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  3. Rational design, synthesis, biological evaluation, molecular docking, and molecular dynamics of substituted uracil derivatives as potent anti-cancer agents

Rational design, synthesis, biological evaluation, molecular docking, and molecular dynamics of substituted uracil derivatives as potent anti-cancer agents

  • Bioorg Chem. 2025 Jan:154:108066. doi: 10.1016/j.bioorg.2024.108066.
Ebtessam A Basiony 1,  Allam A Hassan 2,  Mohamed Elsawalhy 3,  Adel A-H Abdel-Rahman 3,  Hayam Mansour 4,  Reem K Arafa 5,  Nasser A Hassan 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Menoufia University, Egypt; Department of Photochemistry (Synthetic Unit), Chemical Industries Research Institute, National Research Centre, Cairo 12622, Egypt.
  • 2 Department of Chemistry, Faculty of Science, Suez University, Suez 43221, Egypt.
  • 3 Department of Chemistry, Faculty of Science, Menoufia University, Egypt.
  • 4 Department of Cell Biology, Biotechnology Research Institute, National Research Centre, Cairo 12622, Egypt.
  • 5 Drug Design and Discovery Lab, Zewail City of Science and Technology, Cairo 12578, Egypt; Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo 12578, Egypt. Electronic address: rkhidr@zewailcity.edu.eg.
  • 6 Department of Photochemistry (Synthetic Unit), Chemical Industries Research Institute, National Research Centre, Cairo 12622, Egypt. Electronic address: nasserabdelhamid@hotmail.com.
PMID: 39718078 DOI: 10.1016/j.bioorg.2024.108066
Abstract

An efficient synthesis of a series of uracil analogous was performed to obtain new potential Anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three Cancer cell lines, namely hepatic Cancer (HepG-2), colon Cancer (HCT-116), and breast Cancer (MCF-7). Among the tested compounds, 5, 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent Thymidylate Synthase (TS) Enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric Apoptosis and protein expression of pro- and anti-apoptotic markers Bax, Bcl-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing Apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS.

Keywords

Anticancer activity; Flow cytometry; Molecular docking; Molecular dynamics; Thymidylate synthase enzyme inhibition; Uracil derivatives.

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