Supramolecular beta-cyclodextrin adducts of boron-rich DNA metallointercalators containing dicarba-closo-dodecaborane

Abstract

A chiral, isomeric series of novel boron-rich PtII metallointercalators ([PtL2(phen)](NO3)2: L = (x)-(1,y-closo-carboran-1-yl)pyrid-z-ylmethanol: x = R, S; y = 7, 12; z = 3, 4) wre prepared and fully characterized. By means of variable-temperature NMR spectroscopy, different combinations of Δ-head-to-tail, head-to-head, and Λ-head-to-tail rotamers were identified, and the free energies of activation for Pt–N bond rotation were determined for the pyrid-4-yl complexes with ΔG‡307 = 16.1 ± 0.3 kcal mol–1 and ΔG‡325 = 16.2 ± 0.5 kcal mol–1 for the 1,7-carboranyl derivative and ΔG‡307 = 16.4 ± 0.5 kcal mol–1 and ΔG‡325 = 16.2 ± 0.5 kcal mol–1 for the 1,12-carboranyl derivative. The corresponding 2:1 host–guest β-cyclodextrin (β-CD) adducts ([PtL2(phen)·2β-CD](NO3)2) were also prepared and fully characterized by high resolution electrospray ionization mass spectrometry and 2D-1H{11B} nuclear Overhauser enhancement spectroscopy and rotating-frame Overhauser effect spectroscopy NMR experiments. The interaction of the novel supramolecular adducts with calf thymus DNA was investigated by means of linear dichroism, ultraviolet-visible spectroscopy, thermal denaturation, and isothermal titration calorimetry experiments which revealed a bimodal binding regime with DNA intercalation favored at low [drug]/[DNA] ratios, while at higher drug loading, surface aggregation was observed. Furthermore, the data were also consistent with some degree of dissociation of the β-CD host–guest adducts upon DNA binding. When we used a single binding-site model, interpreted as a weighted average of all of the possible equilibrium interactions, the compounds showed high affinity for ct-DNA with Kassoc ranging from (1.3 ± 0.1) × 105 M–1 to (5.7 ± 0.4) × 105 M–1. In general, the overall DNA-binding behavior was enthalpically driven with a minor or unfavorable entropic component, which is consistent with the thermodynamics of an intercalation-dominated process. A higher degree of DNA intercalation was observed for the R-isomer in the pyrid-3-yl compounds, and the opposite trend was observed in the case of pyrid-4-yl derivatives.