Synthesis, Characterization And Biological Activity Of Nitrogen Mustard Derivatives

The nitrogen mustards are an important group of alkylating agents with activity againsttumor cells for clinical application. However, most of these agents have poor selectivity. Inorder to reduce their side effects in normal tissues and improve their specificity to tumor cells,we modified them with several kinds of carbohydrate （glucose, fructose, lactose, chitosan）and vanillin. The glycosylated nitrogen mustards derivatives and vanillin linked nitrogenmustard conjugate were firstly synthesized; And part of the novel derivatives’bioactivitywere studied as prodrugs for further anti-tumor research.In this thesis, bis（2-chloroethyl）carbamic chloride（BCC） was firstly prepared throughbis（2-chloroethyl）amine hydrochloride and bis（trichloromethyl） carbonate. Methanol wasused as quencher in this step, and formation of reaction products was monitored by changes inTLC. Secondly, four kinds glycosylated nitrogen mustards derivatives（GB, FB, LB, CTB） andvanillin linked nitrogen mustard conjugate（VANB） were obtained for estering reactionhappened between bis（2-chloroethyl）carbamic chloride and corresponding carbohydrates orvanillin. Thirdly, the terminal products were characterized by FT-IR, MS and UV spectra, theresult showed that the five novel nitrogen mustards derivatives were successfully obtained.The thermodynamic properties of CTB was studied by TG-DSC. And the thermaldecomposition temperature of CTB was lower about 50oC than chitosan for the formation ofamide group. Lastly, the interaction between glycosylated nitrogen mustards derivatives（GB,FB, LB） and bovine serum albumin （BSA） was investigated by using fluorescence spectra inTri-HCl buffer solution at physiological conditions，and their binding site number weremeasured correspondingly. The quenching mechanism for GB, FB, LB with BSA were the static quenching process, and the quenching rate constant of GB was 7.499×1012L mol^-1 S^-1,the quenching rate constant of FB was 7.088×1012L mol^-1 S^-1, the quenching rate constant ofLB was 1.1098×1013L mol^-1 S^-1. The binding site number of them all were 1.