期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 26, 期 69, 页码 16541-16553出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202002809
关键词
carbonic anhydrase; crystallography; dicarba-closo-dodecaboranes; inhibitors; sulfonamide
资金
- Czech Science Foundation [18-27648S, 15-05677S]
- Technology Agency of the Czech Republic [TE01020028]
- PPLZ from the Czech Academy of Sciences [L200321851]
- European Regional Development Fund [CZ.02.1.01/0.0/0.0/16_019/0000729]
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.
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