Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

0543164 - ÚOCHB 2022 RIV DE eng J - Journal Article
Kugler, Michael - Nekvinda, Jan - Holub, Josef - El Anwar, Suzan - Das, V. - Šícha, Václav - Pospíšilová, Klára - Fábry, M. - Král, V. - Brynda, Jiří - Kašička, Václav - Hajdúch, M. - Řezáčová, Pavlína - Grüner, Bohumír
Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds.
Chembiochem. Roč. 22, č. 18 (2021), s. 2741-2761. ISSN 1439-4227. E-ISSN 1439-7633
R&D Projects: GA ČR(CZ) GA18-27648S; GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LM2015064
Institutional support: RVO:61388963 ; RVO:61388980
Keywords : carbonic anhydrase * carborane * cobalt bis(dicarbollide) * crystallography * enzyme inhibition * SAR studies
OECD category: Organic chemistry; Inorganic and nuclear chemistry (UACH-T)
Impact factor: 3.468, year: 2021
Method of publishing: Limited access
https://doi.org/10.1002/cbic.202100121

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).
Permanent Link: http://hdl.handle.net/11104/0320438