2. Academic Validation
  3. Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking

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

  • Bioorg Chem. 2020 Sep;102:104051. doi: 10.1016/j.bioorg.2020.104051.
Amira A Helwa 1,  Nehad M El-Dydamony 2,  Rasha A Radwan 3,  Sahar M Abdelraouf 4,  Rana M Abdelnaby 5
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October City, Egypt. Electronic address: [email protected].
  • 2 Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October City, Egypt.
  • 3 Biochemistry Department, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University- Kantara Branch, New City, El Ismailia, Egypt.
  • 4 Biochemistry Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.
PMID: 32659486 DOI: 10.1016/j.bioorg.2020.104051
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.

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