Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and synthesized a novel series of pyrimidine–thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine–thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.

Design, Synthesis, and Structure–Activity Relationship of Novel LSD1 Inhibitors Based on Pyrimidine–Thiourea Hybrids As Potent, Orally Active Antitumor Agents

The cholinomimetic agents, physostigmine, neostigmine, and arecoline, and the anticholinergic agents, atropine, scopolamine, and methscopolamine, have been used to explore an acetylcholine hypothesis of affect disorders and stress. Cholinomimetic drugs cause many of the same effects as do naturally occurring stressors. These include increases in negative affect, the induction of affective disorders, increases in stress neuroendocrines including ACThH, cortisol, beta-endorphin, growth hormone, prolactin, epinephrine, and noprepinephrine, increases in blood pressure and pulse rate, and increases in analgesia. These parallel effects, combined with the effect of stress on central acetylcholine activity, suggest a stress-acetylcholine linkage.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ddr.430040202

Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress

Synthesis and antioxidant activity of 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives

Long-acting delivery systems for narcotic antagonists. 1.

C. L. Kaul

Papers

Antihypertensive and monoamine oxidase inhibitory activity of some derivatives of 3-formyl-4-oxo-4H-pyrido (1,2-a) pyrimidine.

Effect of physostigmine upon the output of catecholamines from the adrenal gland of the rat

Antihypertensive and monoamine oxidase inhibitory activity of some azacycloaklyl-substituted benzaldehyde hydrazone derivatives

Synthesis and Antitussive Activity of N-[Indenyl(3)]ureas

Antihypertensive und monoamino-oxidase-inhibierung einiger azacycloalkyl-substituierter benzaldehyd-hydrazon-derivate