Abstract
A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition.
Highlights
Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes which catalyse the reversible hydration of CO2 to bicarbonate and proton[1–4]
Substitution reaction between saccharin or potassium acesulfame with the proper electrophile at 80 C for 24–48 h as appropriate (Scheme 1(a,b)). These reactions were performed in DMF, in the presence of freshly ground anhydrous potassium carbonate (K2CO3) for saccharin derivatives (Scheme 1(a)); Ace K did not require the adding of further base to activate the nucleophile site, being employed as potassium salt (Scheme 1(b))
Inspired by these observations and considering the good results gained by the insertion of the isoxazole/isoxazoline heterocyclic linker in our previous work[42], we tried to evaluate the effects caused by the insertion of triazole core between the methylene group and the phenyl ring, substituting the isoxazole one (41–49)
Summary
Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes which catalyse the reversible hydration of CO2 to bicarbonate and proton[1–4]. The other artificial sweetener potassium acesulfame (Ace K) is a valid scaffold used for the development of hCA inhibitors (Figure 3) It has been largely explored both for its capability to inhibit carbonic anhydrase[47], or after oxygen/nitrogen derivatization with different substituents By adjusting the synthesis conditions (see below), we were able to preferentially address the propargylation and the triazole assembling, either at the oxygen or nitrogen of the acesulfame core to achieve N- and O-substituted analogues, respectively (Figure 3(b)) Even in this case, the insertion of an additional methylene group, disconnecting the phenyl group from the N1 of the triazole ring, was attempted. Seeing as how some compounds differing only for the nucleus (saccharin or acesulfame), it is possible to evaluate the effects on the activity and selectivity of the molecules retaining the same tail but not the main core
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