Design,Synthesis And Antitumor Activity Evaluation Of Novel Purine Small Molecule Compounds Targeting LSD1

Histone lysine specific demethylase 1（LSD1）is a histone demethylase that was first discovered and reported by Dr.Shi Yang in 2004 and is classified as a member of the amine oxidase family.With the participation via the cofactor flavin adenine dinucleotide（FAD）,LSD1 can specifically remove mono-or di-methylated H3K4/K9by oxidation reaction,acts as the role of histone methylation erasers.A large number of studies have shown that LSD1 and its downstream target proteins are involved in a wide range of biological functions,including embryonic development,tumor growth and metastasis.Due to the overexpression of LSD1 in a variety of malignant tumors,the inactivation or down-regulation of LSD1 can be an effective method for the treatment of cancers.Research and development of high-efficiency and low-toxic LSD1 inhibitors with good pharmacokinetic parameters has become a new strategy to prevent and treat cancers.Purines are an important class of intracellular components involved in metabolic,nucleic acid synthesis and multiplicity of biochemical reactions,associated with a broad spectrum of pharmacological activities that lead to many efforts in chemical modification of purine analogues and derivatives.In this thesis,LSD1 was used as the target protein,we designed and synthesized three series of purine analogues based on the previously reported purine LSD1 inhibitors by our group.The specific research work is as follows:1.According to the general principle proposed in a report by our group:the terminal basic group installed with heterocycles are particularly active toward LSD1,and these compounds can occupy the binding region of the H3 peptide substrate and interact with the amino acid residues through hydrogen bond,thereby inhibit the demethylation activity of LSD1.We have linked several types of fragments with terminal amino groups to a pyrimidine triazole fused ring skeleton that has exhibited strong activity,and it was found that the compound I-18 in which the hydrazine group was bonded to the fused ring exhibited strong inhibitory activity.Furthermore,compound I-18 was modified as a lead,and a total of 20 compounds were initially synthesized and evaluated for their LSD1 inhibitory activity,the activity of compound I-26 was observed to be further enhanced IC₅₀=2.26μM).2.Based on the pyrimidine structural unit LSD1 inhibitor reported by our group and the glycine derivative LSD1 inhibitor reported in the literature,the pyrimidine andα-amino acid structural fragments were combined to design and synthesize a new type of purine derivatives.This kind of compounds have been found to have weak inhibitory activity against LSD1,but showed strong anti-lung cancer and moderate-intensity anti-gastric cancer activity.Biological mechanism tests have shown that such compounds could inhibit apoptosis of tumor cells and EMT processes.3.Through the structure-activity relationship of the anti-gastric cancer activity exhibited by the above series of hydrazine derivatives,the C-8 position has been optimized with different kinds of substituents,and a series of purine-chalcone derivatives were designed and synthesized to against gastric cancer cells proliferation through the inhibitory activity evaluation.The results showed that compound III-6o can effectively inhibit the proliferation of gastric cancer MGC803 cells(IC₅₀=0.84μM),and induce apoptosis of MGC803 cells through both of the death receptor-mediated external pathway and mitochondria-mediated internal pathway.Through the above research work,20 pyrimidine triazole derivatives and 37terpenoids were synthesized.The newly synthesized compounds were screened for LSD1 inhibitory activity and evaluated for antitumor activity,a series of structurally novel small-molecule compounds targeting LSD1 were obtained.These findings are a new complement to the chemical structure types of LSD1 inhibitors and anti-tumor agents,and have a certain significance for further research on the biological mechanisms of LSD1,as well as the research and discovery of anti-tumor drugs.