LSD1小分子抑制剂的合成及抗肿瘤活性研究

设计并合成了一系列以苯甲酰肼类结构为母核的赖氨酸特异性组蛋白去甲基化酶1(LSD1)小分子抑制剂,并研究其体外抗肿瘤活性。首先,通过体外酶水平单浓度抑制实验进行了初步评价,并随后进一步考察目标化合物对多种LSD1高表达肿瘤细胞株增殖的抑制作用,化合物结构经质谱及核磁共振表征确证。活性评价结果显示,3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)-N'-(7-羟基-2,3-二氢-1H-茚-1-亚基)苯甲酰肼、N'-(1-(5-氯-2-羟基苯基)亚乙基)-3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)苯甲酰肼和N'-(4-氯-7-羟基-2,3-二氢-1H-茚-1-亚基)-3-((4-吗啉代哌啶-1-基)磺酰基)苯甲酰肼可显著抑制肿瘤细胞的增殖,并有4个目标化合物对体外多种LSD1高表达的肿瘤细胞株增殖有抑制作用,其中3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)-N'-(7-羟基-2,3-二氢-1H-茚-1-亚基)苯甲酰肼对BGC823、HCT116、A2780s的半数抑制浓度分别为0.32、0.54、0.90μmol/L。

Synthesis and Anti-tumor Activity of Small Molecule Inhibitors of LSD1

A series of small molecule inhibitors of LSD1 were synthesized based on the structure of benzoyl hydrazine,and the anti-tumor activities in vitro were investigated.By the compound obtained in vitro enzyme inhibition level single concentration,and the anti-proliferative activity of the compounds for a variety of LSD1 tumor cell lines has been tested.The chemical structure of target compound were confirmed by ESI-MS and NMR.MTT assay showed that compound 3-((3R,5S)-3,5-dimethylmorpholinosulfonyl)-N'-(7-hydroxy-2,3-dihydroinden-1-ylidene) benzohydrazide,N'-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-((3 R,5S)-3,5-dimethylmorpholinosulfonyl) benzohydrazide and N'-(4-chloro-7-hydroxy-2,3-dihydroinden-l-ylidene)-3-(4-morpholinopiperidin-1-ylsulfonyl) benzohydrazide significantly inhibited tumor cell proliferation.Four target compounds showed inhibitory effect on the proliferation of tumor cell lines with high expression of LSD1 in vitro.The half of the compound 3-((3R,5S)-3,5-dimethylmorpholinosulfonyl)-N'-(7-hydroxy-2,3-dihydroinden-l-ylidene) benzohydrazide for BGC823,HCT116,A2780s inhibitory concentration (IC5o) was O.32,0.54,0.90 μmol/L.