Cytotoxicity effects and biochemical investigation of novel tetrakis-phthalocyanines bearing 2-thiocytosine moieties with molecular docking studies

Abstract

In this study, the novel 3-(4-aminopyrimidin-2-ylthio) phthalonitrile (1) as starting material was synthesized and its molecular structure was verified by the experiment of single crystal X-ray diffraction, and it was first brought to the literature. Then, its non-peripherally tetra-substituted phthalocyanines (2,3) and the methylated derivatives (2a,3a) containing cytosine derivative were synthesized herein for the first time. All the compounds used were characterized with various spectroscopic methods such as UV-Vis, FT-IR, H-1 NMR, C-13 NMR and MALDI-TOF MS by obtaining highly satisfactory results. The acetylcholinesterase inhibitor compounds recorded as important therapeutic drugs for the therapy of Alzheimer's disease. So, these novel phthalocyanines effectively inhibited acetylcholinesterase enzyme, with Ki values in the range of 31.75 +/- 5.72 to 107.15 +/- 12.67 mu M. For this enzyme, IC50 values were obtained in the range of 3.41 +/- 0.78 to 10.08 +/- 2.65 mu M. For alpha-glycosidase enzyme, the most effective Ki values of (3) and (3a) were found as 3.41 +/- 0.78 and 5.32 +/- 1.34 mu M, respectively. We used 50 mu L substrates for the acetylcholine esterase and alpha-glycosidase enzymes and 20 mu L enzymes. For AChE, we used distilled water and buffer 800 mu L and 100 mu L, respectively. Also, we pipetted 500 mu L and 300 mu L for alpha-glycosidase and examined the activities. Indeed, the most potent phthalocyanines against both enzymes were recorded for the purpose to investigate interaction modes of these compounds in the active site of the target enzyme. After treatment of compounds, viability was reduced by approximately 25% in cancer cell lines. The cytotoxicity potential of these phthalocyanines against human breast, colon, and prostate cancers demonstrated that these compounds had normal cytotoxic effects.