Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates (628 views)
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2013 Nov 14; 56(21): 8512-8520.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 5.48, 5-year impact factor: 5.504
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84887954229&partnerID=40&md5=7d5350af89014222004a1a3b5a8f354f
Keywords: (2 Nitro Imidazol 1 Yl) Acetic Acid, 2 (2 Nitro Imidazol 1 Yl) N (3 Sulfamoylphenyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylbenzyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylphenyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N [2 (4 Sulfamoylphenyl)ethyl]acetamide, 2 (2 Nitro Imidazol 1 Yl)ethylamine, Antineoplastic Agent, Carbonate Dehydratase Inhibitor, Carbonate Dehydratase Xii, Doxorubicin, N (3 Sulfamoylphenyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylbenzyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylphenyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylphenylethyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl)ethyl]sulfamide, N [2 (2 Methyl Imidazol 1 Yl)propyl]sulfamide, N [2 (2 Nitro Imidazol 1 Yl)ethyl]sulfamide, N Methanesulfonyl 1 (2 Aminoethyl) 2 Methyl 5 Nitroimidazole, N Methanesulfonyl 2 (2 Nitro Imidazol 1 Yl)ethylamine, N[2 (2 Methyl 5 Nitro Imidazol 1 Yl)ethyl]sulfamate, Nitroimidazole Derivative, Sulfamide Derivative, Sulfonamide, Tert Butyl (2 Nitro Imidazol 1 Yl) Acetate, Unclassified Drug, Acidosis, Animal Cell, Animal Experiment, Animal Model, Article, Chemosensitization, Controlled Study, Enzyme Active Site, Enzyme Activity, Hela Cell, Human, Human Cell, Hypoxia, In Vitro Study, In Vivo Study, Mouse, Nonhuman, Protein Expression, X Ray Crystallography, Anoxia, Antigens, Carbonic Anhydrases, Dose-Response Relationship, Enzyme Inhibitors, Ht29 Cells, Molecular, Molecular Structure, Structure-Activity Relationship, Sulfonic Acids, Amides Chemistry, Neoplasm Metabolism, Carbonic Anhydrases Metabolism, Enzyme Inhibitors Chemical Synthesis Chemistry Pharmacology, Nitroimidazoles Chemistry, Sulfonamides Chemistry, Sulfonic Acids Chemistry, 2 (2 Nitro Imidazol 1 Yl) N (3 Sulfamoylphenyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylbenzyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylphenyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N [2 (4 Sulfamoylphenyl) Ethyl] Acetamide, 2 (2 Nitro Imidazol 1 Yl) Ethylamine, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl) Ethyl] Sulfamide, N [2 (2 Methyl Imidazol 1 Yl) Propyl] Sulfamide, N [2 (2 Nitro Imidazol 1 Yl) Ethyl] Sulfamide, N Methanesulfonyl 2 (2 Nitro Imidazol 1 Yl) Ethylamine, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl) Ethyl] Sulfamate,
Affiliations:
*** IBB - CNR ***
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2 Baîtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6200 MD, Maastricht, Netherlands
Istituto di Biostrutture e Bioimmagini - CNR, via Mezzocannone 16, 80134 Naples, Italy
Neurofarba Department, Section of Pharmaceutical Sciences, Università Degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy
References:
Not available.
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2013 Nov 14; 56(21): 8512-8520.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 5.48, 5-year impact factor: 5.504
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84887954229&partnerID=40&md5=7d5350af89014222004a1a3b5a8f354f
Keywords: (2 Nitro Imidazol 1 Yl) Acetic Acid, 2 (2 Nitro Imidazol 1 Yl) N (3 Sulfamoylphenyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylbenzyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylphenyl)acetamide, 2 (2 Nitro Imidazol 1 Yl) N [2 (4 Sulfamoylphenyl)ethyl]acetamide, 2 (2 Nitro Imidazol 1 Yl)ethylamine, Antineoplastic Agent, Carbonate Dehydratase Inhibitor, Carbonate Dehydratase Xii, Doxorubicin, N (3 Sulfamoylphenyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylbenzyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylphenyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N (4 Sulfamoylphenylethyl) N [(2 Aminoethyl) 2 Methyl 5 Nitroimidazolyl] Thiourea, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl)ethyl]sulfamide, N [2 (2 Methyl Imidazol 1 Yl)propyl]sulfamide, N [2 (2 Nitro Imidazol 1 Yl)ethyl]sulfamide, N Methanesulfonyl 1 (2 Aminoethyl) 2 Methyl 5 Nitroimidazole, N Methanesulfonyl 2 (2 Nitro Imidazol 1 Yl)ethylamine, N[2 (2 Methyl 5 Nitro Imidazol 1 Yl)ethyl]sulfamate, Nitroimidazole Derivative, Sulfamide Derivative, Sulfonamide, Tert Butyl (2 Nitro Imidazol 1 Yl) Acetate, Unclassified Drug, Acidosis, Animal Cell, Animal Experiment, Animal Model, Article, Chemosensitization, Controlled Study, Enzyme Active Site, Enzyme Activity, Hela Cell, Human, Human Cell, Hypoxia, In Vitro Study, In Vivo Study, Mouse, Nonhuman, Protein Expression, X Ray Crystallography, Anoxia, Antigens, Carbonic Anhydrases, Dose-Response Relationship, Enzyme Inhibitors, Ht29 Cells, Molecular, Molecular Structure, Structure-Activity Relationship, Sulfonic Acids, Amides Chemistry, Neoplasm Metabolism, Carbonic Anhydrases Metabolism, Enzyme Inhibitors Chemical Synthesis Chemistry Pharmacology, Nitroimidazoles Chemistry, Sulfonamides Chemistry, Sulfonic Acids Chemistry, 2 (2 Nitro Imidazol 1 Yl) N (3 Sulfamoylphenyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylbenzyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N (4 Sulfamoylphenyl) Acetamide, 2 (2 Nitro Imidazol 1 Yl) N [2 (4 Sulfamoylphenyl) Ethyl] Acetamide, 2 (2 Nitro Imidazol 1 Yl) Ethylamine, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl) Ethyl] Sulfamide, N [2 (2 Methyl Imidazol 1 Yl) Propyl] Sulfamide, N [2 (2 Nitro Imidazol 1 Yl) Ethyl] Sulfamide, N Methanesulfonyl 2 (2 Nitro Imidazol 1 Yl) Ethylamine, N [2 (2 Methyl 5 Nitro Imidazol 1 Yl) Ethyl] Sulfamate,
Affiliations:
*** IBB - CNR ***
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2 Baîtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6200 MD, Maastricht, Netherlands
Istituto di Biostrutture e Bioimmagini - CNR, via Mezzocannone 16, 80134 Naples, Italy
Neurofarba Department, Section of Pharmaceutical Sciences, Università Degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy
References:
Not available.
Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates
A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes. © 2013 American Chemical Society.
A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes. © 2013 American Chemical Society.
Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates
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