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

• Published in: Scientific reports Vol. 12; no. 1; p. 22146
• Main Authors: Salem, Maha M., Gerges, Marian N., Noser, Ahmed A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/154; 631/337; 631/45; 631/535; 631/67; 631/92; 639/638; 692/308; 692/4017; 692/4028; 692/53; AKT protein; Antineoplastic Agents - chemistry; Antineoplastic drugs; Apoptosis; Breast cancer; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell growth; Cell Proliferation; Chemistry; Cyclin-dependent kinase inhibitor p21; Cyclin-dependent kinases; Drug Screening Assays, Antitumor; Female; G1 phase; GTP-binding protein; H-Ras protein; Humanities and Social Sciences; Humans; JNK protein; Kinases; Molecular Docking Simulation; Molecular Structure; multidisciplinary; p53 Protein; Pharmacokinetics; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - therapeutic use; Ras protein; Science; Science (multidisciplinary); Structure-Activity Relationship; Thiones - pharmacology; Tumor cell lines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-26571-7

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 IC 50 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.