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. 2022 Feb 16;10(2):461.
doi: 10.3390/biomedicines10020461.

Synthesis, Structure, and Antiproliferative Action of 2-Pyridyl Urea-Based Cu(II) Complexes

Kirill K Geyl  1 , Sergey V Baykov  1 , Stanislav A Kalinin  1   2 , Alexandr S Bunev  2 , Marina A Troshina  2 , Tatiana V Sharonova  1 , Mikhail Yu Skripkin  1 , Svetlana O Kasatkina  1 , Sofia I Presnukhina  1   3 , Anton A Shetnev  3 , Mikhail Yu Krasavin  1 , Vadim P Boyarskiy  1
Affiliations

Synthesis, Structure, and Antiproliferative Action of 2-Pyridyl Urea-Based Cu(II) Complexes

Kirill K Geyl et al. Biomedicines. .

Abstract

Relying on a recently suggested protocol that furnishes convenient access to variously substituted 2-pyridyl ureas, twelve hitherto unknown Cu(II) complexes have been synthesized in the present work and their structures were evaluated by elemental analysis, HRMS, IR spectroscopy, and X-ray diffraction study. Two structural motifs ([Cu(L)2Cl]+[Cl]- or (Cu(L)2Cl2) depending on the substitution pattern on the 2-pyridine fragment were revealed. In addition, antiproliferative action of the obtained compounds have been investigated against lung cancer cell lines (A549, NCI-H460, NCI-H1975), and healthy WI-26 VA4 cells were used to monitor non-specific cytotoxicity. Two nitro-group substituted complexes Cu(U3)2Cl2 (IC50 = 39.6 ± 4.5 μM) and Cu(U11)2Cl2 (IC50 = 33.4 ± 3.8 μM) demonstrate enhanced activity against the drug resistant NCI-H1975 cells with moderate selectivity toward normal WI-26 VA4 cells. The antiproliferative mechanism of cell death underlying the growth inhibitory effect of the synthesized complexes was studied via additional experiments, including the cell cycle analysis and the apoptosis induction test. Reassuringly, certain 2-pyridyl urea-based Cu(II) complexes exerted cell line-specific antiproliferative effect which renders them valuable starting points for further unveiling the anticancer potential of this class of coordination compounds.

Keywords: anti-cancer drugs; cytotoxicity; lung cancer; metal complexes; ureas.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of U1–12 via acid-catalyzed reaction of pyridine-N-oxides with dialkylcyanamides.
Scheme 2
Scheme 2
Reaction of U2 with CuCl2 in methanol solution and X-ray structures of obtained mono- and bis-ligand Cu(II) complexes.
Figure 1
Figure 1
Three types of the obtained Cu(II) complexes as illustrated by X-ray structures of compounds [Cu(U2)2Cl]+[Cl]− (a), [Cu(U4)2Cl]+[Cl]− (b), and [Cu(U3)2Cl2] (c).
Figure 2
Figure 2
Effects of the compound [Cu(U3)2Cl2] on cell cycle progression in NCI-H1975 non-small cell lung carcinoma cells at concentrations of 10, 20, and 35 μM.
Figure 3
Figure 3
Apoptosis induction caused by different concentrations of the compound [Cu(U3)2Cl2] in NCI-H1975 cell line.
Figure 3
Figure 3
Apoptosis induction caused by different concentrations of the compound [Cu(U3)2Cl2] in NCI-H1975 cell line.
See this image and copyright information in PMC

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