4MO8

The crystal structure of the human carbonic anhydrase II in complex with N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfamide

Summary for 4MO8

• Entry DOI: 10.2210/pdb4mo8/pdb
• Related: 4L84
• Descriptor: Carbonic anhydrase 2, ZINC ION, N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfamide, ... (4 entities in total)
• Functional Keywords: sulfamide, zinc binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29603.72

Authors

Alterio, V.,De Simone, G. (deposition date: 2013-09-11, release date: 2013-10-30, Last modification date: 2023-09-20)

Primary citation

Rami, M.,Dubois, L.,Parvathaneni, N.K.,Alterio, V.,van Kuijk, S.J.,Monti, S.M.,Lambin, P.,De Simone, G.,Supuran, C.T.,Winum, J.Y.
Hypoxia-Targeting Carbonic Anhydrase IX Inhibitors by a New Series of Nitroimidazole-Sulfonamides/Sulfamides/Sulfamates.
J.Med.Chem., 56:8512-8520, 2013

PubMed Abstract: 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.

PubMed: 24128000
DOI: 10.1021/jm4009532

Experimental method

X-RAY DIFFRACTION (1.85 Å)