RESUMO
We investigated a series of N-hydroxysulfamides obtained by Ferrier sulfamidoglycosylation for the inhibition of two bacterial carbonic anhydrases (CAs, EC 4.2.1.1) present in the pathogen Brucella suis. bsCA I was moderately inhibited by these compounds with inhibition constants ranging between 522 and 958 nM and no notable differences of activity between the acetylated or the corresponding deacetylated derivatives. The compounds incorporating two trans-acetates and the corresponding deprotected ones were the most effective inhibitors in the series. bsCA II was better inhibited, with inhibition constants ranging between 59.8 and 799 nM. The acetylated derivatives were generally better bsCA II inhibitors compared to the corresponding deacetylated compounds. Although these compounds were not highly isoform-selective CA inhibitors (CAIs) for the bacterial over the human CA isoforms, some of them possess inhibition profiles that make them interesting leads for obtaining better and more isoform-selective CAIs targeting bacterial enzymes.
Assuntos
Aminoglicosídeos/farmacologia , Brucella suis/enzimologia , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Aminoglicosídeos/síntese química , Aminoglicosídeos/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate allowed the preparation of hydroxysulfamide glycosides in good yields with a good α stereoselectivity. A variety of mono-saccharide derivatives was synthesized using this new methodology leading to selective and powerful glycoinhibitors of the tumor associated carbonic anhydrases (CA, EC 4.2.1.1) isoforms CA IX and CA XII.
Assuntos
Boratos/química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Óxido Nítrico/química , Sulfonamidas/química , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/metabolismo , Catálise , Glicosilação , Cinética , Monossacarídeos/química , Ligação Proteica , Estereoisomerismo , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
A general approach for the synthesis of carbonic anhydrases glycoinhibitors belonging to an aminoxysulfonamide series is presented using a Ferrier sulfonamidoglycosylation reaction on glycals. All the compounds showed good in vitro inhibitory activity against four human carbonic anhydrase isoforms, with selectivity against the cytosolic (hCA II) vs the tumor associated (hCA IX and XII) enzymes.
RESUMO
Hydroxylamine-O-sulfonamide, a molecule incorporating two zinc-binding groups (ZBGs), has been investigated as a carbonic anhydrase inhibitor (CAI) by means of kinetic, crystallographic and Raman spectroscopy studies, highlighting interesting results on its mechanism of action. These data can be exploited to design new, effective and selective CAIs.
Assuntos
Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Hidroxilamina/química , Sulfonamidas/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Domínio Catalítico , Desenho de Fármacos , Humanos , Hidroxilamina/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologiaRESUMO
Thiol-ene click chemistry has been applied for obtaining sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors incorporating sugar moieties. Most of these new compounds were moderate CA I inhibitors, effective CA II inhibitors, and low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms CA IX and XII.