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
  • 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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