The interactions of three related cationic porphyrins, TMPyP2, TMPyP3 and TMPyP4 with four Bcl-2 promoter sequence G-quadruplexes were studied using Isothermal Titration Calorimetry, Circular Dichroism, Fluorescence, UV-Vis spectroscopy, and ESI-MS. TMPyP4, (5, 10, 15, 20�meso-tetra (N-methyl-4-pyridyl) porphyrin), is shown to bind to all of the Bcl-2 model G-quadruplexes by two different binding modes, an end binding mode and a weaker mode resembling intercalation. Saturation stoichiometry for all of the TMPyP4/Bcl-2 promoter sequence quadruplexes is 4:1, with the bound TMPyP4 exhibiting both significant absorbance hypochromicity and a red shift in the soret band that is consistent with a planar stacking interaction. The related ligands TMPyP2 and TMPyP3 are shown to bind to all four Bcl-2 model G-quadruplexes by a single end binding mode with a saturation stoichiometry of 2:1. The non-planar shape of the TMPyP2 and TMPyP3 molecules, in which the pyridinium rings are forced out of plane relative to the porphyrin ring, results in reduced affinity for the mode 1 end binding interaction and elimination of intercalation binding. The highest affinity mode for binding the three cationic porphyrin ligands to each of the Bcl-2 promoter sequence quadruplexes follows the general trend: TMPyP4 >TMPyP3 >> TMPyP2. Table 1 ITC Derived Thermodynamic Parameters for the binding of porphyrin ligands (TMPyP2, TMPyP3, and TMPyP4) to the 39Bcl-2 promoter sequence G-Quadruplex.

Case for G-quadruplex intercalation: Bcl-2 promoter sequence interactions with the cationic porphyrins, TMPyP2, TMPyP3, and TMPyP4

246th National Meeting (2013)

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