Comptes rendus des séances de la Société de biologie et de ses filiales
Until recently, nitric oxide (NO.) was considered as a toxic radical, but it appears now as an es... more Until recently, nitric oxide (NO.) was considered as a toxic radical, but it appears now as an essential messenger implicated in a wide range of biological processes, including immune system, cardiovascular system, and nervous system. An aspect of NO. metabolism in vivo is the formation of a variety of high and low molecular weight nitrosothiols. S-nitrosocysteine and S-nitrosoglutathione are among the biologically derived S-nitrosothiols that are postulated to be carriers of NO.. Although most of the S-nitrosothiols are unstable and spontaneously break down to produce NO. and a disulfide, some of them, including protein thiols, can show significant stability. These molecules are able to convey nitric oxide, that is, to keep, to carry, and then to generate NO. in physiological media, and might display pharmacological effects as potential vasodilators or neuroprotectors. Here, we present the development of new thionitrites R-S-NO having intrinsic antioxidant properties. We report the preparation, the characterization, and the stability studies in aqueous solutions of S-nitroso derivatives of dihydro-alpha-lipoic acid, known for its antioxidant properties.
The N-bromosuccinimide bromination of the zinc derivative of meso-tetramesitylporphyrin, Zn(TMP),... more The N-bromosuccinimide bromination of the zinc derivative of meso-tetramesitylporphyrin, Zn(TMP), in methanol at reflux in air, gives the corresponding (β-pyrrole)octabromo derivative, meso-tetramesityl-βoctabromoporphyrinatozinc, Zn(Br 8 TMP), in high yield ...
... preparation. Bismuth(III) salts as Lewis acids have been proved to efficiently catalyze a num... more ... preparation. Bismuth(III) salts as Lewis acids have been proved to efficiently catalyze a number of reactions like Michael reactions, 10 acylation reactions, 11 oxidation of α-ketols 12 or epoxides 13 and Diels–Alder reactions. 14 ...
A procedure for the introduction of two different alkyl chains (myristyl, oleyl and phytanyl) lea... more A procedure for the introduction of two different alkyl chains (myristyl, oleyl and phytanyl) leading to heterodialkyl‐H‐phosphonates is reported, based on two successive transesterification reactions of commercially available diphenyl‐H‐phosphonate with the corresponding alcohols.
Proteins: Structure, Function, and Bioinformatics, 2009
Superoxide dismutases (SODs) are a crucial class of enzymes in the combat against intracellular f... more Superoxide dismutases (SODs) are a crucial class of enzymes in the combat against intracellular free radical damage. They eliminate superoxide radicals by converting them into hydrogen peroxide and oxygen. In spite of their very different life cycles and infection strategies, the human parasites Plasmodium falciparum, Trypanosoma cruzi and Trypanosoma brucei are known to be sensitive to oxidative stress. Thus the parasite Fe-SODs have become attractive targets for novel drug development. Here we report the crystal structures of FeSODs from the trypanosomes T. brucei at 2.0 A and T. cruzi at 1.9 A resolution, and that from P. falciparum at a higher resolution (2.0 A) to that previously reported. The homodimeric enzymes are compared to the related human MnSOD with particular attention to structural aspects which are relevant for drug design. Although the structures possess a very similar overall fold, differences between the enzymes at the entrance to the channel which leads to the active site could be identified. These lead to a slightly broader and more positively charged cavity in the parasite enzymes. Furthermore, a statistical coupling analysis (SCA) for the whole Fe/MnSOD family reveals different patterns of residue coupling for Mn and Fe SODs, as well as for the dimeric and tetrameric states. In both cases, the statistically coupled residues lie adjacent to the conserved core surrounding the metal center and may be expected to be responsible for its fine tuning, leading to metal ion specificity.
Phosphorus, Sulfur, and Silicon and the Related Elements, 1997
... Thionitrites lb to 4b are generated in siru in the NMR tubes: to a solution of thiol (0.2 M) ... more ... Thionitrites lb to 4b are generated in siru in the NMR tubes: to a solution of thiol (0.2 M) in CDCI, (1 ml) are added 200 p1 of a solution of rerr-butyl nitrite in CDC13 (1.1 M ... The authors thank Marie-Thtr&e Boisdon for IR experiments and Emmanuel Margeat for EPR experiments. ...
