Plant‐Derived Stilbenoids as DNA‐Binding Agents: From Monomers to Dimers

Abstract

Stilbenoids are natural compounds endowed with several biological activities, including cardioprotection and cancer prevention. Among them, (±)‐trans‐δ‐viniferin, deriving from trans‐resveratrol dimerization, was investigated in its ability to target DNA duplex and G‐quadruplex structures by exploiting NMR spectroscopy, circular dichroism, fluorescence spectroscopy and molecular docking. (±)‐trans‐δ‐Viniferin proved to bind both the minor and major grooves of duplexes, whereas it bound the 3’‐ and 5’‐ends of a G‐quadruplex by stacking on the outer quartets, accompanied by rearrangement of flanking residues. Specifically, (±)‐trans‐δ‐viniferin demonstrated higher affinity for the investigated DNA targets than its monomeric counterpart. Additionally, the methoxylated derivatives of (±)‐trans‐δ‐viniferin and trans‐resveratrol, i. e. (±)‐pterostilbene‐trans‐dihydrodimer and trans‐pterostilbene, respectively, were evaluated, revealing similar binding modes, affinities and stoichiometries with the DNA targets as their parent analogues. All tested compounds were cytotoxic at μM concentration on several cancer cell lines, showing DNA damaging activity consistent with their ability to tightly interact with duplex and G‐quadruplex structures.

DNA Binding Mode Analysis of a Core-Extended Naphthalene Diimide as a Conformation-Sensitive Fluorescent Probe of G-Quadruplex Structures

“…More in detail, twelve narrow and well-resolved imino proton signals were observed in the range δ 10.5–12.2 ppm in the 1 H NMR spectra of both m-tel24 and M2 G-quadruplexes ( Figure 2 A,B, bottom), consistent with the formation of G-quadruplexes with three stacked G-quartets [ 36 , 37 , 39 , 40 ]. On the other hand, five narrow and well-resolved imino proton signals were observed in the range δ 12.5–13.8 ppm of the 1 H NMR spectrum of the ds12 duplex ( Figure 2 C, bottom), in accordance with previous reports for this self-complementary duplex consisting of twelve Watson-Crick base pairs [ 41 , 42 , 43 ].…”

Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes

“…Moreover, the CD pattern is used for the determination of binding modes with DNA [ 27 ]. The absence of induced CD signal ( Supplementary Figure S3 ) for any of the tested G4s suggests a mode of binding weaker than intercalation (i.e., end-stacking or electrostatic interaction), as reported for other G4 ligands [ 28 , 29 ]. Further binding studies were carried out using UV-vis spectroscopy.…”

Affinity Chromatography‐Based Assays for the Screening of Potential Ligands Selective for G‐Quadruplex Structures

“…Indeed, in the search for selective G4 ligands, natural compounds have been overlooked, though representing very appealing candidates due to the high structural diversity of their scaffolds. [73] First, we investigated a unique high diversity in‐house library composed of ca. 1,000 individual natural products, isolated mainly from indigenous plants collected in biodiversity‐rich countries, especially in tropical and subtropical areas, and enlarged with their semi‐synthetic and synthetic derivatives.…”

“…In addition to the three libraries of synthetic compounds above described, we evaluated thus far also three libraries of natural compounds. Indeed, in the search for selective G4 ligands, natural compounds have been overlooked, though representing very appealing candidates due to the high structural diversity of their scaffolds [73] . First, we investigated a unique high diversity in‐house library composed of ca.…”