Aleš Marek | Academy of Sciences of the Czech Republic (original) (raw)
Papers by Aleš Marek
Journal of Labelled Compounds and Radiopharmaceuticals
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Journal of Labelled Compounds and Radiopharmaceuticals, 2021
The multi-functional radioligand [3 H]T0901317 ([3 H]1) has been employed as a powerful autoradio... more The multi-functional radioligand [3 H]T0901317 ([3 H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X and retinoic acid-related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [3 H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo-intermediate potentially preclude its widespread use in biochemical, pharmacological and pathological studies in research lab settings. We exploit recent reports on hydrogen-isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho-directing group that facilitates C-H activation in the presence of homogenous iridium(I) catalysts. Herein, we report a time- and cost-efficient method for the tritium late-stage labeling of compound 1 - a remarkably electron-poor substrate owing to the tertiary trifluoroethylsulfonamide moiety. Under a straightforward HIE condition using a commercially available Kerr-type NHC Ir(I) complex, [(cod)Ir (NHC)Cl], the reaction with 1 afforded a specific activity of 10.8 Ci/mmol. Additionally, alternative HIE conditions using the heterogeneous catalyst of Ir-black provided sufficient 0.72 D-enrichment of 1, but unexpectedly failed while repeating with tritium gas.
Journal of the American Society for Mass Spectrometry, 2021
We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fi... more We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fixed-charge 6-(trimethylammonium)hexane-1-aminocarbonyl group. The radical generation relied on electron transfer from fluoranthene anion to noncovalent dibenzocrown-ether dication complexes which formed nucleoside cation radicals upon one-electron reduction and crown-ether ligand loss. The cation radicals were characterized by collision-induced dissociation (CID), photodissociation (UVPD), and UV-vis action spectroscopy. Identification of charge-tagged guanosine radicals was challenging because of spontaneous dissociations by loss of a hydrogen atom and guanine that occurred upon storing the ions in the ion trap without further excitation. The loss of H proceeded from an exchangeable position on N-7 in guanine that was established by deuterium labeling and was the lowest energy dissociation of the guanosine radicals according to transition-state energy calculations. Rate constant measurements revealed an inverse isotope effect on the loss of either hydrogen or deuterium with rate constants kH = 0.25-0.26 s-1 and kD = 0.39-0.54 s-1. We used time-dependent density functional theory calculations, including thermal vibronic effects, to predict the absorption spectra of several protomeric radical isomers. The calculated spectra of low-energy N-7-H guanine-radical tautomers closely matched the action spectra. Transition-state-theory calculations of the rate constants for the loss of H-7 and guanine agreed with the experimental rate constants for a narrow range of ion effective temperatures. Our calculations suggest that the observed inverse isotope effect does not arise from the isotope-dependent differences in the transition-state energies. Instead, it may be caused by the dynamics of post-transition-state complexes preceding the product separation.
Journal of Labelled Compounds and Radiopharmaceuticals, 2017
A regio-and enantio-specific synthesis of tritium-labeled 28-homocastasterone is reported. Approp... more A regio-and enantio-specific synthesis of tritium-labeled 28-homocastasterone is reported. Appropriate chlorocarbonate, efficiently synthesized from the starting 28-homocastasterone in an overall yield of 46%, undergoes catalytic tritium dechlorination by the T 2 /Pd[0]/Et 3 N system, providing 28-*3β-3 H]homocastasterone, in a good yield, radiochemical purity (>97%), and with a high specific activity (5.8 Ci/mmol).
Journal of Diabetes Research, 2016
Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD... more Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates ...
