Abstract
The stabilization of G-Quadruplex DNA structures by ligands is a promising strategy for telomerase inhibition in cancer therapy since this enzyme is responsible for the unlimited proliferation of cancer cells. To assess the potential of a compound as a telomerase inhibitor, selectivity for quadruplex over duplex DNA is a fundamental attribute, as the drug must be able to recognize quadruplex DNA in the presence of a large amount of duplex DNA, in the cellular nucleus. By using different spectroscopic techniques, such as ultraviolet-visible, fluorescence and circular dichroism, this work evaluates the potential of a series of multicharged phthalocyanines, bearing four or eight positive charges, as G-Quadruplex stabilizing ligands. This work led us to conclude that the existence of a balance between the number and position of the positive charges in the phthalocyanine structure is a fundamental attribute for its selectivity for G-Quadruplex structures over duplex DNA structures. Two of the studied phthalocyanines, one with four peripheral positive charges (ZnPc1) and the other with less exposed eight positive charges (ZnPc4) showed high selectivity and affinity for G-Quadruplex over duplex DNA structures and were able to accumulate in the nucleus of UM-UC-3 bladder cancer cells.
Highlights
Telomeres are special structures localized at each end of chromosomes which contribute to chromosomal and genomic stability by protecting the end of chromosomes from enzymatic degradation [1,2,3,4]
The UV-Vis spectroscopy is a very useful technique to analyze the interactions between a molecule and deoxyribonucleic acid (DNA)
When a ligand interacts with DNA structures, a red shift accompanied by intensity changes occur in their characteristic absorbance bands
Summary
Telomeres are special structures localized at each end of chromosomes which contribute to chromosomal and genomic stability by protecting the end of chromosomes from enzymatic degradation [1,2,3,4]. Their main functions are to maintain the stability of the chromosome structure, to ensure that the genetic information is perfectly copied when the cell duplicates, and to prevent the junction between the ends of consecutive chromosomes which could lead to the degradation of deoxyribonucleic acid (DNA) or to the occurrence of genetic mutations which can culminate in the appearance of tumors [5]. Telomerase is a reverse enzyme, counteractthis thisprocess process increasing telomerase activity
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