Supramolecular β-Cyclodextrin Adducts of Boron-Rich DNA Metallointercalators Containing Dicarba-closo-dodecaborane(12)

A chiral, isomeric series of novel boron-rich Pt-II metallointercalators ([PtL2(phen)](NO3)(2): L = (x)-( 1,y-c/oso-carboran-1-yppyrid-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 Delta-head-to-tail, head-to-head, and Lambda-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 Delta G(307)double dagger = 16.1 +/- 0.3 kcal mol(-1) and Delta G(325)double dagger = 16.2 +/- 0.5 kcal mol(-1) for the 1,7-carboranyl derivative and Delta G(302)double dagger = 16.4 +/- 0.5 kcal mol(-1) and Delta G(325)double dagger = 16.2 +/- 0.5 kcal mol(-1) for the 1,12-carboranyl derivative. The corresponding 2:1 host guest beta-cyclodextrin (beta-CD) adducts ([PtL2(phen)center dot 2 beta-CD]NO3)(2)) were also prepared and fully characterized by high resolution electrospray ionization mass spectrometry and 2D-H-1{B-11} 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 beta-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 K-assoc ranging from (1.3 +/- 0.1) x 10(5) M-1 to (5.7 +/- 0.4) X 10(5) 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.