Journal of the American Society for Mass Spectrometry, Oct 11, 2016
Heptapeptide ions containing combinations of polar Lys, Arg, and Asp residues with non-polar Leu,... more Heptapeptide ions containing combinations of polar Lys, Arg, and Asp residues with non-polar Leu, Pro, Ala, and Gly residues were designed to study polar effects on gas-phase ion conformations. Doubly and triply charged ions were studied by ion mobility mass spectrometry and electron structure theory using correlated ab initio and density functional theory methods and found to exhibit tightly folded 3D structures in the gas phase. Manipulation of the basic residue positions in LKGPADR, LRGPADK, KLGPADR, and RLGPADK resulted in only minor changes in the ion collision cross sections in helium. Replacement of the Pro residue with Leu resulted in only marginally larger collision cross sections for the doubly and triply charged ions. Disruption of zwitterionic interactions in doubly charged ions was performed by converting the C-terminal and Asp carboxyl groups to methyl esters. This resulted in very minor changes in the collision cross sections of doubly charged ions and even slightly d...
Tetrahedron, 2015
A new catalytic enantiospecific approach to the synthesis of epibrassinosteroids (and other polyh... more A new catalytic enantiospecific approach to the synthesis of epibrassinosteroids (and other polyhydroxylated steroids) regiospecifically labeled by heavy isotopes of hydrogen is reported. Chlorocarbonate, efficiently synthesized from a-hydroxy ketone by a reaction with triphosgene, undergoes reductive tritium dechlorination catalyzed by the [Pd 0 ]/Et 3 N system, providing 24-[3b-3 H]epicastasterone and 24-[3b-3 H]epibrassinolide, respectively, in good yield and with high specific activity (5.8 Ci/ mmol; 20% tritium enrichment per molecule).
ChemInform, 2011
Conditions for the transformation of a 2,3-diol group of common brassinosteroids to a 2,3-bis(sil... more Conditions for the transformation of a 2,3-diol group of common brassinosteroids to a 2,3-bis(silyloxy) enol group, a suitable precursor for regio- and stereoselective labelling reactions, are established.
RSC Adv., 2015
A convenient method for the synthesis of tritium-labeled brassinosteroids with very high specific... more A convenient method for the synthesis of tritium-labeled brassinosteroids with very high specific activity is reported.
Journal of the American Society for Mass Spectrometry, Jan 23, 2015
Electron transfer dissociation of peptide ions with the diazirine-containing residue photomethion... more Electron transfer dissociation of peptide ions with the diazirine-containing residue photomethionine (M*) results in side-chain dissociations by loss of C3H7N2 radicals in addition to standard backbone cleavages. The side-chain dissociations are particularly prominent upon activation of long-lived, charge-reduced, cation radicals (GM*GGR + 2H)(+[Symbol: see text]). Investigation of these cation radicals by near-UV photodissociation and collisional activation revealed different fragmentation products and mechanisms resulting from these ion activation modes. The dissociations observed for photomethionine were dramatically different from those previously reported for the lower homologue photoleucine; here, a difference by a single methylene group in the side chain had a large effect on the chemistries of the cation radicals upon ETD and further activation. ETD intermediates and products were probed by tandem 355-nm UV photodissociation-collision induced dissociation and found to contai...
Journal of mass spectrometry : JMS, 2015
The combination of near-UV photodissociation with electron transfer and collisional activation pr... more The combination of near-UV photodissociation with electron transfer and collisional activation provides a new tool for structure investigation of isolated peptide ions and reactive intermediates. Two new types of pulse experiments are reported. In the first one called UV/Vis photodissociation-electron transfer dissociation (UVPD-ETD), diazirine-labeled peptide ions are shown to undergo photodissociation in the gas phase to form new covalent bonds, guided by the ion conformation, and the products are analyzed by electron transfer dissociation. In the second experiment, called ETD-UVPD wherein synthetic labels are not necessary, electron transfer forms new cation-peptide radical chromophores that absorb at 355 nm and undergo specific backbone photodissociation reactions. The new method is applied to distinguish isomeric ions produced by ETD of arginine containing peptides. Copyright © 2015 John Wiley & Sons, Ltd.
