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  3. Synthesis, biological evaluation and molecular docking studies of novel thiopyrimidine analogue as apoptotic agent with potential anticancer activity

Synthesis, biological evaluation and molecular docking studies of novel thiopyrimidine analogue as apoptotic agent with potential anticancer activity

  • Bioorg Chem. 2020 Nov;104:104249. doi: 10.1016/j.bioorg.2020.104249.
Hesham Haffez 1,  Heba Taha 2,  Maha A Rabie 3,  Samir M Awad 4,  Yasser M Zohny 5
Affiliations

Affiliations

  • 1 Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt; Helwan Structural Biology Center for Excellence, Helwan University, P.O. Box, 11795, Cairo, Egypt.
  • 2 Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt. Electronic address: [email protected].
  • 3 Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, P.O. Box 11562, Cairo, Egypt; Pharmacy Practice Department, College of Pharmacy, Shaqra University, P.O. Box 11961, Dawadmi 11911, Saudi Arabia.
  • 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt; Pharmaceutical Sciences Department, College of Pharmacy, Shaqra University, P.O. Box 11961, Dawadmi 11911, Saudi Arabia.
PMID: 32911199 DOI: 10.1016/j.bioorg.2020.104249
Abstract

This study synthesizes novel 6-amino-5-cyano-4-aryl-2-mercapto pyrimidines and condensed pyrimidines analogues in order to investigate their potential activity as Anticancer agents. The compounds were synthesized via one-pot condensation of p-nitrobenzaldehyde or p-anisaldehyde with malononitrile and thiourea to prepare 6-amino-5-cyano-4-aryl-2-mercaptopyrimidines series (1-9a,b). The pyrimidine analogues were biologically screened In-vitro in HepG2 and MCF-7 compared to normal WI-38. Compound 8a showed higher antiproliferative activity to MCF-7 cells with sensitivity and minimal cytotoxic effect (IC50 53.3 µM- HepG2, 12.9 µM- MCF-7 and >100 µM- WI-38). Compound 8a was able to induce 40% of total antioxidants and 60% following treatment with 50 µM of H2O2 for 3hrs as external source of oxidative stress in MCF-7. 8a was able to significantly induce early stage Apoptosis of 74.37% MCF-7 and cell cycle arrest with cells accumulation in subG0-G1 phase to 69.42% and reduction of cells in G2M phase to 3.6% and high apoptotic index. Compound 8a induced over-expression of Fas Receptor and Cyto C genes. Molecular docking studies suggested that 8a can bind to both phosphodiesterase 4B and 4D binding pockets and inhibit their action through network of hydrophobic interactions in Q-P pockets with preferential selectivity to PDE4B through invariant Glu443. The chemical profile and the biological results suggest that 8a can be a promising Anticancer agent.

Keywords

8a; Anticancer; Apoptosis; Phosphodiesterase; Thiopyrimidines.

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