Structure-activity relationship with pyrazoline-based aromatic sulfamates as carbonic anhydrase isoforms I, II, IX and XII inhibitors: Synthesis and biological evaluation
Moi, DavideFirst
;Deplano, Alessandro;Balboni, Gianfranco;Onnis, ValentinaLast
2019-01-01
Abstract
Four new series of aromatic sulfamates were synthesized and investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IX, and XII. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear 3,5-diarylpyrazoline moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Pyrazolines are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The derivatives were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally, hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 0.42–90.1 nM), IX (KIs in the range of 0.72–63.6 nM), and XII (KIs in the range of 0.88–85.2 nM). The best substitution fragments at the pyrazoline ring included for CA II a 4-sulfamic group on the 3-aryl and halogens on the 5-aryl or a methoxy group on the 3-aryl and a 4-sulfamate group on the 5-aryl; for CA IX and CA XII they included the sulfamic group on the 3- or 4-position of the 5-aryl and an electronwithdrawing group on the 4-postion of the 3-aryl ring.File | Size | Format | |
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Pirazoline_SupplementalMaterial_rev.docx open access
Description: Materiale supplementare
Type: altro documento allegato
Size 9.79 MB
Format Microsoft Word XML
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9.79 MB | Microsoft Word XML | View/Open |
EJMC_2019_pirazoloine sulfamati CAI.pdf Solo gestori archivio
Description: articolo principale
Type: versione editoriale
Size 626.5 kB
Format Adobe PDF
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626.5 kB | Adobe PDF | & nbsp; View / Open Request a copy |
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