4Z1N

Carbonic anhydrase inhibitors: Design and synthesis of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms (hCA VII, hCA IX, and hCA XIV)

Summary for 4Z1N

• Entry DOI: 10.2210/pdb4z1n/pdb
• Related: 4Z0Q 4Z1E 4Z1J 4Z1K
• Descriptor: Carbonic anhydrase 2, ZINC ION, 4-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)carbonyl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: lyase, carbonate dehydratase ii, carbonic anhydrase c, carbonic anhydrase ii, ca-ii, carbonate dehydratase ii- inhibitor complex
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29512.62

Authors

Brynda, J.,Pospisilova, K.,Rezacova, P.,Pachl, P. (deposition date: 2015-03-27, release date: 2015-08-26, Last modification date: 2024-05-08)

Primary citation

Buemi, M.R.,De Luca, L.,Ferro, S.,Bruno, E.,Ceruso, M.,Supuran, C.T.,Pospisilova, K.,Brynda, J.,Rezacova, P.,Gitto, R.
Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.
Eur.J.Med.Chem., 102:223-232, 2015

PubMed Abstract: A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.

PubMed: 26276436
DOI: 10.1016/j.ejmech.2015.07.049

Experimental method

X-RAY DIFFRACTION (1.47 Å)