Synthesis And Characterization Of Amino Acid Conjugates With Asiatic Acid,Glycyrrhetinic Acid, Hydroquinone And The Study On The Biological Activity

Amino acids, as the basic units, constitute of the protein molecule and have a close relationship with the biological activities of life. As one of the indispensable nutrients in vivo, more and more researchers concentrate on the study of amino acids for they play an important part in medicine, pharmacology and biochemistry.With the widely applying of combinatorial chemistry technology and the urgent demanding of peptide drugs,unnatural amino acid as a building block is widely used in synthesis of peptides and alkaloids with medicinal value.Inducing unnatural amino acids into bioactive peptides can limit the conformational flexibility, improve the bioavailability, raise the resistance to protease degradation and lower the toxicity. As the design conception mentioned above, we coupling amino acids with bioactive compounds directly or indirectly through connecting fragment succinic anhydride. We hope to get amino acid conjugates with higher efficiency and lower toxicity.There are three parts in this dissertation:The first part:Briefly introduce the research progress of amino acids and list the pharmacological activities of asiatic acid, glycyrrhetinic acid, hydroquinone and their derivatives. Prospecting the development of amino acid drugs.The second part:Design, synthesis and characterization of amino acid conjugates and the applying of connecting fragment24derivatives were synthesized through exploring the best conditions of synthesizing, separating and purifying, details are as followed:1. Methyl2-hydroxy-3,23-isopropylidenedioxyurs-12-ene-28-oate can be synthesized through the protection of asiatic acid at C-3,23-OH and C-28-COOH. After introducing connecting fragment succinic acid to C-2, we couple it with amino acid methyl ester hydrochloride. Finally we get3amino acid conjugates;2. Protecting the amino groups of the unnatural amino acids, and then coupling with asiatic acid methyl ester at C-2position and glycyrrhetinic acid methyl ester at C-3position. After removing the protecting groups we get ten amino acid conjugates;3. Combination of protected amino acid and-OH of hydroquinone, and then remove the protecting groups. We get6amino acid conjugates;20new structures were characterized by the IR,1H NMR and13C NMR. The third part:The study of GA, G-2a, G-3a, AA, A-5a, A-6a, A-3on anti-tumor activity and anti-viral activity show that:A-3and A-6inhibit the growth of U87ΔGEFR and PC9/G especially on PC9/G. G-3a and A-3are able to inhibit EV71replication and G-3a present more significant inhibition to the expression of EV71vp1gene. The study of HQ-1a, HQ-1b, HQ-1c, HQ-2a, HQ-2b, HQ-1a, HQ-2c shows that HQ-2c and HQ-2b have significant inhibition to tyrosinase. HQ-2b present more significant inhibition to tyrosinase.