Conjugated methyl sulfide and phenyl sulfide derivatives of oxidosqualene as inhibitors of oxidosqualene and squalene‐hopene cyclases

Abstract

Various (1E,3E)- and (1Z,3E)-conjugated methylthio derivatives of oxidosqualene (OS) and conjugated and non-conjugated phenylthio derivatives of OS were obtained. These compounds, designed as inhibitors of pig liver and Saccharomyces cerevisiae 2,3-oxidosqualene-lanosterol cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene-hopene cyclase (SHC) (EC 5.4.99.-), contain the reactive function adjacent to carbons involved in the formation of the third and the fourth cycle during OS cyclization. All the new compounds are inhibitors of OSC and SHC, with various degrees of selectivity. The conjugated methylthio derivatives behaved as potent inhibitors of S. cerevisiae OSC, whereas most of the phenylthio derivatives were especially active toward SHC.

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

“…The IC 50 of both compounds were similar, 4.5 and 2 µM, respectively. IC 50 of phenyl derivatives 12, 16, 17 and 19, tested with the OSC of S. cerevisiae expressed in a SMY8-derived strain (SMY8pSM61.21) were in complete accordance with the data shown in Table 1, obtained previously (18,20) with a wild-type S. cerevisiae (33).…”

“…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 IC 50 values for these derivatives are in the range 70-600 nM, or 10 to 100 times lower than the IC 50 found in pig liver OSC. Furthermore, the corresponding methyl derivatives 9, 13, 14, and 15, which are very active in pig and S. cerevisiae (19,20), are less effective on T. cruzi OSC. The major difference is observed with compound 9, showing, with T.cruzi, a 30 times larger IC 50 than with S. cerevisiae.…”

“…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).…”