Novel Tl(III) complexes containing pyridine-2,6-dicarboxylate derivatives with selective anticancer activity through inducing mitochondria-mediated apoptosis in A375 cells

Sara Abdolmaleki,Alireza Aliabadi,Mohammad Ghadermazi

doi:10.1038/s41598-021-95278-y

Sara Abdolmaleki, Alireza Aliabadi + Show 1 more

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https://doi.org/10.1038/s41598-021-95278-y

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Abstract

Three novel Tl(III) complexes (C1), (C2) and (C3) were synthesized using the one-pot reactions of pyridine dicarboxylic acid derivatives, 2-aminobenzimidazole and/or 4-aminopyridine, and also thallium(III) nitrate trihydrate metal salt. The structure of all three complexes was determined by the single-crystal X-ray diffraction. C1 and C2 were realized to be isostructural with disordered square anti-prismatic geometry and for C3 arrangement of the distorted tricapped triangular prism was proposed. Cyclic voltammetry measurements on the complexes exhibited that formal potential values are more positive for C1 (E0ˊ 0.109 V) and C3 (E0ˊ 0.244 V) compared to C2 (E0ˊ –0.051 V), versus Ag/AgCl under argon. Moreover, cytotoxicity of the compounds was evaluated in vitro against two cancer cell lines including a human melanoma (A375), a human colon adenocarcinoma (HT29), and also one normal cell human foreskin fibroblast (HFF). The selective and potent cytotoxicity effect was exhibited by C1 and C3 on cancer cell lines. The apoptosis through a caspase-dependent mitochondrion pathway was confirmed by ROS production, MMP reduction, p53 activation, Bax up-regulation, and Bcl-2 down-regulation, cytochrome c release, procaspase-9, and 3 expression, for A375 cells treated to C1 and C3. According to similar cellular uptake of the complexes in A375 cell line, the generation of ROS was considered as an effective agent to justify the inhibition effect C1 and C3 on mentioned cells. Furthermore, arresting the cell cycle in the G2-M phase and inducing apoptosis were indicated by these two complexes.

Highlights

Three novel Tl(III) complexes (C1), (C2) and (C3) were synthesized using the one-pot reactions of pyridine dicarboxylic acid derivatives, 2-aminobenzimidazole and/or 4-aminopyridine, and thallium(III) nitrate trihydrate metal salt
When we evaluated cellular uptake of C3 in human foreskin fibroblast (HFF) cells (Figure S12), it was realized that the cellular concentration of thallium was less in normal cells than cancer cells (A375), but the amount of thallium in these cells was not zero; it cannot be concluded with certainty that the reason for the low efficacy of the C3 against normal cells is only due to its low penetration into these cells
Different redox couples were exhibited in electrochemical studies for the complexes

Summary

Introduction

Three novel Tl(III) complexes (C1), (C2) and (C3) were synthesized using the one-pot reactions of pyridine dicarboxylic acid derivatives, 2-aminobenzimidazole and/or 4-aminopyridine, and thallium(III) nitrate trihydrate metal salt. From the point of medicine, thallium has been reported effective in the treatment of diseases such as syphilis, tuberculosis, and malaria Such effectiveness is related to the high toxicity of this metal. The anti-tumor activity of para-substituted tetraphenyl porphyrin Tl(III) salicylate complexes was evaluated and a strong inhibition effect (up to 90%) of 5-SSATl(III) t(4-OCH3)PP was exhibited against all four human cancer cell lines tested including MCF-7, THP-1, PC-3 and A5491. S. El-Tabl et al, synthesized Tl(I) complexes from 2-(2-(4-carboxyphenyl)guanidino)acetic acid as ligand and exhibited a potent anti-proliferative effect on the MCF-7 cell line compared to the standard drug[12]. Besides medicine fields, thallium and its compounds have indicated applications as semiconductors, catalysts, dyes, and pigments[14]. Such diverse uses led to consider thallium compounds in various areas of knowledge[15]

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