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

0534661 - ÚACH 2021 RIV DE eng J - Článek v odborném periodiku
Nekvinda, Jan - Kugler, Michael - Holub, Josef - El Anwar, Suzan - Brynda, Jiří - Pospíšilová, K. - Růžičková, Z. - Řezáčová, Pavlína - Grüner, Bohumír
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 - A European Journal. Roč. 26, č. 69 (2020), s. 16541-16553. ISSN 0947-6539. E-ISSN 1521-3765
Grant CEP: GA ČR(CZ) GA18-27648S; GA ČR(CZ) GA15-05677S
Grant ostatní: AV ČR(CZ) L200321851
Program: Program podpory perspektivníchlidských zdrojů - postdoktorandů
Institucionální podpora: RVO:61388980 ; RVO:68378050
Klíčová slova: medicinal chemistry * indomethacin * carbonic anhydrase * dicarba-closo-dodecaboranes * inhibitors * sulfonamide
Obor OECD: Inorganic and nuclear chemistry; Biochemistry and molecular biology (UMG-J)
Impakt faktor: 5.236, rok: 2020
Způsob publikování: Open access s časovým embargem

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.
Trvalý link: http://hdl.handle.net/11104/0314883