ml9b00590_si_001.pdf (1.55 MB)
Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors
journal contribution
posted on 2020-03-16, 12:37 authored by Debora Pratesi, Camilla Matassini, Andrea Goti, Andrea Angeli, Fabrizio Carta, Claudiu T. Supuran, Rolando Spanevello, Francesca CardonaThe 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).
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presencehCAs inhibitorssulfonamide moietyundesired interactionshCA VIIcarbohydrate-processing enzymeselectivity profilesugar moietyisoformcellulose pyrolysisnovel hCAs inhibitors 2synthesisglycomimetic 3CNScarbohydrate moietylevoglucosenoneiminosugar 2Selective Carbonic Anhydrase Inhibitors35.9 nMparent sugarssugar analogue residue7.4 nMBiological assayscarbonic anhydrasespiperidine iminosugarside effects
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