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Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions
Published on: July 17, 2020
Is Silver a Precious Metal for G-Quadruplex Stabilization Mediated by Porphyrins?
Nuno M M Moura1, Sofia Guedes1, Diana Salvador2,3
1LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
Abstract:
Cancer is a leading cause of death, so continuous efforts into cancer therapy are imperative. In tumor cells, telomerase and oncogene activity are key points for uncontrolled cell growth. Targeting these processes with ligands that inhibit telomerase and/or reduce oncogene expression has been identified as a promising cancer therapy. This study evaluated the selectivity and affinity of the silverII complex of 5,10,15,20-tetrakis(N-methyl-4-pyridinium)porphyrin (AgTMPyP) to stabilize DNA sequences capable of forming G4 structures mimicking the telomeric and oncogene regions, using spectroscopic, biochemical methods and in vitro assays. The tetracationic silver complex was compared with the free base, H, and the zincII complex, ZnTMPyP. The results obtained from UV-Vis and fluorescence methods pointed to a great affinity and good selectivity of AgTMPyP to G4 structures, especially for the oncogene MYC. In general, an increase in the ability of the studied ligands for 1O2 generation when interacting with oncogenic and telomeric G4 sequences was found. The results of the PCR stop assays proved that AgTMPyP has the ability to inhibit Taq polymerase. Additionally, in vitro assays demonstrated that the silverII complex exhibits low cytotoxicity against HaCaT- an immortalized, non-tumorigenic, skin keratinocytes cell line-and, although nonexclusive, AgTMPyP shows nuclear co-localization.
Insights
The silver(II) complex AgTMPyP shows high affinity for G-quadruplex DNA structures in telomeres and oncogenes, inhibiting cancer cell growth. This promising cancer therapy agent exhibits low cytotoxicity and nuclear localization.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Cancer remains a leading cause of death, necessitating novel therapeutic strategies.
- Telomerase and oncogene activity are crucial for uncontrolled tumor cell proliferation.
- Targeting these pathways with specific ligands offers a promising avenue for cancer treatment.
Purpose of the Study:
- To evaluate the selectivity and DNA-binding affinity of the silver(II) complex AgTMPyP.
- To assess its potential to stabilize G-quadruplex (G4) structures in telomeric and oncogenic regions.
- To compare AgTMPyP with its free base and zinc(II) complex counterpart.
Main Methods:
- Spectroscopic techniques (UV-Vis, fluorescence) were employed.
- Biochemical assays, including PCR stop assays, were performed.
- In vitro cytotoxicity assays using HaCaT cells were conducted.
Main Results:
- AgTMPyP demonstrated high affinity and selectivity for G4 structures, particularly the MYC oncogene.
- Ligand interaction with G4 sequences enhanced singlet oxygen (1O2) generation.
- AgTMPyP inhibited Taq polymerase activity and showed low cytotoxicity in non-tumorigenic cells, with nuclear co-localization.
Conclusions:
- AgTMPyP is a potent G4 stabilizer with potential anticancer applications.
- Its ability to generate reactive oxygen species and inhibit key enzymes warrants further investigation.
- The complex shows favorable characteristics for targeted cancer therapy development.
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