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Anticancer Agents Med Chem. 2019 Dec 10. doi: 10.2174/1871520619666191211104128. [Epub ahead of print]

New uracil analog with exocyclic methylidene group as potential anticancer agent.

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Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz. Poland.
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Lodz. Poland.
Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Lodz, Lodz. Poland.



Hybrid molecules combining uracil skeleton with methylidene exo-cyclic group were designed in the search for novel anticancer drug candidates.


Two series of racemic 5-methylidenedihydrouracils, either 1,3-disubstituted or 1,3,6-trisubstituted were synthesized and tested for their possible cytotoxic activity against two cancer cell lines (HL-60 and MCF-7) and two healthy cell lines (HUVEC and MCF-10A). The most cytotoxic analogs were re-synthesized as pure enantiomers. Analog designated U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], which had a very low IC50 value in HL-60 cell line (0.77µM) and was the most selective towards cancer cells was chosen for further experiments on HL-60 cell line, in order to determine the possible mechanism involved in its antineoplastic action.


Cytotoxic activities of compound was assessed by the MTT assay. In order to explore the mechanism of U-332 activity we performed quantitative real-time PCR analysis of p53 and p21 genes. Apoptosis, cell proliferation and DNA damage in HL-60 cells were determined using the flow cytometry. The ability of U-332 to determination of GADD45ɑ protein level in HL-60 cells incubated with U-332 was analyzed by ELISA test.


U-332 was shown to generate excessive DNA damage (70% of cell population), leading to p53 activation, resulting in p21 down-regulation and significant increase of GADD45α protein, responsible for the cell cycle arrest in G2/M phase.


U-332 can be used as a potential lead compound in further development of novel uracil analogs as anticancer agents.


5-Methylidenedihydrouracils; Apoptosis; Cell Cycle; DNA Damage; GADD45 Proteins; MTT Assay; Proliferation

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