Insights into the Small Molecule Targeting of Biologically Relevant G-Quadruplexes: An Overview of NMR and Crystal Structures

Criscuolo, Andrea; Napolitano, Ettore; Riccardi, Claudia; Musumeci, Domenica; Platella, Chiara; Montesarchio, Daniela

doi:10.3390/pharmaceutics14112361

Cited by 13 publications

(3 citation statements)

References 102 publications

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“…Therefore, some innovative anticancer strategies rely on G-quadruplex structure stabilization induced by small molecules at telomeres and oncogene promoters in order to block telomerase activity and oncogene expression, respectively [ 3 , 5 , 6 , 7 ], thus developing targeted therapies potentially endowed with low-to-null side effects. To date, about 3000 different G-quadruplex ligands have been identified [ 8 ], some of which show potential anticancer activities, but only a few have progressed to clinical trials due to selectivity issues [ 5 ]. DNA in duplex form is present in chromosomes in large excess compared with G-quadruplex structures.…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine

Platella

Ghirga

Musumeci

et al. 2023

IJMS

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Aiming to identify highly effective and selective G-quadruplex ligands as anticancer candidates, five natural compounds were investigated here, i.e., the alkaloids Canadine, D-Glaucine and Dicentrine, as well as the flavonoids Deguelin and Millettone, selected as analogs of compounds previously identified as promising G-quadruplex-targeting ligands. A preliminary screening with the G-quadruplex on the Controlled Pore Glass assay proved that, among the investigated compounds, Dicentrine is the most effective ligand of telomeric and oncogenic G-quadruplexes, also showing good G-quadruplex vs. duplex selectivity. In-depth studies in solution demonstrated the ability of Dicentrine to thermally stabilize telomeric and oncogenic G-quadruplexes without affecting the control duplex. Interestingly, it showed higher affinity for the investigated G-quadruplex structures over the control duplex (Kb~106 vs. 105 M−1), with some preference for the telomeric over the oncogenic G-quadruplex model. Molecular dynamics simulations indicated that Dicentrine preferentially binds the G-quadruplex groove or the outer G-tetrad for the telomeric and oncogenic G-quadruplexes, respectively. Finally, biological assays proved that Dicentrine is highly effective in promoting potent and selective anticancer activity by inducing cell cycle arrest through apoptosis, preferentially targeting G-quadruplex structures localized at telomeres. Taken together, these data validate Dicentrine as a putative anticancer candidate drug selectively targeting cancer-related G-quadruplex structures.

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Section: Introductionmentioning

confidence: 99%

Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine

Platella

Ghirga

Musumeci

et al. 2023

IJMS

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“…Nevertheless, resolving the Tel22 structure in these K + environmental conditions via high-resolution techniques is particularly challenging. For instance, while Nuclear Magnetic Resonance (NMR) has proven to be a valuable tool for elucidating the G4 structure alone and in complex with ligands in solution [33][34][35], this approach faces limitations when studying Tel22 in a K + environment due to the spectral overlap of different conformations. In this scenario, Circular Dichroism (CD) data and their refined analysis offer valuable insights into the secondary structures of complex systems with non-unique topologies.…”

Section: Introductionmentioning

confidence: 99%

Stability of Human Telomeric G-Quadruplexes Complexed with Photosensitive Ligands and Irradiated with Visible Light

Libera

Ripanti

Petrillo

et al. 2023

IJMS

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Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, molecular probe applications, and biosensing. In recent years, the use of G4-ligand complexes as photopharmacological targets has shown significant promise for developing novel therapeutic strategies and nanodevices. Here, we studied the possibility of manipulating the secondary structure of a human telomeric G4 sequence through the interaction with two photosensitive ligands, DTE and TMPyP4, whose response to visible light is different. The effect of these two ligands on G4 thermal unfolding was also considered, revealing the occurrence of peculiar multi-step melting pathways and the different attitudes of the two molecules on the quadruplex stabilization.

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“…A large variety of synthetic compounds have been widely explored as putative Gquadruplex binders [8][9][10]. In contrast, natural compounds have been far less studied, notwithstanding that they represent appealing candidates due to their different bioactivities and high structural diversity.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Binding of Natural Compounds to Cancer-Related G-Quadruplex Structures: From 9,10-Dihydrophenanthrenes to Their Dimeric and Glucoside Derivatives

Platella

Criscuolo

Riccardi

et al. 2023

IJMS

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In-depth studies on the interaction of natural compounds with cancer-related G-quadruplex structures have been undertaken only recently, despite their high potential as anticancer agents, especially due to their well-known and various bioactivities. In this frame, aiming at expanding the repertoire of natural compounds able to selectively recognize G-quadruplexes, and particularly focusing on phenanthrenoids, a mini-library including dimeric (1–3) and glucoside (4–5) analogues of 9,10-dihydrophenanthrenes, a related tetrahydropyrene glucoside (6) along with 9,10-dihydrophenanthrene 7 were investigated here by several biophysical techniques and molecular docking. Compounds 3 and 6 emerged as the most selective G-quadruplex ligands within the investigated series. These compounds proved to mainly target the grooves/flanking residues of the hybrid telomeric and parallel oncogenic G-quadruplex models exploiting hydrophobic, hydrogen bond and π-π interactions, without perturbing the main folds of the G-quadruplex structures. Notably, a binding preference was found for both ligands towards the hybrid telomeric G-quadruplex. Moreover, compounds 3 and 6 proved to be active on different human cancer cells in the low micromolar range. Overall, these compounds emerged as useful ligands able to target G-quadruplex structures, which are of interest as promising starting scaffolds for the design of analogues endowed with high and selective anticancer activity.

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Insights into the Small Molecule Targeting of Biologically Relevant G-Quadruplexes: An Overview of NMR and Crystal Structures

Cited by 13 publications

References 102 publications

Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine

Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine

Stability of Human Telomeric G-Quadruplexes Complexed with Photosensitive Ligands and Irradiated with Visible Light

Exploring the Binding of Natural Compounds to Cancer-Related G-Quadruplex Structures: From 9,10-Dihydrophenanthrenes to Their Dimeric and Glucoside Derivatives

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