Tetrahedron, 2015
An alternative and robust method for the reduction of carbonyl groups by frustrated Lewis pairs (... more An alternative and robust method for the reduction of carbonyl groups by frustrated Lewis pairs (FLPs) is reported in this paper. With its very mild reaction conditions, good to excellent yields, absolute regioselectivity and the non-metallic character of the reagent, it provides an excellent tool for 1 H, 2 H as well as 3 H chemistry. It is a new strategy for the one-pot synthesis of aromatic alcohols selectively labeled with heavy isotopes of hydrogen.
![Research paper thumbnail of Electron Transfer Reduction of the Diazirine Ring in Gas-Phase Peptide Ions. On the Peculiar Loss of [NH4O] from Photoleucine](https://attachments.academia-assets.com/91253027/thumbnails/1.jpg)
](Journal of the American Society for Mass Spectrometry, Jan 17, 2014
Electron transfer to gas-phase peptide ions with diazirine-containing amino acid residue photoleu... more Electron transfer to gas-phase peptide ions with diazirine-containing amino acid residue photoleucine (L*) triggers diazirine ring reduction followed by cascades of residue-specific radical reactions. Upon electron transfer, substantial fractions of (GL*GGR +2H)(+[Symbol: see text]) cation-radicals undergo elimination of [NH4O] radicals and N2H2 molecules from the side chain. The side-chain dissociations are particularly prominent on collisional activation of long-lived (GL*GGR +2H)(+[Symbol: see text]) cation-radicals formed by electron transfer dissociation of noncovalent peptide-18-crown-6-ether ion complexes. The ion dissociation products were characterized by multistage tandem mass spectrometry (MS(n)) and ion mobility measurements. The elimination of [NH4O] was elucidated with the help of (2)H, (15) N, and (18)O-labeled peptide ions and found to specifically involve the amide oxygen of the N-terminal residue. The structures, energies, and electronic states of the peptide radic...
The Journal of Physical Chemistry A, 2014
Experimental data from ion mobility measurements and electron transfer dissociation were combined... more Experimental data from ion mobility measurements and electron transfer dissociation were combined with extensive computational analysis of ion structures and dissociation energetics for Gly-Leu-Gly-Gly-Lys cations and cation radicals. Experimental and computational collision cross sections of (GLGGK + 2H) 2+ ions pointed to a dominant folding motif that is represented in all low freeenergy structures. The local folding motifs were preserved in several fragment ions produced by electron transfer dissociation. Gradient optimizations of (GLGGK + 2H) +• cation-radicals revealed local energy minima corresponding to distonic zwitterionic structures as well as aminoketyl radicals. Both of these structural types can isomerize to low-energy tautomers that are protonated at the radical-containing amide group forming a new type of intermediates, −C • O − NH 2 + − and −C • (OH)-NH 2 + −, respectively. Extensive mapping with B3LYP, M06-2X, and MP2(frozen core) calculations of the potential energy surface of the ground doublet electronic state of (GLGGK + 2H) +• provided transition-state and dissociation energies for backbone cleavages of the N−C α and amide C− N bonds leading to ion−molecule complexes. The complexes can undergo facile prototropic migrations that are catalyzed by the Lys ammonium group and isomerize enolimine c-type fragments to the more stable amide tautomers. In contrast, interfragment hydrogen atom migrations in the complexes were found to have relatively high transition energies and did not compete with fragment separation. The extensive analysis of the intermediate and transition-state energies led to the conclusion that the observed dissociations cannot proceed competitively on the same potential energy surface. The reactive intermediates for the dissociations originate from distinct electronic states that are accessed by electron transfer.
Journal of The American Society for Mass Spectrometry, 2014
Journal of Medicinal Chemistry, 2013
3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB ... more 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [ 3 H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity and we demonstrate in vivo brain penetration. In vitro characterization of [ 3 H]-1 binding shows high specificity to the high-affinity GHB binding sites.
