Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking

Two series of novel morpholinopyrimidine derivatives were synthesized and screened for their in-vitro cytotoxic activity against 60 tumor cell line by the National Cancer Institute, USA. The in-vitro cytotoxic IC50 values for the most active compounds 6e, 6g, and 6l against the most sensitive cell line leukemia SR were estimated (IC50 = 0.76, 13.59, and 4.37 uM, respectively). To investigate their PI3K enzyme inhibition activity, the assay was done on Class IA (alpha, beta, & delta) isoforms. The IC50 values were very promising: compound [6e = 11.73 (alpha), 6.09 (beta), 11.18 (delta)], compound [6g = 8.43 (alpha), 15.84 (beta), 30.62 (delta)], and compound [6l = 13.98 (alpha), 7.22 (beta), 10.94 (delta)], compared to the reference compound LY294002 = 6.28 (alpha), 4.51 (beta), 4.60 (delta) uM, respectively. Moreover, cell cycle analysis and annexin V-FITC staining were done on Leukemia SR, there was arrest at G2/M phase and apoptosis was induced. Finally, docking study was performed to analyze the interactive mode of these derivatives in PI3K alpha ATP-binding site. These outcomes proved that compounds 6e, 6g, and 6l are potential leads for further optimization as antileukemic agents.