PDBsum entry 6yok

Lyase

PDB id: 6yok

Contents

Protein chain

257 a.a.

Ligands

P82

Metals

_ZN

Waters ×254

References listed in PDB file

Key reference

• Title: 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.
• Authors: J.Nekvinda, M.Kugler, J.Holub, S.El anwar, J.Brynda, K.Pospíšilová, Z.RůžIčková, P.ŘEzáčová, B.Grüner.
• Ref.: Chemistry, 2020, 26, 16541-16553. [DOI no: 10.1002/chem.202002809]
• PubMed id: 32757220

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_i ) and selectivity towards CA IX. Decreasing trends in K_i and selectivity index (S_I ) 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.