Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives

Abstract

A series of novel indole-pyrimidine biaryl derivatives were designed, synthesized and evaluated for inhibitory activity against Lysine Specific Demethylase 1 (LSD1) and antiproliferative activity against five selected cancer cell lines (MGC-803, PC-3, EC-109, PC-12 and MCF-7). The priliminary structure-activity relationship (SAR) for this indole-pyrimidine biaryl scaffold was explored with evaluation of 22 variants of the structural class. Among these analogues, compound 1-(4-(4-(1-methyl-1 H-indol-3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-((3,4,5-trimethoxyphenyl)amino)ethan-1-one (6i) exhibited the potential inhibitory activity against LSD1 (IC 50=1.03 µmol/L), compounds 1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-(m-tolylamino)ethan-1-one (6c), 2-((4-butylphenyl)amino)-1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (6f) and 2-((3-fluorophenyl)amino)-1-(4-(4-(1-methyl-1 H-indol-3-yl)pyri- midin-2-yl)piperazin-1-yl)ethan-1-one (6k) showed the potential inhibitory activity aginst PC-3 cells. Especially, compound6k exhibited the best antitumor activity (IC50=2.75 µmol/L), which was served as bioactive fragment and hit compound for developing more potent antitumor agents.