SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A SQUALENOID MALEIMIDE AND OTHERCLASSES OF SQUALENE DERIVATIVES AS IRREVERSIBLE INHIBITORS OF 2,3-OXIDOSQUALENE CYCLASE

New classes of squalene derivatives were rationally designed and synth esized as irreversible inhibitors of 2,3-oxido-squalene cyclase (OSC), a key enzyme in sterol biosynthesis. The derivatives synthesized were maleimide 5, disulfides 8-9, alpha,beta-unsaturated nitriles 10-11 an d oxirane 12. The inhibitor activities of these derivatives were deter mined in vitro on OSC associated with pig liver microsomes. Squalene a nd dodecyl maleimide were the best inhibitors of OSC, showing a time-d ependent enzyme from squalene maleimide inactivation whereas the dodec yl derivative did not. This fact and the complex kinetics shown by squ alene maleimide suggest the presence of different classes of thiolic g roups essential to the activity of OSC.