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. Crystall...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8512-8520
Main Authors: Rami, Marouan, Dubois, Ludwig, Parvathaneni, Nanda-Kumar, Alterio, Vincenzo, van Kuijk, Simon J. A, Monti, Simona Maria, Lambin, Philippe, De Simone, Giuseppina, Supuran, Claudiu T, Winum, Jean-Yves
Format: Article
Language:English
Subjects:
Amides - chemistry
Antigens, Neoplasm - metabolism
Carbonic Anhydrase IX
Carbonic Anhydrases - metabolism
Chemical Sciences
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
HeLa Cells
HT29 Cells
Humans
Hypoxia
Models, Molecular
Molecular Structure
Nitroimidazoles - chemistry
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonic Acids - chemistry
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4009532