On a Supramolecular Tightrope: Self-Assembly of 8-HeteroAryl-dG Derivatives

Guanosine forms planar tetramers known as G-tetrads which can further stack and yield supramolecules known as G-quadruplexes (GQs). The main goal is to design reliable GQ-nanostructures with different molecularity (e.g.,  octamers,  dodecamers,  hexadecamers)  for  their  use  in  applications  as  self-assembled drugs, dendrimers, or cellular imaging probes. Though, how we can modulate the self-assembly of guanosine?  The  strategy  of  our  research  team  is  to reprogram  the  native  recognition  features  of  the  guanine  moiety  by  incorporating aromatic/heteroaromatic groups at the C8  position. We hypothesized that the presence  of  heteroaromatic  rings will  impart  a  prominent dipole close  to  the  guanine  base resulting in enhanced attractive interactions between monomeric units allowing the assembly of up to three G-tetrads. To test this hypothesis, we decided to study the self-assembly of a family of 8-HeteroAryl-dG derivatives (8HetGs) in chloroform and acetonitrile. Their molecularity, fidelity, thermodynamic stability, and lower self-assembly concentration was elucidated using primarily ¹H NMR titration experiments, ¹H variable temperature and variable concentration experiments and Mass Spectrometry. Most of the derivatives form dodecamers with high fidelity and thermodynamic stability driven by the strength of the intermolecular interactions within the assembly, not by the number of G-tetrads. Particularly, having a 3-pyridil group at the C8 induce the formation of the most reliable and stable dodecamer. Modulating the intrinsic parameters enable us to fine-tune the guanosine assembly by establishing a balance among repulsive (e.g. steric) and attractive (e.g. π-π, dipole-dipole) non-covalent interactions, enabling the high fidelity formation of stable and discrete self-assembled GQ dodecamers.