Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent

Abstract

In our previous study, 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea (1) was obtained as a potent tyrosine kinase inhibitor. Further structural optimization was performed in this investigation, and a series of novel quinoline derivates were designed, synthesized and evaluated for their biological activity. Among them, compound 8m possessed nanomolar c-Met and Ron inhibitory activity, with IC50 values of 4.32 nM and 2.39 nM, respectively. Kinase profile study demonstrated that it could also inhibit ABL, PDGFRβ, AXL, RET, and FLT3 with submicromolar potency. It also exhibited moderate to excellent cytotoxic activity against different types of human cancer cell lines, especially against COLO 205 cells (IC50 = 0.035 μM) which was remarkably superior to that of Cabozantinib (IC50 = 6.6 μM) and Fruquintinib (IC50 > 10.0 μM). Compared to ( ± )-8m, isomer (S)-8m and (R)-8m showed similar kinase inhibitory activity against c-Met/RON and in vitro anticancer activity against COLO 205 cells. Differently, compound (S)-8m showed an over 238-fold selectivity toward COLO 205 (IC50 = 0.042 μM) cells to FHC cells (IC50 > 10.0 μM), which indicated its low cytotoxicity against human normal tissue cells. Flow cytometry study demonstrated that compound (S)-8m could significantly induce apoptosis in COLO 205 cells in a dose-dependent manner. Cell cycle arrest assays showed that compound (S)-8m could not arrest the cell-cycle progression due to the massive dead cells.