Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII.
Bioorg Chem
; 103: 104204, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32891000
ABSTRACT
Building on the conclusions of previous inhibition studies with pyridinium-benzenesulfonamides from our team and on the X-ray crystal structure of the lead compound identified, a series of 24 pyridinium derivatives of 3-aminobenzenesulfonamide was synthesized and investigated for carbonic anhydrase inhibition. The new pyridinium-sulfonamides were evaluated as inhibitors of four human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely CA I, CA II (cytosolic), CA IX and XII (transmembrane, tumor-associated forms). Excellent inhibitory activity in the nanomolar range was observed against CA IX with most of these sulfonamides, and against CA XII (nanomolar/sub-nanomolar) with some of the new compounds. These sulfonamides were generally potent inhibitors of CA II and CA I too. Docking studies revealed a preference of these compounds to bind the P1 hydrophobic site of CAs, supporting the observed inhibition profile. The salt-like nature of these positively charged sulfonamides can further focus the inhibitory ability on membrane-bound CA IX and CA XII and could efficiently decrease the viability of three human carcinomas under hypoxic conditions where these isozymes are over-expressed, thus recommending the new compounds as potential diagnostic tools or therapeutic agents.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Piridínio
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Sulfonamidas
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Inibidores da Anidrase Carbônica
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Anidrases Carbônicas
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Anidrase Carbônica IX
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Antígenos de Neoplasias
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Neoplasias
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2020
Tipo de documento:
Article