Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells.

Jussara Amato,Giovanni Capranico,Antonio Randazzo,Rita Morigi,Ettore Novellino,Nunzia Iaccarino,Alessandra Locatelli,Bruno Pagano,Giulia Miglietta,Alberto Leoni

doi:10.1021/acs.jmedchem.9b01866

Jussara Amato, Giovanni Capranico + Show 8 more

Open Access

https://doi.org/10.1021/acs.jmedchem.9b01866

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Abstract

Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.

Highlights

G-Quadruplexes (G4s) are noncanonical DNA secondary structures formed by G-rich sequences with important roles in the regulation of basic nuclear processes, including promoter activity,[1−4] chromatin remodeling and replication,[5,6] genome instability,[7−10] and epigenetic alterations.[11,12] G4s consist of four-stranded nucleic acid helical structures formed by the stacking of two or more guanine tetrads cyclic planar arrays of four guanine bases held together by Hoogsteen hydrogen bonds and stabilized by monovalent cations.[13]
Besides a general DNA damage response, the chemical stabilization of G4 structures can lead to recombination repair pathways and genomic rearrangements that can be suppressed by a specific G4-resolvase.[16]
We focused on the investigation of a number of new hydrazone-containing compounds, designed as analogues of a promising lead[41] which was recently demonstrated to stabilize G4s and simultaneously increase R loop levels in human cancer cells.[17]

Summary

Introduction

G-Quadruplexes (G4s) are noncanonical DNA secondary structures formed by G-rich sequences with important roles in the regulation of basic nuclear processes, including promoter activity,[1−4] chromatin remodeling and replication,[5,6] genome instability,[7−10] and epigenetic alterations.[11,12] G4s consist of four-stranded nucleic acid helical structures formed by the stacking of two or more guanine tetrads cyclic planar arrays of four guanine bases held together by Hoogsteen hydrogen bonds and stabilized by monovalent cations.[13]. Whether more-specific G4 binders can enhance the R loops causing genome instability in human cancer cells is not known

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