The preparation and characterization of two vitamin E analogs-sydnonimine conjugates, delta-tocop... more The preparation and characterization of two vitamin E analogs-sydnonimine conjugates, delta-tocopheryloxycarbonyl-3-morpholinosydnonimine (2) and troloxoxycarbonyl-3-morpholinosydnonimine (3), in which the hydroxyl group of the tocopheryl moieties is linked via an enzymatically cleavable urethane group to the sydnone moiety is described. In the presence of porcine liver esterase, these tocopheryl-sydnonimine conjugates generated the expected antioxidant moieties, i.e., delta-tocopherol or Trolox, and were found to convert oxyhemoglobin to methemoglobin at 37 degrees C in 50 mM phosphate buffer at pH 7.4, thus providing evidence for nitric oxide release. Their potency as antioxidants was indirectly studied by associating the two products of the hydrolysis, SIN-1, and delta-tocopherol or Trolox. Our findings suggest that unlike the other members of the sydnonimine family these chromane-sydnonimine derivatives do not act as peroxynitrite donors, and require enzymatic bioactivation before nitric oxide or nitroxyl anion (NO(-)) can be released.
This paper describes an efficient synthetic route to pentalongin (1H-naphtho[2,3-c]pyran-5,10-dio... more This paper describes an efficient synthetic route to pentalongin (1H-naphtho[2,3-c]pyran-5,10-dione), a naphthoquinoid isolated from the aerial parts of Mitracarpus scaber, and to the structurally-related compound psychorubrin(3-hydroxy-1H-3, 4-dihydronaphtho[2,3-c]pyran-5,10-dione).
Journal of Enzyme Inhibition and Medicinal Chemistry, 2008
The preparation of a phosphorylated alpha-dicarbonyl compound designed to specifically react with... more The preparation of a phosphorylated alpha-dicarbonyl compound designed to specifically react with arginine residues of enzymes accepting phosphorylated compounds as effectors is reported, and shown to inhibit rabbit muscle aldolase in a time-dependent and irreversible manner. This irreversible inhibition occured in a buffer devoid of borate ions, suggesting that the presence of the phosphate moiety contributes in the stabilization of the adduct formed with arginine residues. Under the same conditions, the metalloenzyme iron superoxide dismutase, in which an arginine is known to be critical for the catalytic function, is not significantly inhibited.
Comptes rendus des séances de la Société de biologie et de ses filiales
Until recently, nitric oxide (NO.) was considered as a toxic radical, but it appears now as an es... more Until recently, nitric oxide (NO.) was considered as a toxic radical, but it appears now as an essential messenger implicated in a wide range of biological processes, including immune system, cardiovascular system, and nervous system. An aspect of NO. metabolism in vivo is the formation of a variety of high and low molecular weight nitrosothiols. S-nitrosocysteine and S-nitrosoglutathione are among the biologically derived S-nitrosothiols that are postulated to be carriers of NO.. Although most of the S-nitrosothiols are unstable and spontaneously break down to produce NO. and a disulfide, some of them, including protein thiols, can show significant stability. These molecules are able to convey nitric oxide, that is, to keep, to carry, and then to generate NO. in physiological media, and might display pharmacological effects as potential vasodilators or neuroprotectors. Here, we present the development of new thionitrites R-S-NO having intrinsic antioxidant properties. We report the preparation, the characterization, and the stability studies in aqueous solutions of S-nitroso derivatives of dihydro-alpha-lipoic acid, known for its antioxidant properties.
The N-bromosuccinimide bromination of the zinc derivative of meso-tetramesitylporphyrin, Zn(TMP),... more The N-bromosuccinimide bromination of the zinc derivative of meso-tetramesitylporphyrin, Zn(TMP), in methanol at reflux in air, gives the corresponding (β-pyrrole)octabromo derivative, meso-tetramesityl-βoctabromoporphyrinatozinc, Zn(Br 8 TMP), in high yield ...
... preparation. Bismuth(III) salts as Lewis acids have been proved to efficiently catalyze a num... more ... preparation. Bismuth(III) salts as Lewis acids have been proved to efficiently catalyze a number of reactions like Michael reactions, 10 acylation reactions, 11 oxidation of α-ketols 12 or epoxides 13 and Diels–Alder reactions. 14 ...
A procedure for the introduction of two different alkyl chains (myristyl, oleyl and phytanyl) lea... more A procedure for the introduction of two different alkyl chains (myristyl, oleyl and phytanyl) leading to heterodialkyl‐H‐phosphonates is reported, based on two successive transesterification reactions of commercially available diphenyl‐H‐phosphonate with the corresponding alcohols.
