info:eu-repo/semantics/article
Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors
Fecha
2020-05Registro en:
Pratesi, Debora; Matassini, Camilla; Goti, Andrea; Angeli, Andrea; Carta, Fabrizio; et al.; Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors; American Chemical Society; ACS Medicinal Chemistry Letters; 11; 5; 5-2020; 727-731
1948-5875
1948-5875
CONICET Digital
CONICET
Autor
Pratesi, Debora
Matassini, Camilla
Goti, Andrea
Angeli, Andrea
Carta, Fabrizio
Supuran, Claudiu T.
Spanevello, Rolando Angel
Cardona, Francesca
Resumen
The synthesis of selective inhibitors of human carbonic anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targeted pathology, and this was partially addressed with the introduction of a sugar moiety (the so-called "sugar approach"). Since glycomimetics are considered more selective than the parent sugars in inhibiting carbohydrate-processing enzyme, we explored the possibility of further tuning the selectivity of hCAs inhibitors by combining the sulfonamide moiety with a sugar analogue residue. In particular, we report the synthesis of two novel hCAs inhibitors 2 and 3 which feature the presence of a piperidine iminosugar and an additional carbohydrate moiety derived from levoglucosenone (1), a key intermediate derived from cellulose pyrolysis. Biological assays revealed that iminosugar 2 is a very strong inhibitor of the central nervous system (CNS) abundantly expressed hCA VII (KI of 7.4 nM) and showed a remarkable selectivity profile toward this isoform. Interestingly, the presence of levoglucosenone in glycomimetic 3 imparted a strong inhibitory activity toward the tumor associated hCA IX (KI of 35.9 nM).