Carborane derivatives as inhibitors of human carbonic anhydrase isoenzymes
Human carbonic anhydrases (CAs) play essential roles in many pathological processes and several CA isoenzymes thus represent diagnostic and therapeutic targets. The development of isoform-specific inhibitor is still an important task in current medicine.
We have developed selective CAIX inhibitors with anticancer properties based on carborane scaffold to the structure-assisted design of novel and original inhibitors targeting therapeutically relevant isoenzymes of human carbonic anhydrase.
Laboratory scale, data on cell lines, crystal structure, limited ADME/Tox data, in vivo pharmacology and pharmacodynamics.
Novelty, in brief, is represented by the intended elaboration of carborane, heteroborane and metalloborane compounds as active-site inhibitors of CA isoenzymes. All currently used inhibitors anhydrase inhibitors contain a sulfonamide or a sulfamate moiety connected to so-called ‘ring structure’ which is usually a 5- or 6-membered aromatic ring or conjugated ring system containing nitrogen, oxygen, and/or sulfur heteroatoms. The ‘ring structure’ bears characteristics or functionality which modulates the affinity toward particular CA isoform. The use of three-dimensional boron cluster is a novel approach in the development of isoform-specific CA inhibitors. Selected sulfamides incorporate cluster with inhibitory effects toward CAs (IC50 values in the submicromolar and nanomolar range, some of the inhibitors being more than 50-times more selective toward the tumor-specific CAIX than for CAII abundantly present in normal tissues).
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Mader P., A. Pecina, P. Cígler, M. Lepšík, V. Šícha, P. Hobza, B. Grüner, J. Fanfrlík, J. Brynda, P. Řezáčová. Carborane-based carbonic anhydrase inhibitors: insight into CAII/CAIX specificity from a high-resolution crystal structure, modeling, and quantum chemical calculations. BioMed research international. 2014, 389869. ISSN: 2314-6141. IF: 2.583. PMID: 25309911
EP 2 771 015 US 9,290,529
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague Institute of Molecular Genetics, Czech Academy of Sciences, Prague Institute of Inorganic Chemistry, Czech Academy of Sciences, Prague Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc
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