Histone Deacetylase-Activatable BODIPY-Based G-Quadruplex Stabilizer Significantly Reducing Colon Cancer Proliferation

Abstract

G-Quadruplexes are non-canonical nucleic acid structures mostly located in gene promoters and telomeres. Although G4 stabilization with synthetic/natural ligands is a promising anticancer approach, dense distribution throughout the genome restricts their selective targeting. Additionally, cationic G4 ligands are widely used for good aqueous solubility and G-quadruplex binding, yet the charges reduce the ligand’s cellular permeabilization. In this work, the first example of a histone deacetylase-activatable G4 ligand, displaying a significant stabilization upon activation (26 °C, ΔTm), was developed. Having 1.8-fold more cellular uptake, the ligand increased G-quadruplexes in the cell almost 3-fold as verified by the G4-specific antibody. Oncogene expression including anti-apoptotic BCL-2 and telomerase was significantly suppressed, more selectively in HDAC2/HDAC6-overexpressing microsatellite unstable colon cancer, leading to a 73% decrease in proliferation. With a versatile chemical structure and a very large activity difference between ON and OFF states, the ligand has a promising therapeutic potential and can be a useful building block for the development of novel activatable G-quadruplex ligands.