The Interaction of Telomere DNA G-Quadruplex with Threebis-Benzyltetrahydroisoquinoline Alkaloids

Abstract

Telomeres are important multifunctional nucleoprotein structures located at the ends of eukaryotic chromosomes. Telomerase regulates telomere elongation, and its activity is associated with tumorigenesis. Because the activity of telomerase can be inhibited by G-quadruplex (G4) formation (a four-stranded DNA with stacks of G-quartets formed by four guanines in a planar structure), the role of G4 in cancer therapy has attracted many research interests. We studied the effects of three natural alkaloids-tetrandrine, fangchinoline, and berbamine-on the stability and formation of telomere DNA G4 with circular dichroism melting spectroscopy (melting-CD), variable temperature ultraviolet (melting-UV), proton nuclear magnetic resonance spectroscopy ((1)H NMR), and molecular docking, and examined the relationships among the alkaloid structure and their activities. We further investigated their cytotoxicity with the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FCM). The results demonstrated that alkaloids increased G4 stability and induced its formation, which added structure diversity of G4-ligands. The results showed that -OH at R(1), -OCH(3) at R(2), and [Formula: see text] at R(3) had higher stability than other substituent groups for these alkaloids. We also found a transition of antiparallel to parallel G4 as the temperature increased. The result indicated the possible advantage of parallel G4 in adversity. In addition, the alkaloids demonstrated a moderate cytotoxicity and proved to be cell cycle blocker in the G(1) phase. These alkaloids have revealed promising potentials to be the agents for antitumor therapy.

The genomic sequences near the mir‐23b‐27b‐24‐1 cluster form G‐quadruplexes and are selectively bound by the natural alkaloid tetrandrine

“…Tetrandrine is a bis‐benzylisoquinoline alkaloid (Fig. (B)) extracted from Stephania tetrandra , and has been used as an effective G‐quadruplexes ligand . Our study further verified that tetrandrine‐G‐quadruplex binding affinity was related to the conformations of the G‐quadruplexes.…”

“…1(B)) extracted from Stephania tetrandra, [26] and has been used as an effective G-quadruplexes ligand. [27,28] Our study further verified that tetrandrine-G-quadruplex binding affinity was related to the conformations of the G-quadruplexes. We further performed CD variable temperature measurements to evaluate the stability of the G-quadruplex-ligand complexes.…”

The Interaction of Telomeric DNA and C-myc22 G-Quadruplex with 11 Natural Alkaloids

“…INTERACTION OF DNA G-QUADRUPLEX WITH 11 ALKALOIDS alkaloids, which we reported to be G4-ligands ( Ji et al, 2011a). So far, there is no report on the interaction of S2 with G4.…”

“…Molecular modeling simulations were performed according to a method described previously (Luu et al, 2006;Ji et al, 2011a). All the molecular modeling works and simulations were performed using the Insight II 2005 software package on a Dell Precision T5400 workstation under CHARMM force field.…”

“…Notably, a few of the ligands have already entered preclinical or clinical trials, among which quarfloxin (CX-3543) has entered phase 2 clinical trials (Bates et al, 2007). Considering the importance of G4 and its ligands, our team has carried out a series of research in this area (Sun et al, 2006(Sun et al, , 2007(Sun et al, , 2009Zhou et al, 2008bZhou et al, , 2009Li et al, 2009;Yang et al, 2009Yang et al, , 2010aYang et al, , 2010bYang et al, , 2010cTian et al, 2010;Yang and Okamoto, 2010;Zhang et al, 2010;Ji et al, 2011aJi et al, , 2011b.…”