Zinc(II) Terpyridine Complexes: Substituent Effect on Photoluminescence, Antiproliferative Activity, and DNA Interaction

Abstract

A series of ZnCl2 complexes (compounds 1–10) with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine that bears hydrogen (L1), p-methyl (L2), p-methoxy (L3), p-phenyl (L4), p-tolyl (L5), p-hydroxyl (L6), m-hydroxyl (L7), o-hydroxyl (L8), p-carboxyl (L9), or p-methylsulfonyl (L10) were prepared and then characterized by 1H NMR, electrospray mass-spectra (ESI-MS), IR, elemental analysis, and single crystal X-ray diffraction. In vitro cytotoxicity assay was used to monitor the antiproliferative activities against tumor cells. Absorption spectroscopy, fluorescence titration, circular dichroism spectroscopy, and molecular modeling studied the DNA interactions. All of the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The cell viability studies indicate that the compounds have excellent antiproliferative activity against four human carcinoma cell lines, A549, Bel-7402, MCF-7, and Eca-109, with the lowest IC50 values of 0.33 (10), 0.66 (6), 0.37 (7), and 1.05 (7) μM, respectively. The spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalator and induce DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π…π stacking and hydrogen bonds, providing an order of nucleotide sequence binding selectivity as ATGC > ATAT > GCGC. These compounds intercalate into the base pairs of the DNA of the tumor cells to affect their replication and transcription, and the process is supposed to play an important role in the anticancer mechanism.

Synthesis, Characterization, Photoluminescence, Molecular Docking and Bioactivity of Zinc (II) Compounds Based on Different Substituents

“…Notably, the antiproliferative activity of 1 and 2 is better than that of the other compounds towards the three cell lines and, when the para-substituent is the same, the activity of the iodide anion complexes is generally better than that of the bromide anion ones. Compared with that of zinc chloride complexes [ 34 ], the antiproliferative activity of these complexes is stronger. This activity of the bromide complexes follows the order of 1 > 3 > 5 and that of the iodide complexes is 2 > 4 > 6 .…”

“…Therefore, the interaction between complexes and proteins plays a key role in the distribution and transport of small molecules into the biological system, which affects the concentration and overall efficacy of drug molecules [ 31 ]. In our previous studies, it has been found that zinc complexes have strong antitumor activity [ 22 , 23 , 32 , 33 , 34 ]. It is noteworthy that the antitumor properties of these complexes can be regulated by the substituents at their 4′-position.…”

Zinc Complexes with Nitrogen Donor Ligands as Anticancer Agents

“…In order to find out a possible correlation between the cytotoxic activity in vitro and the chemical features of the surveyed complexes, we have cumulated the most active reported species (43 out of 102, i.e., all the complexes which exhibit an antitumoral activity with IC 50 values ≤ 10 µM ( Table 13 against one or more cancer cell lines, reaching in some cases the nanomolar range. In detail, penta-coordinated terpyridine derivatives 14a – j , [ 141 ] 15a – h [ 136 ] and 16 [ 142 ] and hexacoordinate bis-terpyridine 17 exhibited very high activity towards a large panel of cancer cell lines, and in the case of 16 and 17 demonstrated also a good specificity for tumor cells. On the other hand, at least for 16 and 17 , the free ligand is highly active per se and metal coordination did not lead to any improvements.…”

“…Extremely active penta-coordinated zinc complexes 14a – j [ 141 ] and 15a – h [ 136 ] ( Figure 9 ) have been obtained by using terpyridine derivatives as ligands.…”

Chlorido(4′-chloro-2,2′:6′,2′′-terpyridine-κ3 N,N′,N′′)(trifluoromethanesulfonato-κO)zinc(II) acetonitrile monosolvate

“…Substituted terpyridines such as 4 0 -chloro-2,2 0 :6 0 ,2 00 -terpyridine continue to be recognized as useful chelating ligands for many transition-metal ions, including platinum(II) (Qin et al, 2019), copper(II) (Choroba et al, 2019), cadmium(II) (Li et al, 2020), and zinc(II) (Li et al, 2019). Metal complexes containing zinc(II) and substituted terpyridines as chelating ligand have been shown to have promising antitumor activity (Liang et al, 2019).…”