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

Abstract

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 (α, β, & δ) isoforms. The IC₅₀ values were very promising: compound [6e = 11.73 (α), 6.09 (β), 11.18 (δ)], compound [6g = 8.43 (α), 15.84 (β), 30.62 (δ)], and compound [6l = 13.98 (α), 7.22 (β), 10.94 (δ)], compared to the reference compound LY294002 = 6.28 (α), 4.51 (β), 4.60 (δ) 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 PI3Kα ATP-binding site. These outcomes proved that compounds 6e, 6g, and 6l are potential leads for further optimization as antileukemic agents.

Keywords: Apoptosis; Cytotoxicity; Leukemia; Molecular modeling; Morpholinopyrimidine; PI3K inhibition.