Shan Lihong, Li Zhaoxiang, Chen Huabin, Ge Meng, Sun Yingying, Sun Ying, Li Yaru, Li Hongyu, Fu Ling, Liu Hongmin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Bioorg Chem. 2023 Feb;131:106150. doi: 10.1016/j.bioorg.2022.106150. Epub 2022 Sep 13.
Gliotoxin is a representative compound of the epipolythiodioxopiperazine (ETP) class of fungal metabolites. Histone Lysine Specific Demethylase 1 (LSD1) is highly expressed in a variety of cancers. Herein, a series of 6-heterocyclic carboxylic ester derivatives of gliotoxin was designed and synthesized as new LSD1 inhibitors and their biological evaluations in human gastric MGC-803 and HGC-27 cells were carried out. All of the derivatives effectively suppressed the enzymatic activities of LSD1. In particular, compound 4e exhibited excellent LSD1 inhibition with IC = 62.40 nM, as well as anti-proliferation against MGC-803 and HGC-27 cells with IC values of 0.31 μM and 0.29 μM, respectively. 4e also had a remarkable capacity to inhibit the colony formation, suppress migration and induce the apoptosis of these two cancer cell lines. In sum, our findings identified and characterized the 6-heterocyclic carboxylic ester derivatives of gliotoxin as potent and cellular active LSD1 inhibitors, which may provide a novel chemotype of LSD1 inhibitors for gastric cancer treatment.
Gliotoxin是真菌代谢产物中表硫代二氧哌嗪（ETP）类的代表性化合物。组蛋白赖氨酸特异性去甲基化酶1（LSD1）在多种癌症中高表达。在此，设计并合成了一系列gliotoxin的6-杂环羧酸酯衍生物作为新型LSD1抑制剂，并在人胃癌MGC-803和HGC-27细胞中进行了生物学评价。所有衍生物均有效抑制LSD1的酶活性。特别是，化合物4e表现出优异的LSD1抑制活性，IC50 = 62.40 nM，对MGC-803和HGC-27细胞的抗增殖IC50值分别为0.31 μM和0.29 μM。4e还具有显著的抑制这两种癌细胞系集落形成、抑制迁移和诱导凋亡的能力。总之，我们的研究结果鉴定并表征了gliotoxin的6-杂环羧酸酯衍生物为有效的细胞活性LSD1抑制剂，这可能为胃癌治疗提供一种新型的LSD1抑制剂化学类型。
