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Antiproliferative activity and associated DNA interactions of [Co2L3]6+ cylinders derived from bis(bidentate) 2-pyridyl-1,2,3-triazole ligands.

Autoři: Crlikova H., Malina J., Novohradsky V., Kostrhunova H., Vasdev R.A.S., Crowley J.D. Kasparkova J., Brabec V.Publikováno : Organometallics 39(8), 1448-1455Rok: 2020

Antineoplastic activity and DNA interactions of kinetically inert dicobalt(III) [Co2(Lpytrz)3](OTf)6 type cylinders containing ligands consisting of 1,2,3-triazoles linked with either methylene (1) or a 1,4-xylyl (2) have been studied. For this study, the smaller cylinder (meso-1 (ΔΛ) isomer) and the larger cylinder (a racemic (rac-2) mixture of the (ΔΔ and ΛΛ) helicates) were chosen. Both meso-1 and rac-2 exhibit potent and selective activities against cancer cells. The bigger and more lipophilic rac-2 is more active, with the IC50 values in the low micromolar range, comparable to that of clinically used cisplatin. Notably, for both cylinders, the level of cobalt in nuclei correlates with cobalt concentration measured in the whole cells, and a significant amount of total cobalt present in the cell accumulates in the cell nucleus. Further experiments have demonstrated that the apoptotic pathway is a predominant mechanism of cell death. The experiments performed in cell-free media indicate that both cylinders are potent DNA binding agents recognizing the genetic code in a sequence-dependent manner; this property is more pronounced for rac-2 compared to meso-1. Additionally, both cylinders effectively condense/aggregate DNA. Notably, it has been also shown for the first time that supermolecular metallohelices or cylinders induce condensation of chromatin in living cells. This finding represents a significant novelty in the field of biologically active supramolecular systems. Consistently with its higher antiproliferative potency, the bigger and more lipophilic rac-2 is more powerful in chromatin condensation as compared with meso-1.


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