Journal of Heterocyclic Chemistry, 2013
ABSTRACT Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole to... more ABSTRACT Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole toward substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of substituted phenyl isocyanate, three N,O‐dicarboxamides were prepared (substituents are H, 4‐NO2, and 4‐CH3). Subsequently, N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was prepared and selective deprotection method was developed for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline using diethylamine in acetone. Six carbamates derived from this imidazoline were then prepared using 1.1 equiv of substituted phenyl isocyanates (substituents are H, 4‐CH3, 4‐OCH3, 4‐NO2, 4‐CN, and 3‐CF3). Finally, two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐1H‐imidazole (substituents are 4‐NO2 and 4‐CN). No reactivity to imidazole ring was observed in this case. Eight derivatives were subjected to antimycobacterial screening. Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and 2‐(2‐ hydroxyphenyl)‐1H‐imidazole toward aliphatic and aromatic isocyanates was studied. Eight ureas were prepared using equivalent mixture of 2‐(2‐aminophenyl)‐1H‐imidazole and isocyanate (Et, Pr, isoPr, terc‐Bu, Cy, Ph, 4‐CH3C6H4, 4‐CNC6H4). Similar attempts to obtain related carbamates from 2‐(2‐ hydroxyphenyl)‐1H‐imidazole lead only to three substituted phenyl carbamates (substituents are 4‐CH3, 4‐NO2, and 4‐CN). In both cases, no reactivity to imidazole ring was observed again.
This thesis is focused on synthesis and physico-chemical resp. biological properties of imidazole... more This thesis is focused on synthesis and physico-chemical resp. biological properties of imidazole derivatives. Optically active imidazole derivatives structurally similar to derivatives of BiPy were prepared by cross-coupling reaction. Bridged imidazoles, dicationic pincers, cyclophanes and ionic liquids were synthetized by using of N-alkylation of imidazole(s) nitrogen(s). Their coordination and catalytic properties have been studied too. All of these chiral alfa-amino acid derivatives were investigated for ability of cholinesterase inhibition, property of drugs for Alzheimer disease. Selected derivatives were tested for antibacterial and antifungal properties.
Journal of Labelled Compounds and Radiopharmaceuticals
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Journal of Labelled Compounds and Radiopharmaceuticals, 2021
The multi-functional radioligand [3 H]T0901317 ([3 H]1) has been employed as a powerful autoradio... more The multi-functional radioligand [3 H]T0901317 ([3 H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X and retinoic acid-related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [3 H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo-intermediate potentially preclude its widespread use in biochemical, pharmacological and pathological studies in research lab settings. We exploit recent reports on hydrogen-isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho-directing group that facilitates C-H activation in the presence of homogenous iridium(I) catalysts. Herein, we report a time- and cost-efficient method for the tritium late-stage labeling of compound 1 - a remarkably electron-poor substrate owing to the tertiary trifluoroethylsulfonamide moiety. Under a straightforward HIE condition using a commercially available Kerr-type NHC Ir(I) complex, [(cod)Ir (NHC)Cl], the reaction with 1 afforded a specific activity of 10.8 Ci/mmol. Additionally, alternative HIE conditions using the heterogeneous catalyst of Ir-black provided sufficient 0.72 D-enrichment of 1, but unexpectedly failed while repeating with tritium gas.
