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

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.

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

“…For example, Boyarskiy et al reported the successful synthesis of 1,2,4-oxadiazoles substituted by pyridine N -oxides [ 115 ], and the N -oxide functionality was compatible with both “ester” and “acid” protocols. Furthermore, these N -oxides were converted into corresponding N -pyridyl ureas [ 115 , 116 ], which are valuable “masked isocyanates” [ 117 , 118 ] and ligands of metal-based anticancer drugs [ 119 , 120 ]. Krasavin et al continued the exploration of 1,2,4-oxadiazole motif for the design of carbonic anhydrase inhibitors [ 14 , 114 ].…”

“Urea to Urea” Approach: Access to Unsymmetrical Ureas Bearing Pyridyl Substituents

“… [1,2] There are numerous examples of their manifestation as therapeutics for treatment of neurodegenerative diseases (especially Alzheimer's disease [3–6] ), diabetes, [7–11] cardiovascular disorders, [12] and also as anti‐inflammatory agents [13] and antibiotics [14–17] . Moreover, there is a growing body of research shows that substances bearing N‐ pyridylurea moiety have antitumor activity [18–22] . For example, N‐ (pyridin‐2‐yl)urea derivative Roblitinib (FGF401) has been discovered as a highly selective first‐in‐class clinical candidate for medication of a hepatocellular carcinomas subset [23] .…”

“…[14][15][16][17] Moreover, there is a growing body of research shows that substances bearing N-pyridylurea moiety have antitumor activity. [18][19][20][21][22] For example, N-(pyridin-2-yl)urea derivative Roblitinib (FGF401) has been discovered as a highly selective first-in-class clinical candidate for medication of a hepatocellular carcinomas subset. [23] The clinical candidate Golvatinib (E7050) with dual c-MET/VEGFR2 inhibition action was discovered toward platinum-resistant squamous cell carcinoma of the head and neck.…”

Fumarato and phthalato bridged dinuclear metal–organic Cu(ii) and Mn(ii) compounds involving infinite fumarate–water assemblies and unusual structure-guiding H-bonded synthons: antiproliferative evaluation and theoretical studies

“…9 In recent times, the design, synthesis and development of promising biologically relevant copper based coordination compounds have received remarkable emphasis in medicinal chemistry. 10 Their clinical success has triggered immense interest among researchers to develop new coordination compounds of copper as anticancer agents. 11…”