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. 2021 Apr 7;22(8):3825.
doi: 10.3390/ijms22083825.

Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study

Beata Tylińska  1 , Benita Wiatrak  2 , Żaneta Czyżnikowska  3 , Aneta Cieśla-Niechwiadowicz  4 , Elżbieta Gębarowska  5 , Anna Janicka-Kłos  3
Affiliations

Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study

Beata Tylińska et al. Int J Mol Sci. .

Abstract

In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking.

Keywords: 3,4-dihydronaphthalen; 6-hydrazinopyrimidine; DNA intercalating; QSAR study; anticancer; lipophilicity; pyrimidine; topoisomerase II.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of new pyrimidine derivatives.
Figure 1
Figure 1
The probability of biological activity predicted based on the 3D/4D QSAR algorithm (0.0–0.2—extremely low, 0.2–0.8—moderate, 0.8–1.0—very high).
Figure 2
Figure 2
Cytotoxicity effect after incubation of cells with the tested compounds: (A) NHDF cells; (B) HeLa cells; (C) A549 cells; (D) MCF7 cells; (E) CCRF-CEM cells; (F) THP-1 cells; (G) LoVo cells; (H) LoVo/Dx cells. Data presented as a mean and SEM (standard error of the mean); * p < 0.05—significant difference compared to the control.
Figure 3
Figure 3
Rhodamine accumulation after incubation with the tested compounds and doxorubicin in various concentration ranges in LoVo/DX cells. Data presented as a mean and SEM (standard error of the mean); * p < 0.05—significant difference compared to the control.
Figure 4
Figure 4
Effect of tested compounds and doxorubicin (Dox) on the level of apoptotic cells (apoptosis, late apoptosis and necrosis after 24 h of incubation): (A) A549 cell line; (B) CCRF-CEM cell line. Apoptosis—annexin V (conjugated with fluorescein) combines with phosphatidylserine, which as a result of damage is located on the outer side of the cell membrane (the color of the cell is green); late apoptosis—when the continuity of the cell membrane has been broken and propidium iodide has entered the cell (the cell has two colors—green and red); necrosis—when the membrane is degraded and the cell stains only red as a result of propidium iodide fusion with the cell nucleus.
Figure 5
Figure 5
Effect of the tested compounds and doxorubicin (Dox) on the cell cycle after 24 h of incubation: (A) CCRF-CEM cell line; (B) A549 cell line.
Figure 6
Figure 6
Effect of the tested compounds and doxorubicin (Dox) on the migration of cells in the scratch assay after 24 h of incubation for the A549 cell line: (A) migration speed; (B) wound area after 24 h.
Figure 7
Figure 7
The binding mode of: (A) the most potent inhibitor 4, (B) etoposide in the active site of Topo IIα; 3D representation, DNA structure is marked in cyan, the protein chain is yellow, ligand structures are grey.
Figure 8
Figure 8
Intermolecular interactions in the active site of Topo IIα (2D representation) of: (A) the most potent inhibitor 4, (B) etoposide.
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