247132-69-0Relevant articles and documents
Design, synthesis, and biological evaluation of 5-aminotetrahydroquinoline-based LSD1 inhibitors acting on Asp375
Yan, Jiangkun,Gu, Yanting,Sun, Yixiang,Zhang, Ziheng,Zhang, Xiangyu,Wang, Xinran,Wu, Tianxiao,Zhao, Dongmei,Cheng, Maosheng
, (2021)
The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1?inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1–B5, and C4 showed preferable inhibitory effects on LSD1, with IC50 = 0.19–0.82 μM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible LSD1 inhibitors
Cheng, Maosheng,Jiang, Qinwen,Wang, Jiming,Wang, Xinran,Yan, Jiangkun,Zhang, Cai,Zhang, Xiangyu,Zhao, Dongmei,Zhao, Liyu
, (2020/03/30)
The targeted regulation of LSD1, which is highly expressed in a variety of tumor cells, is a promising cancer therapy strategy. Several LSD1 inhibitors are currently under clinical evaluation, and most of these inhibitors are irreversible. Here, we report the design, synthesis and biochemical evaluation of novel tetrahydroquinoline-based reversible LSD1 inhibitors. Compounds 18s and 18x, which are selective to LSD1 over MAO-A/B, exhibit excellent LSD1 inhibition at the molecular levels with IC50 = 55 nM and 540 nM, respectively. The classic Lineweaver–Burk plots revealed that compound 18s could reversibly bind the LSD1 enzyme in a noncompetitive manner. Molecular docking was used to reveal the potential binding-mode of the compounds and interpret the structure-activity relationships. Furthermore, compounds 18s and 18x significantly inhibited proliferation (IC50 = 1.13 μM and 1.15 μM, respectively) and induced apoptosis in MGC-803 cells with high expression of LSD1. Compound 18x showed acceptable liver microsomal stability. Meanwhile, 18x did not appear to inhibit CYPs at 10 μM in vitro. Remarkably, the oral administration of compound 18x can inhibit the growth of MGC-803 xenograft tumors without significant side effects. Our findings suggest that tetrahydroquinoline-based LSD1 inhibitors deserve further investigation for the treatment of LSD1 overexpressing cancer.
CYCLOALKOXY-SUBSTITUTED 4-PHENYL-3,5-DICYANOPYRIDINES AND THEIR USE
-
Page/Page column 22, (2011/02/18)
The present application relates to novel cycloalkoxy-substituted 4-phenyl-3,5-dicyanopyridine derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, preferably for the treatment and/or prevention of cardiovascular and metabolic disorders.
Amidine compounds
-
, (2008/06/13)
A compound of the formula [I] wherein R1, R2and R3are the same or different and each is hydrogen atom, wherein each symbol is as defined in the specification, a salt thereof or a prodrug thereof. The compound of the presen
