8CR0

Crystal structure of human carbonic anhydrase II in complex with a triazolyl benzoxaborole inhibitor

8CR0 の概要

• エントリーDOI: 10.2210/pdb8cr0/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: benzoxaborole, boron, zinc enzyme, complex, lyase
• 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: 29774.71

構造登録者

Alterio, V.,De Simone, G.,Esposito, D. (登録日: 2023-03-07, 公開日: 2023-06-21, 最終更新日: 2024-02-07)

主引用文献

Nocentini, A.,Bonardi, A.,Bazzicalupi, C.,Alterio, V.,Esposito, D.,Monti, S.M.,Smietana, M.,De Simone, G.,Supuran, C.T.,Gratteri, P.,Winum, J.Y.
6-Substituted Triazolyl Benzoxaboroles as Selective Carbonic Anhydrase Inhibitors: In Silico Design, Synthesis, and X-ray Crystallography.
J.Med.Chem., 66:8118-8129, 2023

PubMed Abstract: Benzoxaborole is currently a scaffold of great relevance in medicinal chemistry. In 2016, it was reported to be a new and valuable chemotype for designing carbonic anhydrase (CA) inhibitors. Herein, using an design, we report the synthesis and characterization of substituted 6-(1-1,2,3-triazol-1-yl)benzoxaboroles. 6-Azidobenzoxaborole was described for the first time as a molecular platform to prepare libraries of inhibitors by a copper(I)-catalyzed azide-alkyne cycloaddition a click chemistry strategy. With inhibition constants below 30 nM, some derivatives, such as compound , showed efficacy as selective hCA VII and IX inhibitors. The design hypothesis was validated by crystallographic investigation on the hCA II/ adduct, which provided explanations over the different inhibition behavior observed against the five evaluated hCA isoforms. Overall, this study identified as a new promising lead compound to develop novel anticancer agents targeting the tumor-associated hCA IX but also potent neuropathic pain relievers targeting hCA VII.

PubMed: 37283561
DOI: 10.1021/acs.jmedchem.3c00433

実験手法

X-RAY DIFFRACTION (1.22 Å)