Proteins: Structure, Function, and Bioinformatics, 2009
Superoxide dismutases (SODs) are a crucial class of enzymes in the combat against intracellular f... more Superoxide dismutases (SODs) are a crucial class of enzymes in the combat against intracellular free radical damage. They eliminate superoxide radicals by converting them into hydrogen peroxide and oxygen. In spite of their very different life cycles and infection strategies, the human parasites Plasmodium falciparum, Trypanosoma cruzi and Trypanosoma brucei are known to be sensitive to oxidative stress. Thus the parasite Fe-SODs have become attractive targets for novel drug development. Here we report the crystal structures of FeSODs from the trypanosomes T. brucei at 2.0 A and T. cruzi at 1.9 A resolution, and that from P. falciparum at a higher resolution (2.0 A) to that previously reported. The homodimeric enzymes are compared to the related human MnSOD with particular attention to structural aspects which are relevant for drug design. Although the structures possess a very similar overall fold, differences between the enzymes at the entrance to the channel which leads to the active site could be identified. These lead to a slightly broader and more positively charged cavity in the parasite enzymes. Furthermore, a statistical coupling analysis (SCA) for the whole Fe/MnSOD family reveals different patterns of residue coupling for Mn and Fe SODs, as well as for the dimeric and tetrameric states. In both cases, the statistically coupled residues lie adjacent to the conserved core surrounding the metal center and may be expected to be responsible for its fine tuning, leading to metal ion specificity.
Phosphorus, Sulfur, and Silicon and the Related Elements, 1997
... Thionitrites lb to 4b are generated in siru in the NMR tubes: to a solution of thiol (0.2 M) ... more ... Thionitrites lb to 4b are generated in siru in the NMR tubes: to a solution of thiol (0.2 M) in CDCI, (1 ml) are added 200 p1 of a solution of rerr-butyl nitrite in CDC13 (1.1 M ... The authors thank Marie-Thtr&e Boisdon for IR experiments and Emmanuel Margeat for EPR experiments. ...
The preparation and characterization of two vitamin E analogs-sydnonimine conjugates, delta-tocop... more The preparation and characterization of two vitamin E analogs-sydnonimine conjugates, delta-tocopheryloxycarbonyl-3-morpholinosydnonimine (2) and troloxoxycarbonyl-3-morpholinosydnonimine (3), in which the hydroxyl group of the tocopheryl moieties is linked via an enzymatically cleavable urethane group to the sydnone moiety is described. In the presence of porcine liver esterase, these tocopheryl-sydnonimine conjugates generated the expected antioxidant moieties, i.e., delta-tocopherol or Trolox, and were found to convert oxyhemoglobin to methemoglobin at 37 degrees C in 50 mM phosphate buffer at pH 7.4, thus providing evidence for nitric oxide release. Their potency as antioxidants was indirectly studied by associating the two products of the hydrolysis, SIN-1, and delta-tocopherol or Trolox. Our findings suggest that unlike the other members of the sydnonimine family these chromane-sydnonimine derivatives do not act as peroxynitrite donors, and require enzymatic bioactivation before nitric oxide or nitroxyl anion (NO(-)) can be released.
This paper describes an efficient synthetic route to pentalongin (1H-naphtho[2,3-c]pyran-5,10-dio... more This paper describes an efficient synthetic route to pentalongin (1H-naphtho[2,3-c]pyran-5,10-dione), a naphthoquinoid isolated from the aerial parts of Mitracarpus scaber, and to the structurally-related compound psychorubrin(3-hydroxy-1H-3, 4-dihydronaphtho[2,3-c]pyran-5,10-dione).
Journal of Enzyme Inhibition and Medicinal Chemistry, 2008
The preparation of a phosphorylated alpha-dicarbonyl compound designed to specifically react with... more The preparation of a phosphorylated alpha-dicarbonyl compound designed to specifically react with arginine residues of enzymes accepting phosphorylated compounds as effectors is reported, and shown to inhibit rabbit muscle aldolase in a time-dependent and irreversible manner. This irreversible inhibition occured in a buffer devoid of borate ions, suggesting that the presence of the phosphate moiety contributes in the stabilization of the adduct formed with arginine residues. Under the same conditions, the metalloenzyme iron superoxide dismutase, in which an arginine is known to be critical for the catalytic function, is not significantly inhibited.
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Papers by Pascal Hoffmann