SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX.
Bioorg Chem
; 83: 549-558, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30471577
ABSTRACT
SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs 0.21-7.1â¯nM), with 6- to 21-fold enhanced activity than SLC-0111 (KIâ¯=â¯45â¯nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI 32 - >35714), hCA II (SI 2 - 1689) and hCA IV (SI 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.
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MEDLINE
Assunto principal:
Sulfonamidas
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Inibidores da Anidrase Carbônica
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Anidrase Carbônica IX
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Compostos de Anilina
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Antígenos de Neoplasias
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article