6YOK

Para-Carborane di-propyl-sulfonamide in complex with CA IX mimic

6YOK の概要

• エントリーDOI: 10.2210/pdb6yok/pdb
• 関連するPDBエントリー: 6YO2 6YO4 6YO7 6YOI
• 分子名称: Carbonic anhydrase 2, ZINC ION, Para-Carborane di-propyl-sulfonamide, ... (4 entities in total)
• 機能のキーワード: carbonic anhydrase, ca inhibitor, 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: 29642.76

構造登録者

Kugler, M.,Brynda, J.,Pospisilova, K.,Rezacova, P. (登録日: 2020-04-14, 公開日: 2020-08-19, 最終更新日: 2024-01-24)

主引用文献

Nekvinda, J.,Kugler, M.,Holub, J.,El Anwar, S.,Brynda, J.,Pospisilova, K.,Ruzickova, Z.,Rezacova, P.,Gruner, B.
Direct Introduction of an Alkylsulfonamido Group on C-sites of Isomeric Dicarba-closo-dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer-Associated Carbonic Anhydrase IX Isoenzyme.
Chemistry, 26:16541-16553, 2020

PubMed Abstract: Carbonic anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closo-dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with a different geometric position of carbon atoms. The closo-compounds from the ortho- and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1-) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant (K ) and selectivity towards CA IX. Decreasing trends in K and selectivity index (S ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity.

PubMed: 32757220
DOI: 10.1002/chem.202002809

実験手法

X-RAY DIFFRACTION (1.25 Å)