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  2. Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells

Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells

  • Sci Rep. 2022 Dec 22;12(1):22146. doi: 10.1038/s41598-022-26571-7.
Maha M Salem 1 Marian N Gerges 2 Ahmed A Noser 3
Affiliations

Affiliations

  • 1 Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt. maha_salem@science.tanta.edu.eg.
  • 2 Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
  • 3 Organic Chemistry, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
Abstract

In the present investigation, derivatives from (2-6) containing pyrimidine-2-thione moiety incorporated with different heterocycles such as pyrazoline, phenyl pyrazoline, and pyrimidine were synthesized using different methods. These pyrimidine-2-thione derivatives were evaluated in-silico for their capability to inhibit the H-RAS-GTP active form protein with insight to their pharmacokinetics properties. According to our findings, compound 5a was selected for in vitro studies as it has the in-silico top-ranked binding energy. Furthermore, compound 5a induced Apoptosis to panels of Cancer cell lines with the best IC50 on MCF-7 breast Cancer cells (2.617 ± 1.6 µM). This effect was associated with the inhibition of phosphorylated Ras, JNK proteins, and PI3K/Akt genes expression. Thus, compound 5a has upregulated p21 gene and p53 protein levels. Moreover, 5a arrested the cell cycle progression at the sub-G0/G1 phase. In conclusion, the synthesized compound, 5a exhibited potent antineoplastic activity against breast Cancer cell growth by targeting Ras/ PI3K/Akt/ JNK signaling cascades.

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