Page 154 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

SESSION 11

NOVEL CANCER THERAPIES AND DRUG DEVELOPMENT STRATEGIES

P62

New bis-pyrazolate zinc(II) complexes as potential anticancer drugs: from structure to anticancer activity

Majda Kolenović Serezlić , Angelina Caković , Jovana Bogojeski , Danijela Nikodijević , Milena Milutinovic , Aleksandra
2
2
2
2
1
Stanojević , Milena Čavić , Tanja V. Soldatović 1
3
2
1Department of Natural-Mathematical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
2Faculty of Science, University of Kragujevac, Kragujevac, Serbia
3Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
Keywords: DNA binding, cytotoxicity, apoptosis

Background: Zinc(II) plays a vital role in biological systems due to its unique properties: it is redox-inactive, a strong Lewis
acid, and supports flexible coordination. Unlike redox-active metals, Zn(II) does not generate free radicals, contributing
to antioxidant protection. It is involved in over 3000 human proteins, essential for DNA/protein synthesis, immune
response, and brain function.1,2 Zinc imbalance is linked to cancer; chelation is used in excess, while ionophores help
restore levels in deficiency. Recent heterometalllic Pt-L-Zn complexes show higher cytotoxicity than cisplatin, likely due
to their interaction with multiple cellular targets.
Material and Methods: The binding affinity of the studied complexes with CT-DNA via intercalation was determined
using fluorescence spectroscopy while with human serum albumin (HSA) was determined through fluorescence
quenching experiments. The influence of different zinc(II) complexes on colon cancer HCT-116 and pancreatic cancer
MIA PaCa-2 (obtained from the American Type Culture Collection, USA) cells viability was investigated, by measuring
the intensity of purple formazan in control and treated cell samples (MTT assay). The type of cell death induced by
different zinc(II) complexes was determined by the fluorescent dye acridine orange (AO, obtained from Acros Organics,
New Jersey, USA), and ethidium bromide (EB, obtained from SERVA, Germany). The quality and quantity of RNA were
evaluated using a BioSpec-nano spectrophotometer (Shimadzu Scientific Instruments). The generated cDNA was used
as a template for gene expression analysis using quantitative real-time PCR (qRT-PCR).
Results: Three novel Zn(II) complexes [ZnCl2(H2LtBu)], [ZnCl2(Me2LtBu)] and [Zn2Cl4(H2LCatBiPyPh)2] (where H2LtBu
is 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, Me2LtBu is 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3- yl)pyridine and
H2LCatBiPyrPh is 1,2-bis((5-phenyl-1H-pyrazol-3-yl)methoxy)benzene) were synthesized and characterized. Structural
analysis revealed different coordination geometries: distorted trigonal bipyramidal ([ZnCl2(H2LtBu)]) and tetrahedral
([Zn2Cl4(H2LCatBiPyPh)2]). The complexes were examined for their potential antitumor activity. The complexes showed
moderate binding to CT-DNA and human serum albumin (HSA), with DNA-binding affinity in the order: [ZnCl₂(Me₂LtBu)]
< [Zn₂Cl₄(H₂LCatBiPyPh)₂] < [ZnCl₂(H₂LtBu)]. Cytotoxicity tests demonstrated significant antiproliferative effects against
HCT-116 and MIA PaCa-2 cancer cells, with [ZnCl₂(H₂LtBu)] being the most active than cisplatin in pancreatic cancer
cells after 72 h. especially in inducing apoptosis. Gene expression studies revealed downregulation of TP53 (homo
sapiens tumor protein p53) across all complexes, while [ZnCl₂(H₂LtBu)] also reduced CASP3 (Caspase 3) and IGF1R
(insulin-like growth factor 1) expression, indicating interference with apoptosis and cell proliferation.3-5 These findings
suggest the complexes have potential as anticancer agents and warrant further molecular-level investigation.
Conclusions: Among investigated complexes [ZnCl₂(H₂LtBu)] showed the most pronounced induction of apoptosis.
Gene expression analysis suggested activation of apoptotic and necrotic signaling pathways, warranting further studies
at transcriptomic and proteomic levels.

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