Intercalation of a Heterocyclic Ligand between Quartets in a G‐Rich Tetrahelical Structure

Abstract

YES G-rich oligonucleotide VK2 folds into an AGCGA-quadruplex tetrahelical structure distinct ands ignificantly differentf rom G-quadruplexes, even thoughi t contains four G 3 tracts. Herein, ab is-quinoliniuml igand 360A with high affinity for G-quadruplex structures and selective telomerase inhibition is shown to strongly bind to VK2. Upon binding, 360A does not induce ac onformational switch from VK2 to an expected G-quadruplex. In contrast, NMR structural study revealed formation of a well-definedV K2-360A complex with a1 :1 binding stoichiometry,i nw hich3 60A intercalates between GAGA-a nd GCGC-quartets in the central cavity of VK2. This is the first high-resolution structure of aG -quadruplex ligand intercalating into aG -rich tetrahelical fold. This unique mode of ligand binding into tetrahelical DNA architecture offers insights into the stabilization of an AGCGA-quadruplexb ya heterocyclic ligand and provides guidelines for rational design of novel VK2 bindingm olecules with selectivity for different DNA secondary structures.

Quadruplex–Duplex Junction: A High‐Affinity Binding Site for Indoloquinoline Ligands

“…Interestingly, however, the G4 ligand 360A has recently been reported to intercalate between GC‐GC and GA‐GA duplexes within a tetrahelical topology with a flexible central cavity. Binding tightens the structure to create GCGC and GAGA tetrads while increasing the distance between adjacent bases to accommodate the inserted ligand [44] …”

“…Interestingly,h owever,t he G4 ligand 360Ah as recently been reported to intercalate between GC-GC and GA-GA duplexes within at etrahelical topology with af lexible central cavity.B inding tightens the structure to create GCGC and GAGA tetrads while increasing the distance betweena djacent bases to accommodate the inserted ligand. [44] Given high-affinity binding at the Q-D junction for quadruplexes with either 3'-o r5 '-duplexe xtensions, the absence or presenceo fexchange crosspeaks betweenf ree and ligand bound Q-D hybrids in ROESY spectra of Myc-dup3 and Myc-dup5 deserves further discussion. In contrast to Myc-dup5,e xchange rates are slow compared to the mixing time of the ROESY experiment for Myc-dup3.…”

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

“…However, such a binding mode has not yet been confirmed on short cation-stabilized quadruplexes and only intercalation between non-conventional GAGA and GCGC quartets of an unusual G-rich tetrahelical structure has been reported for a bis-quinolinium compound. [37] Also, porphyrin intercalation into long G4 DNA nanowires has only been evidenced in the absence of monovalent cations whereas nonintercalative binding was suggested in a K + solution. [38] Apparently, in addition to the considerable energetic cost when unstacking G-tetrads associated with the unwinding of four strands to provide for an intercalation pocket, a metal ion located within the central channel between tetrads seems to restrict access of a corresponding ligand.…”

Virtual Screening of Phenylenediamine Schiff`s Base Derivatives as Possible DNA Intercalating Agents

“…Lipophilicity (LogP o/w) values of all synthesized compounds were in the range from 1.83 to 3.44 for mono-substituted compounds, and 3.10 to 6.31 for disubstituted compounds while their molecular weights are generally within the accepted range-with a few exceptions. The compounds were found with optimum number of hydrogen bonding donors (0-4) and hydrogen bonding acceptors (1)(2)(3)(4)(5)(6)(7)(8). The achieved results indicate that most of the compounds follow Lipinski rule and have a good partition coefficient.…”