HAL (Le Centre pour la Communication Scientifique Directe), Feb 2, 2004
Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèl... more Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèle du CYP2C9 et choix des acides aminés à muter.
Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèl... more Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèle du CYP2C9 et choix des acides aminés à muter.
New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, ox... more New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-β-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.
Supplementary Figure 5 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 5 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 10 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BC... more Supplementary Figure 10 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 8 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 8 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 9 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 9 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 1 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 1 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
HAL (Le Centre pour la Communication Scientifique Directe), Feb 2, 2004
Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèl... more Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèle du CYP2C9 et choix des acides aminés à muter.
Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèl... more Positionnement de l'acide tiénilique, du diclofénac et du sulfaphénazole dans le site actif modèle du CYP2C9 et choix des acides aminés à muter.
New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, ox... more New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-β-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.
Supplementary Figure 5 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 5 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 10 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BC... more Supplementary Figure 10 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 8 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 8 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 9 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 9 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Supplementary Figure 1 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR... more Supplementary Figure 1 from Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
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