Synthesis and preliminary DNA binding studies of a novel series of carbocyclic cleft molecules

The synthesis, characterization, photophysical properties, and DNA binding abilities of a novel class of carbocyclic molecular clefts, is described. Initial experiments were carried out by production of multi-gram amounts of the parent carbocyclic cleft (±)-47. Functionalisation of the aromatic rings of (±)-47 was achieved through nitration and selective reduction to give a key diamine intermediate (±)-65. This intermediate (±)-65 was used as precursor for condensation reaction with naphthalic anhydride 121 to deliver the first potential ligand, (±)-129. This ligand, (±)-129, is the first example of the carbocyclic cleft analogue to Tröger's base (TB) possessing naphthalimide groups in its structure with the potential to interact with DNA. Although, (±)-47 is deactivated, due to the electronegative carbonyl groups, the direct bromination at meta-positions of the aromatic rings was successfully achieved under highly acidic conditions. This delivered a key dibromide (±)-54a that has the potential to undergo palladium cross coupling reactions, delivering an alternate route to (±)-129. The solubility of (±)-129 proved challenging in assessing its interaction with ct-DNA using UV-Vis titrations, therefore an alternate ligand class was examined.

Extending the aromaticity within the carbocyclic core was also examined. This led to the formation of a novel series of carbocyclic analogues possessing naphthyl groups. Two synthetic routes were examined to access this class of ligands. The key final step(s) in these routes were the cyclisation through a unique double Friedel–Crafts acylation, and this provided five unique ligands whose binding affinity to ct-DNA was determined.

The DNA-binding affinities of the naphthyl ligands was determined at pH 7.4 (phosphate buffer), in the presence of increasing concentrations of calf-thymus DNA (ct-DNA), using UV-Vis absorption. The UV-Vis spectroscopic findings demonstrated that the majority of the ligands displayed hypochromicity and a bathochromic shift, which is indicative of an intercalation mode-of-binding. Specifically, ligands (±)-146 and (±)-150 - (±)-152 exhibited significant DNA-binding abilities, with moderate to large binding K_b values in the range of 10⁵ - 10⁶ M^-1 being reported.