TY - JOUR
T1 - Dinuclear doubly bridged phenoxido copper(II) complexes as efficient anticancer agents
AU - Massoud, Salah S.
AU - Louka, Febee R.
AU - Salem, Nahed M.H.
AU - Fischer, Roland C.
AU - Torvisco, Ana
AU - Mautner, Franz A.
AU - Vančo, Ján
AU - Belza, Jan
AU - Dvořák, Zdeněk
AU - Trávníček, Zdeněk
N1 - Funding Information:
J.V., J.B., Z.D. and Z.T. are grateful for the financial support from ERDF/ESF project Nanotechnologies for Future ( CZ.02.1.01/0.0/0.0/16_019/0000754 ). S.S.M. and F.R.L. acknowledge the financial support of this work received from the Department of Chemistry-University of Louisiana at Lafayette . The authors also thank to Dr. Michal Čajan for performing thermal TG/DSC analyses.
Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2023/1/15
Y1 - 2023/1/15
N2 - Two cationic [Cu2(L1-2)2](ClO4)2 (1, 2), and four neutral doubly bridged-phenoxido-copper(II) complexes [Cu2(L3-4)2] (3, 4) and [Cu2(L5-6)2(H2O)]‧2H2O (5, 6) as well as 1D polymeric catena-[Cu(L7)] (7), where HL1-2 and H2L3-7 represent tripodal tetradentate pyridyl or aliphatic-amino groups based 2,4-disubstituted phenolates, were synthesized and thoroughly characterized by various spectroscopic methods and single crystal X-ray analysis. The molecular structures of the complexes exhibited diverse geometrical environments around the central Cu(II) atoms. The in vitro antiproliferative activity of the isolated complexes and selected parent free ligands were screened against some human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, MCF-7). The most promising cytotoxicity against cancer cells were obtained for 1–6, while complex 6 was found as the best performing as compared to the reference drug cisplatin. The cytotoxicity study of complex 6 was therefore extended to wider variety of cancer cell lines (HOS, A549, PANC-1, CaCo2, HeLa) and results revealed its significant cytotoxicity on all investigated human cancer cells. The cell uptake study showed that cytotoxicity of 6 (3 μM concentration and 24 h of incubation) against A2780 cells was almost independent from the intracellular levels of copper. The effect of complexes 4, 6 and 7 on cell cycle of A2780 cells indicates that the mechanism of action in these complexes is not only different from that of cisplatin but also different among them. Complex 7 was able to induce apoptosis in A2780 cells, while complexes 4 and 6 did not and on the other hand, they showed considerable effect on autophagy induction and there are some clues that these complexes were able to induce cuproptosis in A2780 cells.
AB - Two cationic [Cu2(L1-2)2](ClO4)2 (1, 2), and four neutral doubly bridged-phenoxido-copper(II) complexes [Cu2(L3-4)2] (3, 4) and [Cu2(L5-6)2(H2O)]‧2H2O (5, 6) as well as 1D polymeric catena-[Cu(L7)] (7), where HL1-2 and H2L3-7 represent tripodal tetradentate pyridyl or aliphatic-amino groups based 2,4-disubstituted phenolates, were synthesized and thoroughly characterized by various spectroscopic methods and single crystal X-ray analysis. The molecular structures of the complexes exhibited diverse geometrical environments around the central Cu(II) atoms. The in vitro antiproliferative activity of the isolated complexes and selected parent free ligands were screened against some human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, MCF-7). The most promising cytotoxicity against cancer cells were obtained for 1–6, while complex 6 was found as the best performing as compared to the reference drug cisplatin. The cytotoxicity study of complex 6 was therefore extended to wider variety of cancer cell lines (HOS, A549, PANC-1, CaCo2, HeLa) and results revealed its significant cytotoxicity on all investigated human cancer cells. The cell uptake study showed that cytotoxicity of 6 (3 μM concentration and 24 h of incubation) against A2780 cells was almost independent from the intracellular levels of copper. The effect of complexes 4, 6 and 7 on cell cycle of A2780 cells indicates that the mechanism of action in these complexes is not only different from that of cisplatin but also different among them. Complex 7 was able to induce apoptosis in A2780 cells, while complexes 4 and 6 did not and on the other hand, they showed considerable effect on autophagy induction and there are some clues that these complexes were able to induce cuproptosis in A2780 cells.
KW - Cell cycle
KW - Copper(II) complexes
KW - Crystal structure
KW - In vitro cytotoxicity
KW - Phenolate compounds
KW - ROS
KW - Tripodal ligands
UR - http://www.scopus.com/inward/record.url?scp=85144060026&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2022.114992
DO - 10.1016/j.ejmech.2022.114992
M3 - Article
C2 - 36525695
AN - SCOPUS:85144060026
SN - 0223-5234
VL - 246
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114992
ER -
