Tranylcypromine (TCP) is a useful pharmacophore for lysine-specific demethylase 1 (LSD1) inhibitors. Based on the mode of action (MOA) of TCP and structure of LSD1, divalent TCP derivatives with aliphatic and benzylic linkers were designed, synthesized, and evaluated for their LSD1 inhibitory activity, MV4-11 antiproliferative activity, and CD86 mRNA expression enhancement. All ten new compounds showed improved activity against LSD1 than TCP and GSK2879552. Several compounds with rigid aliphatic linkers demonstrated nanomolar enzymatic and cellular activities, as well as good MAO-A/B selectivity. Further supported by their significant CD86 mRNA expression enhancement effect, divalent TCP derivative can be promising lead for new LSD1 inhibitors.

tranylcypromine（TCP）是赖氨酸特异性脱甲基酶1（LSD1）抑制剂的有用药效团。根据TCP的作用方式（MOA）和LSD1的结构，设计，合成具有脂肪族和苄基连接子的二价TCP衍生物，并评估其对LSD1的抑制活性，MV4-11抗增殖活性和CD86 mRNA表达增强。与TCP和GSK2879552相比，所有十种新化合物均显示出对LSD1更好的活性。具有刚性脂族连接基的几种化合物表现出纳摩尔的酶和细胞活性，以及​​良好的MAO-A / B选择性。二价TCP衍生物进一步受到其显着的CD86 mRNA表达增强作用的支持，有望成为新型LSD1抑制剂的有前途的先导。