Compelling DNA intercalation through 'anion-anion' anti-coulombic interactions: boron cluster self-vehicles as promising anticancer agents.

Anticancer drugs inhibit DNA replication by intercalating between DNA base pairs, forming covalent bonds with nucleotide bases, or binding to the DNA groove. To develop safer drugs, novel molecular structures with alternative binding mechanisms are essential. Stable boron hydrides offer a promising alternative for cancer therapy, opening up additional options like boron neutron capture therapy based on B and thermal neutron beams or proton boron fusion therapy using B and proton beams. These therapies are more efficient when the boron compound is ideally located inside cancer cells, particularly in the nucleus. Current cancer treatments often utilize small, polycyclic, aromatic, planar molecules that intercalate between ds-DNA base pairs, requiring only a spacing of approximately 0.34 nm. In this paper, we demonstrate another type of intercalation. Notably, [3,3'-Fe(1,2-CBH)], ([-FESAN]), a compact 3D molecule measuring 1.1 nm × 0.6 nm, can as well intercalate by strong non-bonding interactions preferentially with guanine. Unlike known intercalators, which are positive or neutral, [-FESAN] is a negative species and when an [-FESAN] molecule approaches the negatively charged DNA phosphate chain an anion-anion interaction consistently anti-electrostatic C-H⋯O-P bonds occurs. Then, when more molecules approach, an elongated outstandingly self-assembled structure of [-FESAN]-[-FESAN] forms moving anions towards the interthread region to interact with base pairs and form aggregates of four [-FESAN] anions per base pair. These aggregates, in this environment, are generated by C-H⋯O-C, N-H⋯H-B and C-H⋯H-B interactions. The ferrabis(dicarbollide) boron-rich small molecules not only effectively penetrate the nucleus but also intercalate with ds-DNA, making them promising for cancer treatment. This amphiphilic anionic molecule, used as a carrier-free drug, can enhance radiotherapy in a multimodal perspective, providing healthcare professionals with improved tools for cancer treatment. This work demonstrates these findings with a plethora of techniques.