Targeting C-myc G-quadruplex: dual recognition by aminosugar-bisbenzimidazoles with varying linker lengths

Abstract

G-quadruplexes are therapeutically important biological targets. In this report, we present biophysical studies of neomycin-Hoechst 33258 conjugates binding to a G-quadruplex derived from the C-myc promoter sequence. Our studies indicate that conjugation of neomycin to a G-quadruplex binder, Hoechst 33258, enhances its binding. The enhancement in G-quadruplex binding of these conjugates varies with the length and composition of the linkers joining the neomycin and Hoechst 33258 units.

Figure 1

The arrangement of guanine bases in a G-tetrad. The cavity in the middle is occupied by the metal cations.

Figure 2

Structures of neomycin-Hoechst 33258 conjugates used in the studies.

Figure 3

FID plots showing the change in the fluorescence upon ligand binding in a DNA -thiazole orange (TO) complex (a) C-myc quadruplex (b) TFO C-myc duplex. The number of atoms between the neomycin and Hoechst 33258 units in these conjugates is displayed in the parenthesis on the X-axis. Neomycin and Hoechst 33258 have been abbreviated as ‘Neo’ and ‘HS’ in the figure.

Figure 4

Circular dichroism studies of C-myc quadruplex with (a) Hoechst 33258 and (b) DPA 173.

Figure 5

UV-Vis absorption spectra of (a) Hoechst 33258 and (b) DPA 173 in the presence of C-myc quadruplex. Arrows indicated isobestic points.