Structural Insight into the interaction of Flavonoids with Human Telomeric Sequence.

Arpita Tawani,Amit Kumar

doi:10.1038/srep17574

Abstract

Flavonoids are a group of naturally available compounds that are an attractive source for drug discovery. Their potential to act as anti-tumourigenic and anti-proliferative agents has been reported previously but is not yet fully understood. Targeting human telomeric G-quadruplex DNA could be one of the mechanisms by which these flavonoids exert anticancer activity. We have performed detailed biophysical studies for the interaction of four representative flavonoids, Luteolin, Quercetin, Rutin and Genistein, with the human telomeric G-quadruplex sequence tetramolecular d-(T2AG3T) (Tel7). In addition, we used NMR spectroscopy to derive the first model for the complex formed between Quercetin and G-quadruplex sequence. The model showed that Quercetin stabilises the G-quadruplex structure and does not open the G-tetrad. It interacts with the telomeric sequence through π-stacking at two sites: between T1pT2 and between G6pT7. Based on our findings, we suggest that Quercetin could be a potent candidate for targeting the telomere and thus, act as a potent anti-cancer agent.

Highlights

Flavonoids are a group of naturally available compounds that are an attractive source for drug discovery
The results suggest that Quercetin acts as a groove binder for the monomeric conformation, whereas it binds to the dimeric conformation via a stacking mode[39]
Our present study focused on four different flavonoids, Luteolin, Quercetin, Rutin and Genistein, and their interaction with Tel[7] G-quadruplex sequence

Summary

Introduction

Flavonoids are a group of naturally available compounds that are an attractive source for drug discovery. Many groups have investigated the interaction of the G-quadruplex with naturally available small molecules such as berberine[17], sanguinarine[18], and others[19,20,21], which usually offer relatively less toxicity and fewer side effects than the synthetic molecules. Most of these compounds stabilise the G-tetrad by π -stacking due to the presence of extended aromatic rings[22]. The flavonoid skeleton contains a planar chromophore with an additional carboxyl group for protonation and can effectively intercalate into the planar scaffold of G-tetrads[35,36]

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Conclusion