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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.

Author information

1
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz. Poland.
2
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Lodz. Poland.
3
Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Lodz, Lodz. Poland.

Abstract

BACKGROUND:

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

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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

KEYWORDS:

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

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