Aminoglycosylation can enhance the G-quadruplex binding activity of epigallocatechin.

Fenfei Leng,Li-Ping Bai,Hing-Man Ho,Dik-Lung Ma,Wai-Chung Fu,Hui Yang,Zhi-Hong Jiang

doi:10.1371/journal.pone.0053962

Abstract

With the aim of enhancing G-quadruplex binding activity, two new glucosaminosides (16, 18) of penta-methylated epigallocatechin were synthesized by chemical glycosylation. Subsequent ESI-TOF-MS analysis demonstrated that these two glucosaminoside derivatives exhibit much stronger binding activity to human telomeric DNA and RNA G-quadruplexes than their parent structure (i.e., methylated EGC) (14) as well as natural epigallocatechin (EGC, 6). The DNA G-quadruplex binding activity of 16 and 18 is even more potent than strong G-quadruplex binder quercetin, which has a more planar structure. These two synthetic compounds also showed a higher binding strength to human telomeric RNA G-quadruplex than its DNA counterpart. Analysis of the structure-activity relationship revealed that the more basic compound, 16, has a higher binding capacity with DNA and RNA G-quadruplexes than its N-acetyl derivative, 18, suggesting the importance of the basicity of the aminoglycoside for G-quadruplex binding activity. Molecular docking simulation predicted that the aromatic ring of 16 π-stacks with the aromatic ring of guanine nucleotides, with the glucosamine moiety residing in the groove of G-quadruplex. This research indicates that glycosylation of natural products with aminosugar can significantly enhance their G-quadruplex binding activities, thus is an effective way to generate small molecules targeting G-quadruplexes in nucleic acids. In addition, this is the first report that green tea catechin can bind to nucleic acid G-quadruplex structures.

Highlights

Nucleic acid G-quadruplexes, four-stranded helical structures held together by a core of guanine tetrads, are secondary structures formed in particular G-rich sequences
A recent study revealed that nucleic acids are binding targets of green tea catechins: nucleic acids extracted from epigallocatechin gallate (EGCG)-treated human cancer cells were catechin-colored, and direct binding of catechins with single-stranded and double-stranded DNA/RNA was observed by cold spray ionization-mass spectrometry [34]
Synthesis of EGC Glucosaminosides Glycosylation is an effective method for connecting saccharide units to natural products in order to obtain biologically active glycosides [39,40]

Summary

Introduction

Nucleic acid G-quadruplexes, four-stranded helical structures held together by a core of guanine tetrads, are secondary structures formed in particular G-rich sequences. Potential nucleic acid G-quadruplex structures have been identified in telomeric DNA and RNA sequences [1,2,3,4,5] as well as non-telomeric chromosomal promoters [6,7,8,9] of biological significance. These higher-order structures in nucleic acids represent a new class of molecular targets for selective DNA- and RNA-interacting compounds; in view of the fact that cancer cells have high telomerase activity and abnormal overexpression of oncogenes relative to normal cells, they are promising targets for cancer drug discovery [10]. Structural modification of EGC is necessary for enhancing its G-quadruplex binding affinity

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Results

Conclusion