Structural insights and shedding light on preferential interactions of dietary flavonoids with G-quadruplex DNA structures: A new horizon

Abstract

G-quadruplex, a structurally unique structure in nucleic acids present all throughout the human genome, has sparked great attention in therapeutic investigations. Targeting G-quadruplex structure is a new strategy for the drug development. Flavonoids are found in almost all dietary plant-based beverages and food products; therefore, they are ingested in significant proportions through the human diet. Although synthetically developed drug molecules are used vigorously but they have various adverse effects. While on the other hand, nature supplies chemically unique scaffolds in the form of distinct dietary flavonoids that are easily accessible, less poisonous, and have higher bioavailability. Because of their great pharmacological effectiveness and minimal cytotoxicity, such low molecular weight compounds are feasible alternatives to synthetic therapeutic medicines. Therefore, from a drug-development point of view, investigation on screening the binding capabilities of quadruplex-interactive small natural compounds like dietary flavonoids are expected to be highly effective, with a particular emphasis on the selectivity towards polymorphic G-quadruplex structures. In this respect, quadruplexes have scintillated research into their potential interaction with these dietary flavonoids. The purpose of this review is to offer an up-to-date close-up look at the research on their interaction with structurally varied dietary flavonoids with the goal of providing newer perspectives to construct novel therapeutic agents for next-generation disease managements.

Keywords: Dietary flavonoids; G-quadruplex; G-quadruplex ligands; G-quadruplex-DNA probes; G-quadruplex-dietary flavonoids interaction.

Graphical abstract

Fig. 1

G-quadruplex schematic layouts. G-quadruplex structures in this picture depict three stacks of G-tetrads and are divided into three categories based on their topology: parallel, antiparallel, and hybrid (direction of the 4 strands). M⁺ and dots in the G-tetrad represent cationic ions, Na⁺ or K⁺, and Hoogsteen hydrogen bonding, accordingly.

Fig. 2

Schematic diagram depicting the impact of G-quadruplex ligands on cancerous cells. The majority of G-quadruplex ligands promote slower development. These growth alterations are the result of changes in biological mechanisms. Based on the ligands and cell types G-quadruplex stabilisation can result in alterations in (a) telomere maintenance (b) oncogenic gene expression (c) enhanced genomic instability.

Fig. 3

Schematic representation of G-quadruplex (G4) targeting probes and G-quadruplex stabilising ligands.

Fig. 4

Fundamental chemical structure of flavonoids and their sub-groups.

Fig. 5

Interaction of G-quadruplex with dietary flavonoids. (A) Rutin, a flavonoid glycoside, has higher G-quadruplex selectivity than quercetin. The rutinose portion is highlighted in red. Rutin was expected to interact through stacking, the most effective strategy for G-quadruplex stabilisation, in this computational model. (B) The structural differences between naringenin and fisetin allow these compounds to interact differently with various DNA configurations. C-ring planarity seems to be a critical element in preferred G-quadruplex DNA binding of flavonoids. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 6

Schematic diagram of conversation from cancer cell to senescent cell by G-quadruplex-dietary flavonoid interaction.