Journal of the American Society for Mass Spectrometry, 2021
We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fi... more We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fixed-charge 6-(trimethylammonium)hexane-1-aminocarbonyl group. The radical generation relied on electron transfer from fluoranthene anion to noncovalent dibenzocrown-ether dication complexes which formed nucleoside cation radicals upon one-electron reduction and crown-ether ligand loss. The cation radicals were characterized by collision-induced dissociation (CID), photodissociation (UVPD), and UV-vis action spectroscopy. Identification of charge-tagged guanosine radicals was challenging because of spontaneous dissociations by loss of a hydrogen atom and guanine that occurred upon storing the ions in the ion trap without further excitation. The loss of H proceeded from an exchangeable position on N-7 in guanine that was established by deuterium labeling and was the lowest energy dissociation of the guanosine radicals according to transition-state energy calculations. Rate constant measurements revealed an inverse isotope effect on the loss of either hydrogen or deuterium with rate constants kH = 0.25-0.26 s-1 and kD = 0.39-0.54 s-1. We used time-dependent density functional theory calculations, including thermal vibronic effects, to predict the absorption spectra of several protomeric radical isomers. The calculated spectra of low-energy N-7-H guanine-radical tautomers closely matched the action spectra. Transition-state-theory calculations of the rate constants for the loss of H-7 and guanine agreed with the experimental rate constants for a narrow range of ion effective temperatures. Our calculations suggest that the observed inverse isotope effect does not arise from the isotope-dependent differences in the transition-state energies. Instead, it may be caused by the dynamics of post-transition-state complexes preceding the product separation.
Journal of Labelled Compounds and Radiopharmaceuticals, 2017
A regio-and enantio-specific synthesis of tritium-labeled 28-homocastasterone is reported. Approp... more A regio-and enantio-specific synthesis of tritium-labeled 28-homocastasterone is reported. Appropriate chlorocarbonate, efficiently synthesized from the starting 28-homocastasterone in an overall yield of 46%, undergoes catalytic tritium dechlorination by the T 2 /Pd[0]/Et 3 N system, providing 28-*3β-3 H]homocastasterone, in a good yield, radiochemical purity (>97%), and with a high specific activity (5.8 Ci/mmol).
Journal of Diabetes Research, 2016
Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD... more Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates ...
Journal of the American Society for Mass Spectrometry, Oct 11, 2016
Heptapeptide ions containing combinations of polar Lys, Arg, and Asp residues with non-polar Leu,... more Heptapeptide ions containing combinations of polar Lys, Arg, and Asp residues with non-polar Leu, Pro, Ala, and Gly residues were designed to study polar effects on gas-phase ion conformations. Doubly and triply charged ions were studied by ion mobility mass spectrometry and electron structure theory using correlated ab initio and density functional theory methods and found to exhibit tightly folded 3D structures in the gas phase. Manipulation of the basic residue positions in LKGPADR, LRGPADK, KLGPADR, and RLGPADK resulted in only minor changes in the ion collision cross sections in helium. Replacement of the Pro residue with Leu resulted in only marginally larger collision cross sections for the doubly and triply charged ions. Disruption of zwitterionic interactions in doubly charged ions was performed by converting the C-terminal and Asp carboxyl groups to methyl esters. This resulted in very minor changes in the collision cross sections of doubly charged ions and even slightly d...
Tetrahedron, 2015
A new catalytic enantiospecific approach to the synthesis of epibrassinosteroids (and other polyh... more A new catalytic enantiospecific approach to the synthesis of epibrassinosteroids (and other polyhydroxylated steroids) regiospecifically labeled by heavy isotopes of hydrogen is reported. Chlorocarbonate, efficiently synthesized from a-hydroxy ketone by a reaction with triphosgene, undergoes reductive tritium dechlorination catalyzed by the [Pd 0 ]/Et 3 N system, providing 24-[3b-3 H]epicastasterone and 24-[3b-3 H]epibrassinolide, respectively, in good yield and with high specific activity (5.8 Ci/ mmol; 20% tritium enrichment per molecule).
ChemInform, 2011
Conditions for the transformation of a 2,3-diol group of common brassinosteroids to a 2,3-bis(sil... more Conditions for the transformation of a 2,3-diol group of common brassinosteroids to a 2,3-bis(silyloxy) enol group, a suitable precursor for regio- and stereoselective labelling reactions, are established.
