6EBE

Bioreductive 4-hydroxy-3-nitro-5-ureido-benzenesulfonamides selectively target the tumor-associated carbonic anhydrase isoforms IX and XII and show hypoxia-enhanced cytotoxicity against human cancer cell lines.

6EBE の概要

• エントリーDOI: 10.2210/pdb6ebe/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 4-hydroxy-3-nitro-5-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)benzene-1-sulfonamide, ... (4 entities in total)
• 機能のキーワード: hypoxia, carbonic anhydrase ix, carbonic anhydrase xii, inhibition, anti-proliferative., lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29418.37

構造登録者

Singh, S.,McKenna, R.,Supuran, C.T.,Nocentini, A.,Lomelino, C.,Lucarini, E.,Bartolucci, G.,Mannelli, L.D.C.,Ghelardini, C.,Gratteri, P. (登録日: 2018-08-06, 公開日: 2018-11-28, 最終更新日: 2023-10-11)

主引用文献

Nocentini, A.,Trallori, E.,Singh, S.,Lomelino, C.L.,Bartolucci, G.,Di Cesare Mannelli, L.,Ghelardini, C.,McKenna, R.,Gratteri, P.,Supuran, C.T.
4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative Profiles.
J. Med. Chem., 61:10860-10874, 2018

PubMed Abstract: Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia-activated antitumor CAIs.

PubMed: 30433782
DOI: 10.1021/acs.jmedchem.8b01504

実験手法

X-RAY DIFFRACTION (1.88 Å)