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Published on: September 19, 2017
Dual Targeting Topoisomerase/G-Quadruplex Agents in Cancer Therapy-An Overview
Silvia Salerno1, Elisabetta Barresi1, Emma Baglini1
1Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Abstract:
Topoisomerase (Topo) inhibitors have long been known as clinically effective drugs, while G-quadruplex (G4)-targeting compounds are emerging as a promising new strategy to target tumor cells and could support personalized treatment approaches in the near future. G-quadruplex (G4) is a secondary four-stranded DNA helical structure constituted of guanine-rich nucleic acids, and its stabilization impairs telomere replication, triggering the activation of several protein factors at telomere levels, including Topos. Thus, the pharmacological intervention through the simultaneous G4 stabilization and Topos inhibition offers a new opportunity to achieve greater antiproliferative activity and circumvent cellular insensitivity and resistance. In this line, dual ligands targeting both Topos and G4 emerge as innovative, efficient agents in cancer therapy. Although the research in this field is still limited, to date, some chemotypes have been identified, showing this dual activity and an interesting pharmacological profile. This paper reviews the available literature on dual Topo inhibitors/G4 stabilizing agents, with particular attention to the structure-activity relationship studies correlating the dual activity with the cytotoxic activity.
Insights
Dual ligands targeting both topoisomerase (Topo) and G-quadruplex (G4) structures offer a novel cancer therapy approach. This strategy combines G4 stabilization with Topo inhibition for enhanced antiproliferative activity and overcoming drug resistance.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Topoisomerase (Topo) inhibitors are established cancer therapeutics.
- G-quadruplex (G4) structures are emerging targets for cancer treatment.
- G4 stabilization can impair telomere replication and activate Topo.
Purpose of the Study:
- To review literature on dual Topoisomerase inhibitors/G-quadruplex stabilizing agents.
- To explore the potential of simultaneous G4 stabilization and Topo inhibition in cancer therapy.
- To analyze structure-activity relationships of these dual-acting compounds.
Main Methods:
- Literature review of dual Topo inhibitors/G4 stabilizing agents.
- Analysis of structure-activity relationships (SAR).
- Evaluation of cytotoxic activity linked to dual action.
Main Results:
- Dual ligands targeting both Topo and G4 represent an innovative strategy.
- Some chemotypes exhibiting dual activity and favorable pharmacological profiles have been identified.
- SAR studies correlate dual activity with enhanced cytotoxic effects.
Conclusions:
- Simultaneous G4 stabilization and Topo inhibition present a promising therapeutic opportunity.
- Dual-acting agents offer potential for increased antiproliferative activity.
- This approach may help circumvent cellular resistance mechanisms in cancer treatment.
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