A series of 2,5-dibromo-3-R-thiophenes
(R = COONa 1, CN 2, CONH2
3, CON(H)Me 4, CON(H)Bn 5, CON(CH2CH2)2O 6, CON(H)NH2
7, CON(H)OH 8) were prepared and
studied via high-resolution
ESI-MS, 1H and 13C{H} NMR, IR, and X-ray diffraction.
The analysis of the X-ray structures revealed Br···Br
halogen bonds (XBs) as structure-directing interactions. A search
of the Cambridge Structural Database showed an additional 12 structures
of 2,5-dibromothiophenes whose structures featured Br···Br
XBs. The crystal packing patterns for all these 2,5-dibromothiophenes
were classified, and three general types were identified: (i) chains
held by XBs, where each Br acts either as an XB donor or as an XB
acceptor; (ii) zigzag arrays, where each Br functions simultaneously
as an XB donor and acceptor; and (iii) rhombic assemblies with Br
atoms at each vertex. DFT calculations, followed by topological analyses
of the electron density distribution (QTAIM analysis) at the M06-2X/DZP-DKH
level of theory, were performed to evaluate the strength of these
XBs. The established energies were in the range from 0.5 to 2.2 kcal/mol,
regardless of the packing type.
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.
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