title: Investigation of the interactions between Pt(II) and Pd(II) derivatives of 5,10,15,20-tetrakis (N-methyl-4-pyridyl) porphyrin and G-quadruplex DNA.
abstract: G-quadruplexes are non-canonical DNA structures formed by guanine-rich DNA sequences that are implicated in cancer and aging. Understanding how small molecule ligands interact with quadruplexes is essential both to the development of novel anticancer therapeutics and to the design of new quadruplex-selective probes needed for elucidation of quadruplex biological functions. In this work, UV-visible, fluorescence, and circular dichroism spectroscopies, fluorescence resonance energy transfer (FRET) melting assays, and resonance light scattering were used to investigate how the Pt(II) and Pd(II) derivatives of the well-studied 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) interact with quadruplexes formed by the human telomeric DNA, Tel22, and by the G-rich sequences from oncogene promoters. Our results suggest that Pt- and PdTMPyP4 interact with Tel22 via efficient π-π stacking with a binding affinity of 10(6)-10(7) M(-1). Under porphyrin excess, PtTMPyP4 aggregates using Tel22 as a template; the aggregates reach maximum size at [PtTMPyP4]/[Tel22] ~8 and dissolve at [PtTMPyP4]/[Tel22] ≤ 2. FRET assays reveal that both porphyrins are excellent stabilizers of human telomeric DNA, with stabilization temperature of 30.7 ± 0.6 °C for PtTMPyP4 and 30.9 ± 0.4 °C for PdTMPyP4 at [PtTMPyP4]/[Tel22] = 2 in K(+) buffer, values significantly higher as compared to those for TMPyP4. The porphyrins display modest selectivity for quadruplex vs. duplex DNA, with selectivity ratios of 150 and 330 for Pt- and PdTMPyP4, respectively. This selectivity was confirmed by observed 'light switch' effect: fluorescence of PtTMPyP4 increases significantly in the presence of a variety of DNA secondary structures, yet the strongest effect is produced by quadruplex DNA.
authors.affiliation: Department of Chemistry and Biochemistry, Swarthmore College, 500 College Ave., Swarthmore, PA, 19081, USA.|Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA.
authors.forename: Navin C
authors.initials: NC
authors.lastname: Sabharwal
authors.affiliation: INSERM U1212, CNRS, 33600, Pessac, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Oscar
authors.initials: O
authors.lastname: Mendoza
authors.affiliation: Department of Chemistry and Biochemistry, Swarthmore College, 500 College Ave., Swarthmore, PA, 19081, USA.|Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, MA, 02138, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Nicoludis
authors.affiliation: Department of Chemistry and Biochemistry, Swarthmore College, 500 College Ave., Swarthmore, PA, 19081, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruan
authors.affiliation: INSERM U1212, CNRS, 33600, Pessac, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: Department of Chemistry and Biochemistry, Swarthmore College, 500 College Ave., Swarthmore, PA, 19081, USA. lyatsun1@swarthmore.edu.
authors.forename: Liliya A
authors.initials: LA
authors.lastname: Yatsunyk
mesh_terms: D054856:G-Quadruplexes; D010165:Palladium / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D011166:Porphyrins / Q000737:chemistry*; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
chemical_list: D011166:Porphyrins; D010984:Platinum; D010165:Palladium
keywords: Fluorescence; G-quadruplex DNA; Human telomeric DNA; Light switch effect; Metalloporphyrin