Design And Synthesis Of Cholesterol Derivatives And Studies On Their Ubiquitination And Degradation Of HMG-CoA Reductase

3-Hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) is the key enzyme that catalyzes the production of cholesterol which has become the main target of cholesterol-lowering drugs. In this thesis, a series of cholesterol derivatives have been designed and synthesized, and their activity for ubiquitination-degradation of HMGCR was assayed. The thesis includes two parts:(1) Preliminary study on improvement of the selective activity upon ubiquitination-degradation of HMGCR with cholesterol derivativesA series of cholesterol derivatives were designed and synthesized with cholesterol as the starting material. The bioassay showed that five of the compounds had nice activity upon ubiquitination-degradation of HMGCR which indicated that introducing substituents, such as hydroxyl group, at C-7position not only improved the ubiquitination-degradation of HMGCR, but also ameliorated the selectivity of the bioactivity.(2) Certification of the importance of4,4-dimethyl group for ubiquitination-degradation of HMGCRBased on the previous results some new cholesterol derivatives with no substituents at C-4position or4,4-diallyl group were designed and prepared. The bioassay test exhibited no activity upon ubiquitination-degradation of HMGCR which confirmed that the4,4-dimethyl group was necessary for the ubiquitination-degradation of HMGCR.All of the above results provide some information for the further structure-activity relationship investigation of these compounds, and also afford some lead compounds for the cholesterol lowering drug development.