RSC Adv., 2015
A convenient method for the synthesis of tritium-labeled brassinosteroids with very high specific... more A convenient method for the synthesis of tritium-labeled brassinosteroids with very high specific activity is reported.
Journal of the American Society for Mass Spectrometry, Jan 23, 2015
Electron transfer dissociation of peptide ions with the diazirine-containing residue photomethion... more Electron transfer dissociation of peptide ions with the diazirine-containing residue photomethionine (M*) results in side-chain dissociations by loss of C3H7N2 radicals in addition to standard backbone cleavages. The side-chain dissociations are particularly prominent upon activation of long-lived, charge-reduced, cation radicals (GM*GGR + 2H)(+[Symbol: see text]). Investigation of these cation radicals by near-UV photodissociation and collisional activation revealed different fragmentation products and mechanisms resulting from these ion activation modes. The dissociations observed for photomethionine were dramatically different from those previously reported for the lower homologue photoleucine; here, a difference by a single methylene group in the side chain had a large effect on the chemistries of the cation radicals upon ETD and further activation. ETD intermediates and products were probed by tandem 355-nm UV photodissociation-collision induced dissociation and found to contai...
Journal of mass spectrometry : JMS, 2015
The combination of near-UV photodissociation with electron transfer and collisional activation pr... more The combination of near-UV photodissociation with electron transfer and collisional activation provides a new tool for structure investigation of isolated peptide ions and reactive intermediates. Two new types of pulse experiments are reported. In the first one called UV/Vis photodissociation-electron transfer dissociation (UVPD-ETD), diazirine-labeled peptide ions are shown to undergo photodissociation in the gas phase to form new covalent bonds, guided by the ion conformation, and the products are analyzed by electron transfer dissociation. In the second experiment, called ETD-UVPD wherein synthetic labels are not necessary, electron transfer forms new cation-peptide radical chromophores that absorb at 355 nm and undergo specific backbone photodissociation reactions. The new method is applied to distinguish isomeric ions produced by ETD of arginine containing peptides. Copyright © 2015 John Wiley & Sons, Ltd.
Tetrahedron, 2015
An alternative and robust method for the reduction of carbonyl groups by frustrated Lewis pairs (... more An alternative and robust method for the reduction of carbonyl groups by frustrated Lewis pairs (FLPs) is reported in this paper. With its very mild reaction conditions, good to excellent yields, absolute regioselectivity and the non-metallic character of the reagent, it provides an excellent tool for 1 H, 2 H as well as 3 H chemistry. It is a new strategy for the one-pot synthesis of aromatic alcohols selectively labeled with heavy isotopes of hydrogen.
Journal of the American Society for Mass Spectrometry, Jan 17, 2014
Electron transfer to gas-phase peptide ions with diazirine-containing amino acid residue photoleu... more Electron transfer to gas-phase peptide ions with diazirine-containing amino acid residue photoleucine (L*) triggers diazirine ring reduction followed by cascades of residue-specific radical reactions. Upon electron transfer, substantial fractions of (GL*GGR +2H)(+[Symbol: see text]) cation-radicals undergo elimination of [NH4O] radicals and N2H2 molecules from the side chain. The side-chain dissociations are particularly prominent on collisional activation of long-lived (GL*GGR +2H)(+[Symbol: see text]) cation-radicals formed by electron transfer dissociation of noncovalent peptide-18-crown-6-ether ion complexes. The ion dissociation products were characterized by multistage tandem mass spectrometry (MS(n)) and ion mobility measurements. The elimination of [NH4O] was elucidated with the help of (2)H, (15) N, and (18)O-labeled peptide ions and found to specifically involve the amide oxygen of the N-terminal residue. The structures, energies, and electronic states of the peptide radic...
