Study On Synthesis And Properties Of 2-Amino-1,3-Propanediol-Based Gene Vectors And Synthesis Of Abiraterone Derivatives

The paper includes two parts: Part one.Study on synthesis and properties of 2-amino-1,3-propanediol-based gene vector.Gene therapy has gained significant attention as a potential method for treating genetic disorders,which aroused researchers' curiousity.Currently,The biggest obstacle is to find a safe and efficient carrier,which make the specific gene to the target cells,Besides that,cationic liposome has proved to be the most effective non-viral gene and received significant attention.In this paper,a series of cationic lipids were synthesized.The five cationic lipids di-C8-Ser-TMA,di-C10-Ser-TMA,di-C12-Ser-TMA,di-C14-Ser-TMA,di-C16-Ser-TMA with different hydrophobic chain lengths were constructed by using 2-amino-1,3-propanediol(Serinol)as starting material,via Williamson etherification,amidation with chloroacetic chloride and quaternarization with trimethylamine.The formation of lipoplexes of cationic liposomes and DNA was assessed by Gel retardation assay.Results revealed the increased amount of liposomes,the less light in DNA lane.When the N/P ratio added to 2,the liposome was fully integrated with plasmid DNA.The average particle size,size distribution and zeta potential of cationic liposomes and liposome/DNA complexes were characterized with Dynamic Ligh Scattering.The results suggested that the average particle size was 80-120 nm,and the size of cationic liposome/DNA complexes was between 150-360 nm.Zeta potential of cationic liposomes were about 60 mV and its complexes were between 20 mV and 50 mV.All physical parameters indicate that cationic liposomes are suitable for cell transfection.In vitro gene transfection results in HEK293,Mat and PC-3 cell lines reveal that di-C12-Ser-TMA shows better transfections efficiency and cell uptake rate,especially in PC-3 cells,which is better than commercially transfection agent Lipo2000.Moreover,Cell viabilities of all liposomes were found to be remarkably high(more than 70%).Thus cationic liposome di-C12-Ser-TMA can be a useful tool for intracellular gene delivery.Part two.Synthesis of abiraterone derivatives.Prostate cancer is the most common tumor and agerelated cause of death in elder men worldwide.Abiraterone as an effective inhibitor of CYP17,widely used in the treatment of prostate cancer.However,because of its poor water solubility,resulting in the high cost of medication,increasing the toxic side effects.The purpose of this paper is to improve its water solubility by structural modification and promote its drug absorption.In this paper,The design and synthesis of Three types new abiraterone derivatives.One derivative 5 Was constructed by using abiraterone as starting material,amidation with chloroacetic chloride and quaternarizationwith trimethylamine.The other five derivatives 13a-13 e with different hydrophobic chain lengths Were constructed using ethylenediamine as starting material,via Boc-ation of amino group,tertiary amination,Boc-deprotection,condensation and quaternization.Another five derivatives 15a-15 e with different hydrophobic chain lengths Were constructed using ethylenediamine as starting material,via Boc-ation of amino group,tertiary amination,quaternization Boc-deprotection,condensation.