Synthesis and biological activity of a squalenoid maleimide and other classes of squalene derivatives as irreversible inhibitors of 2,3-oxidosqualene cyclase

Article abstract of DOI:10.1016/0223-5234(94)90121-X

New classes of squalene derivatives were rationally designed and synthesized as irreversible inhibitors of 2,3-oxidosqualene cyclase (OSC), a key enzyme in sterol biosynthesis. The derivatives synthesized were maleimide 5, disulfides 8-9, α,β-unsaturated nitriles 10-11 and oxirane 12. The inhibitor activities of these derivatives were determined in vitro on OSC associated with pig liver microsomes. Squalene and dodecyl maleimide were the best inhibitors of OSC, showing a time-dependent enzyme inactivation. Moreover 2,3-oxidosqualene (OS), the natural substrate of OSC, partially protected the enzyme from squalene maleimide inactivation whereas the dodecyl derivative did not. This fact and the complex kinetics shown by squalene maleimide suggest the presence of different classes of thiolic groups essential to the activity of OSC.