Abstract
The evidence that telomerase is overexpressed in almost 90% of human cancers justifies the proposal of this enzyme as a potential target for anticancer drug design. The inhibition of telomerase by quadruplex stabilizing ligands is being considered a useful approach in anticancer drug design proposals. Several aromatic ligands, including porphyrins, were exploited for telomerase inhibition by adduct formation with G-Quadruplex (GQ). 5,10,15,20-Tetrakis(N-methyl-4-pyridinium)porphyrin (H2TMPyP) is one of the most studied porphyrins in this field, and although reported as presenting high affinity to GQ, its poor selectivity for GQ over duplex structures is recognized. To increase the desired selectivity, porphyrin modifications either at the peripheral positions or at the inner core through the coordination with different metals have been handled. Herein, studies involving the interactions of TMPyP and analogs with different DNA sequences able to form GQ and duplex structures using different experimental conditions and approaches are reviewed. Some considerations concerning the structural diversity and recognition modes of G-quadruplexes will be presented first to facilitate the comprehension of the studies reviewed. Additionally, considering the diversity of experimental conditions reported, we decided to complement this review with a screening where the behavior of H2TMPyP and of some of the reviewed metal complexes were evaluated under the same experimental conditions and using the same DNA sequences. In this comparison under unified conditions, we also evaluated, for the first time, the behavior of the AgII complex of H2TMPyP. In general, all derivatives showed good affinity for GQ DNA structures with binding constants in the range of 106–107 M−1 and ligand-GQ stoichiometric ratios of 3:1 and 4:1. A promising pattern of selectivity was also identified for the new AgII derivative.
Highlights
The discovery of telomeres was reported first by H
An enhanced binding affinity was proposed for metalloporphyrins through an additional electrostatic interaction induced by the presence of metal ions
For CoIII TMPyP (Table 3, entry 4 and Figure S6D) the most significant bathochromic effect was observed for the unimolecular GQ while the bimolecular GQ structure showed a blue shift of 3 nm; the insignificant or absent bathochromic effect observed in the spectra of the tetramolecular conformation (∆λ = 0 nm) and of the salmon sperm (∆λ = 1 nm) can be associated with the presence of water molecules as axial ligands confirming their negative influence in the macrocycle interaction with deoxyribonucleic acid (DNA) structures, as previously reported [71,72]
Summary
The discovery of telomeres was reported first by H. The relative strand orientation influence the glycosidic bond angle of the guanines involved in the quartets that can assume an anti and/or syn geometry (Figure 5). All the described structural properties of concerning the length, base of parallel GQ, all the guanine glycosidic torsion angles are characteristic of an equivalent and directionality of the loops, and the the stabilizing metal cations, anti composition conformation, the four grooves’. If one ofcondithe strand tionsorientations in the presence of monovalent cations such as 4+, Na+ and K+ [19] was of particular changes to an antiparallel arrangement, changes in guanine glycosidic torsion valueangles in theoccur wideand range of studies involving investigationThese of GQ as targets drugalter adopt both syn and anti the conformations. With different metal ions (e.g., ZnII, CoIII, NiII, CuII, PdII, AuIII and MnIII) in the ligan
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