Study On Total Synthesis Of P57 And Synthesis The Designed Inhibitor Of The Bcl-X_L By Computer

1.Study on total synthesis of P57P57 is an oxypregnane steroidal glycoside isolated from the African cactiform Hoodia gordonii.P57 is the only active constituent from this plant that has been reported to be responsible for the potential appetite suppressant activity of Hoodia extracts.The studies demonstrated that the compound increases the content of ATP by 50-150%in hypothalamic neurons.In addition,third ventricle administration of P57 reduced subsequent 24 hours food intake by 40-60%.Starting from the commercially available Hecogenin,this paper attempted to achieve the aglycones of the P57.This thesis developed a new method that selectively reducingα,β-carbon-carbon double bond in pregn-14, 16-dien-20-one with triethylsilane in presence of Indium(Ⅲ) chloride. The key steroid 35 was prepared in a linear 18-step sequence. Unfortunately,diversion the C-4,C-5 double bond to C-5,C-6 double bond was not successful under a variety conditions,for the hydroxyl of the C-14 was easily elimination.Starting from D-mannose,the sugar acceptor 63 was prepared in a linear 17-step sequence.The desired thevetose donor 75 was obtained from diacetone D-glucose in 8 steps.Another 10 steps were spent on the preparation of the 2,6-dioxyl sugar donor 94,The aglycone was prepared from Hecogenin in 15 steps.Finally,this paper finished the synthesis of the P57 analogue 101 and coasted a total of 59 steps,with longest linear sequence of 24 steps and in 2.18%overall yield.A new 2-deoxy glycosyl donor was successfully used in the synthesis of the glycosyl steroid 101. 2.Synthesis the designed inhibitor of the Bcl-X_L by computerProteins in the Bcl-2 family are central regulators of programmedcell death,and members that inhibit apoptosis,such as Bcl-X_L and Bcl-2,are overexpressed in many cancers and contribute to tumour initiation,progression and resistance to therapy.Via inhibition or deactivation of Bcl-X_L function,can therapy human tumor.So the goal was to specifically target Bcl-X_L activity as a strategy for developing a small molecule that would act primarily as a potentiator in conjunction with standard cancer chemotherapies.Part of this thesis was focused on the synthetic work of inhibitor that designed of the Bcl-X_L by computer.Starting from D-glucose,the key intermediate 1,6:2,3 Cerny epoxide 139 was prepared and the aryl ether(at C-2) was successfully obtained,via nucleophile attacked in epoxide.This paper finished the synthesis of fourteen designed compounds in a linear 12-step sequence.This serves as a basis for screening out new inhibitor of the Bcl-X_L.