Zn(II)-Chlorido Complexes of Phytohormone Kinetin and Its Derivatives Modulate Expression of Inflammatory Mediators in THP-1 Cells

Abstract

Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(Ln)2Cl2]·Solv (1–5) and [Zn(HLn)Cl3]·xLn (6–7); n = 1–5, Solv = CH3OH for 1 and 2H2O for 2; x = 1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (Ln) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS)-activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 µM), apart from complex 4, with an IC50 = 10.9±1.1 µM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1β production by a factor of 1.47–2.22 compared with the control (DMSO), but did not affect TNF-α and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes.

Synthesis, X-ray crystal structure and biological evaluation of zinc(II)-dichlorido complexes with 9-deazahypoxathine derivatives

“…4B, C). Similar behaviour was previously observed for the zinc(II)-dichlorido compounds with kinetin and its derivatives [11], which pointed to the ability of zinc(II) complexes to effectively activate the MMP-2 protein.…”

“…Inflammatory response was triggered by lipopolysaccharide (LPS) as described previously [11]. The IL-1b secretion was evaluated by ELISA test.…”

“…MMP-2 activity of complexes 1-5 was evaluated by zymography pursuant to the procedure published in [11].…”

“…Subsequently, a great number of organic compounds showing MMP-modulating activity, as well as a wide spectrum of metal-based complexes acting as inhibitors or activators of MMP activity, were previously reported [10]. For example, zinc(II)-based complexes involving derivatives of kinetin demonstrated MMP-2 activation properties [11]. In addition, such zinc(II)-based compounds were also investigated as potential therapeutic agents in the treatment of the prostate cancer.…”

Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells

“…Previous studies have revealed that in cells that TLR4 is activated during the inflammatory responses, and binding of LPS to TLR4 leads to MAPKs activation and nuclear translocation of NF-κB [12,18,19]. Therefore, THP-1 cells induced by LPS could serve as an excellent model for screening the important cellular mechanisms underlying the anti-inflammation effect of PTL [20]. The mechanism by which PTL blocks LPS-induced inflammation is unclear.…”