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Inhibition of lysine-specific demethylase 1 (LSD1) has recently emerged as an attractive therapeutic target for treating cancer and other diseases. As a continuity of our ongoing effort to identify novel small-molecule LSD1-inhibitors, we designed and synthesized a series of resveratrol derivatives, which were shown to be potent inhibitors of LSD1. Among them, compounds 4e and 4m displayed the most potent LSD1-inhibitory activities in enzyme assays, with IC 50 values of 121 nM and 123 nM, respectively. Biochemistry study and docking analysis indicated that compounds 4e and 4m were reversible LSD1 inhibitors. High content analysis showed that 4e and 4m induced a dose-dependent increase of dimethylated Lys4 of histone H3 and had no impact on the expression of LSD1 in MGC-803 cells. Furthermore, 4e or 4m could remarkably increase the mRNA level of CD86, a surrogate cellular biomarker for LSD1 activity, in MGC-803 cells, suggesting that they are likely to exhibit LSD1-inhibitory activities intracellularly. These findings should encourage further modification of these compounds to produce more potent LSD1 inhibitors with potential anticancer activity. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 1,2,3-triazole–dithiocarbamate–urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 μM and 0.76 to 13.55 μM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 μM and 70 μM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques. [Copyright &y& Elsevier]