The Journal of Physical Chemistry A, 2014
Experimental data from ion mobility measurements and electron transfer dissociation were combined... more Experimental data from ion mobility measurements and electron transfer dissociation were combined with extensive computational analysis of ion structures and dissociation energetics for Gly-Leu-Gly-Gly-Lys cations and cation radicals. Experimental and computational collision cross sections of (GLGGK + 2H) 2+ ions pointed to a dominant folding motif that is represented in all low freeenergy structures. The local folding motifs were preserved in several fragment ions produced by electron transfer dissociation. Gradient optimizations of (GLGGK + 2H) +• cation-radicals revealed local energy minima corresponding to distonic zwitterionic structures as well as aminoketyl radicals. Both of these structural types can isomerize to low-energy tautomers that are protonated at the radical-containing amide group forming a new type of intermediates, −C • O − NH 2 + − and −C • (OH)-NH 2 + −, respectively. Extensive mapping with B3LYP, M06-2X, and MP2(frozen core) calculations of the potential energy surface of the ground doublet electronic state of (GLGGK + 2H) +• provided transition-state and dissociation energies for backbone cleavages of the N−C α and amide C− N bonds leading to ion−molecule complexes. The complexes can undergo facile prototropic migrations that are catalyzed by the Lys ammonium group and isomerize enolimine c-type fragments to the more stable amide tautomers. In contrast, interfragment hydrogen atom migrations in the complexes were found to have relatively high transition energies and did not compete with fragment separation. The extensive analysis of the intermediate and transition-state energies led to the conclusion that the observed dissociations cannot proceed competitively on the same potential energy surface. The reactive intermediates for the dissociations originate from distinct electronic states that are accessed by electron transfer.
Journal of The American Society for Mass Spectrometry, 2014
Journal of Medicinal Chemistry, 2013
3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB ... more 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [ 3 H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity and we demonstrate in vivo brain penetration. In vitro characterization of [ 3 H]-1 binding shows high specificity to the high-affinity GHB binding sites.
Journal of Heterocyclic Chemistry, 2013
ABSTRACT Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole to... more ABSTRACT Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole toward substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of substituted phenyl isocyanate, three N,O‐dicarboxamides were prepared (substituents are H, 4‐NO2, and 4‐CH3). Subsequently, N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was prepared and selective deprotection method was developed for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline using diethylamine in acetone. Six carbamates derived from this imidazoline were then prepared using 1.1 equiv of substituted phenyl isocyanates (substituents are H, 4‐CH3, 4‐OCH3, 4‐NO2, 4‐CN, and 3‐CF3). Finally, two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐1H‐imidazole (substituents are 4‐NO2 and 4‐CN). No reactivity to imidazole ring was observed in this case. Eight derivatives were subjected to antimycobacterial screening. Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and 2‐(2‐ hydroxyphenyl)‐1H‐imidazole toward aliphatic and aromatic isocyanates was studied. Eight ureas were prepared using equivalent mixture of 2‐(2‐aminophenyl)‐1H‐imidazole and isocyanate (Et, Pr, isoPr, terc‐Bu, Cy, Ph, 4‐CH3C6H4, 4‐CNC6H4). Similar attempts to obtain related carbamates from 2‐(2‐ hydroxyphenyl)‐1H‐imidazole lead only to three substituted phenyl carbamates (substituents are 4‐CH3, 4‐NO2, and 4‐CN). In both cases, no reactivity to imidazole ring was observed again.
This thesis is focused on synthesis and physico-chemical resp. biological properties of imidazole... more This thesis is focused on synthesis and physico-chemical resp. biological properties of imidazole derivatives. Optically active imidazole derivatives structurally similar to derivatives of BiPy were prepared by cross-coupling reaction. Bridged imidazoles, dicationic pincers, cyclophanes and ionic liquids were synthetized by using of N-alkylation of imidazole(s) nitrogen(s). Their coordination and catalytic properties have been studied too. All of these chiral alfa-amino acid derivatives were investigated for ability of cholinesterase inhibition, property of drugs for Alzheimer disease. Selected derivatives were tested for antibacterial and antifungal properties.