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. 2022 Dec;37(1):2742-2754.
doi: 10.1080/14756366.2022.2128797.

Design, synthesis and antitumor activity of 5-trifluoromethylpyrimidine derivatives as EGFR inhibitors

Yaqing Zuo  1   2 , Rongrong Li  1   2 , Yan Zhang  1   2 , Guochen Bao  3 , Yi Le  1   2 , Longjia Yan  1   2
Affiliations

Design, synthesis and antitumor activity of 5-trifluoromethylpyrimidine derivatives as EGFR inhibitors

Yaqing Zuo et al. J Enzyme Inhib Med Chem. 2022 Dec.

Abstract

A new series of 5-trifluoromethylpyrimidine derivatives were designed and synthesised as EGFR inhibitors. Three tumour cells A549, MCF-7, PC-3 and EGFR kinase were employed to evaluate their biological activities. The results were shown that most of the target compounds existed excellent antitumor activities. In particular, the IC50 values of compound 9u (E)-3-((2-((4-(3-(3-fluorophenyl)acrylamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylthiophene-2-carboxamide against A549, MCF-7, PC-3 cells and EGFR kinase reached to 0.35 μM, 3.24 μM, 5.12 μM, and 0.091 μM, respectively. Additionally, further researches revealed that compound 9u could induce early apoptosis of A549 cells and arrest the cells in G2/M phase. Taken together, these findings indicated that compound 9u was potential for developing as antitumor reagent.

Keywords: EGFR; antitumor; inhibitor; pyrimidine; reagent.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Structures of antitumor reagents in literature.
Figure 2.
Figure 2.
Designed strategy of target compounds.
Scheme 1.
Scheme 1.
Synthetic route of compound 5. Reagents and conditions: (a) NaOCH3, MeOH, rt, 57% yield; (b) di-tert-butyl dicarbonate, DMAP, DIEA, 40 °C, 50% yield; (c) THF, NaOH, 70 °C, 97% yield; (d) CH3NH2HCl, HATU, DIEA, DMF, 25 °C, 96% yield; (e) HCl, NaHCO3, DCM, 25 °C, 76% yield.
Scheme 2.
Scheme 2.
Synthetic route of compound 9a-9x. Reagents and conditions: (a) NaH, DMF, rt, 37% yield; (b) TFA, TFE, 80 °C, 83% yield; (c) H2, Pd/C, rt, 69% yield; (d) HATU, DIEA, DMF, rt, 14% −69% yield.
Figure 3.
Figure 3.
In vitro cytotoxicity of 9a–9x and Gefitinib on NRK-52E.
Figure 4.
Figure 4.
Predicted ADMET properties of the target compounds and Gefitinib.
Figure 5.
Figure 5.
(a) Density plots were obtained by flow cytometry in the presence of different concentrations (0.1 μM, 0.5 μM and 1 μM); Gefitinib was used as the positive control. (b) Total apoptotic cells (%) at various concentrations of 9u and Gefitinib.
Figure 6.
Figure 6.
Proportion of A549 cells treated with compound 9u (0.1 μM, 0.5 μM and 1 μM) or Gefitinib (0.1 μM, 0.5 μM and 1 μM) at G0/G1, S and G2/M phases.
Figure 7.
Figure 7.
(a) Binding configuration of compound 9u with EGFR (PDB: 1M17); (b) The 2 D model of compound 9u bound to EGFR (PDB: 1M17); (c) Binding configuration of compound 9u with EGFR (PDB: 6DUK); (d) The 2D model of compound 9u bound to EGFR (PDB: 6DUK).
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