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Platinum(II) and Copper(II) complexes of asymmetric halogen-substituted [NNʹO] ligands: Synthesis, characterization, structural investigations and antiproliferative activity


Amiri Rudbari, Hadi; Saadati, Arezoo; Aryaeifar, Mahnaz; Blacque, Olivier; Cuevas-Vicario, Jose V; Cabral, Rui; Raposo, Luis R; Fernandes, Alexandra R (2022). Platinum(II) and Copper(II) complexes of asymmetric halogen-substituted [NNʹO] ligands: Synthesis, characterization, structural investigations and antiproliferative activity. Bioorganic Chemistry, 119:105556.

Abstract

In order to better understand the effect of structure, halogen substitution, metal ions and ligand flexibility on antiproliferative activity, eight Cu(II) complexes and eight Pt(II) complexes were obtained of 2,4-X1,X2-6-((pyridine-2-ylmethylamino)methyl)phenol and 2,4-X1,X2-6-((pyridine-2-ylmethylamino)ethyl)phenol (where X is Cl, Br, or I) ligands. The compounds were characterized with various techniques, such as FT-IR, NMR, elemental analysis and single-crystal X-ray diffraction (SCXRD). The X-ray structures showed that ligand acts as a bidentate and tridentate donor in Cu(II) and Pt(II) complexes, respectively. This difference in structures is due to the use or non-use of base in the preparation of complexes. Also, complexation of Cl2-H2L1 with CuCl2·2H2O gives two different types of structures: polymer (Cl2-H2L1-Cupolymer) and dimer (Cl2-H2L1-Cudimer), according to the crystal color. In addition, 1H NMR spectrum for platinum complexes display two set of signals that can be attributed to the presence of two isomers in solution.

All complexes induced moderate to high reduction in A2780 and HCT116 cancer cell viability. However, only complexes bearing iodo- substituted in ligands exhibited significantly low cytotoxicity in normal fibroblasts when compared with cancer cell lines. The antiproliferative effect exhibited by I2-H2L2-Cu complex in A2780 cell line was due to induction of cell death mechanisms, namely by apoptosis and autophagy. I2-H2L2-Cu complex does not cause DNA cleavage but a slight delay in cell cycle was observed for the first 24 h of exposition. High cytotoxicity was related with the induction of intracellular ROS. This increase in intracellular ROS was not accompanied by destabilization of the mitochondrial membrane which is an indication that ROS are being triggered externally by I2-H2L2-Cu complex and in agreement with an extrinsic apoptosis activation. I2-H2L2-Cu complex has a pro-angiogenic effect, increasing the vascularization of the CAM in chicken embryos. This is also a very important characteristic in cancer treatment since the increased vascularization in tumors might facilitate the delivery of therapeutic drugs. Taken together, these results support the potential therapeutic of the I2-H2L2-Cu complex.

Abstract

In order to better understand the effect of structure, halogen substitution, metal ions and ligand flexibility on antiproliferative activity, eight Cu(II) complexes and eight Pt(II) complexes were obtained of 2,4-X1,X2-6-((pyridine-2-ylmethylamino)methyl)phenol and 2,4-X1,X2-6-((pyridine-2-ylmethylamino)ethyl)phenol (where X is Cl, Br, or I) ligands. The compounds were characterized with various techniques, such as FT-IR, NMR, elemental analysis and single-crystal X-ray diffraction (SCXRD). The X-ray structures showed that ligand acts as a bidentate and tridentate donor in Cu(II) and Pt(II) complexes, respectively. This difference in structures is due to the use or non-use of base in the preparation of complexes. Also, complexation of Cl2-H2L1 with CuCl2·2H2O gives two different types of structures: polymer (Cl2-H2L1-Cupolymer) and dimer (Cl2-H2L1-Cudimer), according to the crystal color. In addition, 1H NMR spectrum for platinum complexes display two set of signals that can be attributed to the presence of two isomers in solution.

All complexes induced moderate to high reduction in A2780 and HCT116 cancer cell viability. However, only complexes bearing iodo- substituted in ligands exhibited significantly low cytotoxicity in normal fibroblasts when compared with cancer cell lines. The antiproliferative effect exhibited by I2-H2L2-Cu complex in A2780 cell line was due to induction of cell death mechanisms, namely by apoptosis and autophagy. I2-H2L2-Cu complex does not cause DNA cleavage but a slight delay in cell cycle was observed for the first 24 h of exposition. High cytotoxicity was related with the induction of intracellular ROS. This increase in intracellular ROS was not accompanied by destabilization of the mitochondrial membrane which is an indication that ROS are being triggered externally by I2-H2L2-Cu complex and in agreement with an extrinsic apoptosis activation. I2-H2L2-Cu complex has a pro-angiogenic effect, increasing the vascularization of the CAM in chicken embryos. This is also a very important characteristic in cancer treatment since the increased vascularization in tumors might facilitate the delivery of therapeutic drugs. Taken together, these results support the potential therapeutic of the I2-H2L2-Cu complex.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Life Sciences > Drug Discovery
Physical Sciences > Organic Chemistry
Uncontrolled Keywords:Organic Chemistry, Drug Discovery, Molecular Biology, Biochemistry
Language:English
Date:1 February 2022
Deposited On:09 Nov 2022 13:47
Last Modified:27 Apr 2024 01:41
Publisher:Elsevier
ISSN:0045-2068
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.bioorg.2021.105556
PubMed ID:34959175
  • Content: Accepted Version
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)