Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene‐hopene cyclases

Abstract

Various vinyl sulfide and ketene dithioacetal derivatives of truncated 2,3-oxidosqualene were developed. These compounds, having the reactive functions at positions C-2, C-15 and C-19 of the squalene skeleton, were studied as inhibitors of pig liver and Saccharomyces cerevisiae oxidosqualene cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene hopene cyclase (SHC) (EC 5.4.99.-). They contain one or two sulfur atoms in alpha-skeletal position to carbons considered to be cationic during enzymatic cyclization of the substrate and should strongly interact with enzyme nucleophiles of the active site. Most of the new compounds are inhibitors of the OSC and of SHC, with various degrees of selectivity. The methylthiovinyl derivative, having the reactive group at position 19, was the most potent and selective inhibitor of the series toward S. cerevisiae OSC, with a concentration inhibiting 500% of the activity of 50 nM, while toward the animal enzyme it was 20 times less potent. These results could offer new insight for the design of antifungal drugs.

Analogs of squalene and oxidosqualene inhibit oxidosqualene cyclase of Trypanosoma cruzi expressed in Saccharomyces cerevisiae

“…The design of these compounds was based on the hypothesis that a partial cyclization of these compounds in the active site of the enzyme, because of the excellent properties of the sulfur in stabilizing the electron-deficient α-carbon, owing to its good π-and σ-donor properties, could generate carbocationic intermediates that were more stable and more able to interact strongly with nucleophilic amino acid residues. Our previous results showed that a methyl sulfide derivative, such as compound 9, is a very effective inhibitor of S. cerevisiae OSC and a time-dependent inhibitor of pig OSC, whereas phenyl sulfide derivatives, such as 16, 17, and 19, are poor inhibitors of both pig and yeast OSC (17,19,20). The T. cruzi OSC seems to be specifically inhibited by all the phenyl derivatives tested (compounds 12, 16-19).…”

“…The synthesis of the inhibitors tested (compounds 1-19 of Fig. 2) has been described elsewhere (16,17,19,20,23,25,26). The identity and purity of inhibitors was checked by TLC, 1 H NMR and mass spectra before testing the inhibition of T. cruzi OSC.…”

“…2) or to bear reactive functions able to interact with the active site residues, as the methylidene (compounds 4-8), vinyl sulfide (compounds 9, 12, 13, 16), conjugated vinyl sulfide (compounds 10, 11, 14, 15, 17), hydroxysulfide (compound 19), or hydroxyphenyl derivatives (compound 18) (15)(16)(17)(18)(19)(20). OSC of different origins can have significantly different susceptibilities to the inhibitors, showing the possibility of selective inhibition (19,20). Therefore, it would be worth testing the activity of these inhibitors on the OSC of the pathogen protozoon Trypanosoma cruzi, which recently has been shown to be susceptible to pyridinium ionbased inhibitors and to some umbelliferone aminoalkyl derivatives (11,12).…”

Novel Squalene-Hopene Cyclase Inhibitors Derived from Hydroxycoumarins and Hydroxyacetophenones

“…21,22) SHC may therefore be used as a model to predict how newly designed inhibitors may interact with OSCs. Recently, the interaction of several new inhibitors of human OSC 17) with the active site of SHC was investigated by co-crystallization experiments.23) Because comparative studies on the two enzyme types 24,25) have shown close correspondence of their inhibitor activities, we recently investigated a group of meroterpenoids that proved to be excellent inhibitors of SHC.26) The basic structure of bioactive oxyprenylcoumarins is derived from umbelliprenine (7-farnesyloxycoumarin) by the insertion of either a tetrahydrofuran unit (farnesylferol C, 1) or 1-2 oxiran rings (2, 3) (Fig. 1).…”

“…23) Because comparative studies on the two enzyme types 24,25) have shown close correspondence of their inhibitor activities, we recently investigated a group of meroterpenoids that proved to be excellent inhibitors of SHC.…”