid state was retained in aqueous solution; the circular dichroism spectrum was consistent with an axial complexation model. Fluorescence spectra showed that the inclusion of the Dansyl Group in the cyclodextrin cavity considerably increases the quantum yield: time-resolved fluorescence experiments showed the presence of a long-lifetime component (16.1 ns), which was attributed to the included fluorophore. The ability of 2 to act as a fluorescence sensor was evaluated by the addition of several guests of different shape: fluorescence intensity was lowered, especially upon addition of adamantanecarboxylic acid. All the data obtained were consistent with the model of the in-out movement of the Dansyl Group from the self-included conformation observed in the solid state to a position more exposed to the bulk solvent. Copper(II) was shown to enhance the difference in the fluorescence of 2 in the presence of guests by additional static quenching.
Eduard Paschke - One of the best experts on this subject based on the ideXlab platform.
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fluorous iminoalditols act as effective pharmacological chaperones against gene products from glb1 alleles causing gm1 gangliosidosis and morquio b disease
Journal of Inherited Metabolic Disease, 2012Co-Authors: Katrin Fantur, Tanja M Wrodnigg, Arnold E Stutz, Bettina M Pabst, Eduard PaschkeAbstract:Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N2-(Dansyl)-N6-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a Dansyl Group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)2OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-d-galactitol) and (TFM)3OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-d-galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5–10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.
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Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1-gangliosidosis and Morquio B disease
Journal of Inherited Metabolic Disease, 2012Co-Authors: Katrin Fantur, Tanja M Wrodnigg, Arnold E Stutz, Bettina M Pabst, Eduard PaschkeAbstract:Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N^2-(Dansyl)-N^6-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a Dansyl Group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)_2OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino- d -galactitol) and (TFM)_3OHex-DGJ ( N -(Nonafluoro- tert -butyloxy)hexyl-1,5-dideoxy-1,5-imino- d -galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5–10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.
Katrin Fantur - One of the best experts on this subject based on the ideXlab platform.
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fluorous iminoalditols act as effective pharmacological chaperones against gene products from glb1 alleles causing gm1 gangliosidosis and morquio b disease
Journal of Inherited Metabolic Disease, 2012Co-Authors: Katrin Fantur, Tanja M Wrodnigg, Arnold E Stutz, Bettina M Pabst, Eduard PaschkeAbstract:Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N2-(Dansyl)-N6-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a Dansyl Group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)2OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-d-galactitol) and (TFM)3OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-d-galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5–10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.
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Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1-gangliosidosis and Morquio B disease
Journal of Inherited Metabolic Disease, 2012Co-Authors: Katrin Fantur, Tanja M Wrodnigg, Arnold E Stutz, Bettina M Pabst, Eduard PaschkeAbstract:Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N^2-(Dansyl)-N^6-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a Dansyl Group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)_2OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino- d -galactitol) and (TFM)_3OHex-DGJ ( N -(Nonafluoro- tert -butyloxy)hexyl-1,5-dideoxy-1,5-imino- d -galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5–10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.
