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

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 p-p 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.

Automated summary

Despite their well-known and various bioactivities, in-depth studies on the interaction of natural compounds with cancer-related G-quadruplex structures have only recently been undertaken. In this study, a mini-library of phenanthrenoid analogues was investigated for their selective recognition of G-quadruplexes. Compounds 3 and 6 emerged as the most selective and active ligands, targeting the grooves/flanking residues of G-quadruplex structures. These compounds showed a preference for the hybrid telomeric G-quadruplex and exhibited anticancer activity in human cancer cells. Overall, these compounds are promising starting scaffolds for the design of analogues with high and selective anticancer activity.