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

Abstract

Three novel Zn(II) complexes [ZnCl₂(H₂L^tBu)], [ZnCl₂(Me₂L^tBu)] and [Zn₂Cl₄(H₂L^CatBiPyPh)₂] (where H₂L^tBu is 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, Me₂L^tBu is 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine and H₂L^CatBiPyrPh is 1,2-bis((5-phenyl-1H-pyrazol-3-yl)methoxy)benzene) were synthesized and characterized using various spectroscopic techniques, including UV-vis, IR, ¹D (¹H and ¹³C) and 2D (¹H–¹H COSY) NMR. The structures of complexes [ZnCl₂(H₂L^tBu)] and [Zn₂Cl₄(H₂L^CatBiPyPh)₂] were elucidated through X-ray crystallography. The interactions of the complexes with CT-DNA and human serum albumin (HSA) were investigated using UV-vis spectroscopy and fluorescence emission titration. All examined complexes exhibited quenching constant, K_sv, values in the order of 10⁴ with CT-DNA. Constant values followed the trend [ZnCl₂(Me₂L^tBu)] < [Zn₂Cl₄(H₂L^CatBiPyPh)₂] < [ZnCl₂(H₂L^tBu)]. The results indicated a moderate interaction between the complexes and HSA. In terms of cytotoxic activity, the zinc(II) complexes significantly decreased the viability of colon (HCT-116) and pancreatic (MIA PaCa-2) cancer cell lines, where the effect on pancreatic cells after 72 h is especially emphasized. The most pronounced occurrence of apoptosis, as the dominant type of complex-induced cell death, was associated with complex [ZnCl₂(H₂L^tBu)], while necrosis was observed at lower percentages in all investigated treatments. All complexes demonstrated downregulation of the tumor suppressor gene TP53 (homo sapiens tumor protein p53). Treatment with [ZnCl₂(H₂L^tBu)] resulted in downregulation of TP53, CASP3 (Caspase 3) and IGF1R (insulin-like growth factor 1), potentially impairing the effective apoptotic process and reducing cell proliferation.