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

4MO8 の概要

• エントリーDOI: 10.2210/pdb4mo8/pdb
• 関連するPDBエントリー: 4L84
• 分子名称: Carbonic anhydrase 2, ZINC ION, N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfamide, ... (4 entities in total)
• 機能のキーワード: sulfamide, zinc binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29603.72

構造登録者

Alterio, V.,De Simone, G. (登録日: 2013-09-11, 公開日: 2013-10-30, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.85 Å)