The Synthesis Of Aldosterone And The Structure-guided Development And Activity Evaluation Of USP7 Inhibitors

This thesis involves two parts:the first part is the structure-guided development and activity evaluation of USP7 inhibitors based on the pyrimidine-4(3H)-one.The second part is the preparation of Aldosterone by light-induced O-radical directed remote functionalization of sp3 C-H bonds.The first part:ubiquitin-specific protease 7(USP7),also known as herpesvirus-associated ubiquitin-specific protease(HAUSP),which can deubiquitinate MDM2,stabilize the tumor suppressor gene p53,and regulate its activity to inhibit tumor growth and cancer cell proliferation.However,in recent years,research on USP7 has mainly focused on its physiological role.USP7 plays a key role in regulating the activity and function of intracellular tumor suppressor protein,DNA repair protein,immune response protein and other protein substrates.But there are few reports on the development of small molecule USP7 inhibitors.Therefore,this paper designs small molecule compounds with pyrimidine-4(3H)-one structure as the core and evaluates their activity.It is hoped that these discoveries can enable further research into the wider biological role of USP7.Through a series of synthetic explorations,we finally use 3-(Boc-amino)cyclopentanone as the starting material,first prepare exocyclic olefins through the wittig reaction,and then prepare the epoxidized intermediate through the mCPBA epoxidation reaction The oxygen intermediate reacts with 6-chloropyrimidin-4(3H)-one in an epoxy ring-opening reaction.The intermediate obtained is directly deprotected and then undergoes an amide condensation reaction with(R)-3-phenylbutyric acid.The obtained intermediate was finally subjected to a nucleophilic substitution reaction with 1-(2-aminoethyl)pyrrole to obtain the target compound.The activity of this compound was evaluated.Part 2:Aldosterone is an important steroid hormone synthesized in the human body by the adrenal cortex globular band and released into the blood.It has extensive research prospects in the pharmaceutical field.However,there are few reports about the synthesis of grams of Aldosterone.This article attempts two strategies for the synthesis of Aldosterone:(1)The hydroxyl group at the C-1 1 position is used as the guiding group,and the nitrite and iodine are used as the photosensitive group,respectively,and then aldosterone is prepared by exciting oxygen radicals,and modifying the designated remote site by 1,5-hydrogen atom transfer(1,5-HAT)reaction to modify the inactive methyl group at the C-18 position.(2)Aldosterone was prepared by using the hydroxyl group at the C-20 position as the guiding group,and using nitrite and iodine as the photosensitive groups,respectively,under the action of 1,5-HAT reaction to make the methyl group at the C-18 position functionalized.Through a series of synthetic exploration,we finally used hydrocortisone as the starting material,through TMSI dehydroxylation,acetyl protection,NaBH4 reduction,MnO2 selective oxidation to produce C-20-position hydroxyl intermediate.The intermediate is C-18-methyl iodinated under tungsten light,then oxidized by DMP,hydrolyzed by agoac to hemiketal,reduced by NaBH4,selectively oxidized by MnO2,oxidized by Swern,hydrolyzed by LiOH.The total yield of aldosterone is 3%.