title: DNA intercalating Ru(II) polypyridyl complexes as effective photosensitizers in photodynamic therapy.
abstract: Six substitutionally inert [Ru(II) (bipy)2 dppz](2+) derivatives (bipy=2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazine) bearing different functional groups on the dppz ligand [NH2 (1), OMe (2), OAc (3), OH (4), CH2 OH (5), CH2 Cl (6)] were synthesized and studied as potential photosensitizers (PSs) in photodynamic therapy (PDT). As also confirmed by DFT calculations, all complexes showed promising (1) O2 production quantum yields, well comparable with PSs available on the market. They can also efficiently intercalate into the DNA double helix, which is of high interest in view of DNA targeting. The cellular localization and uptake quantification of 1-6 were assessed by confocal microscopy and high-resolution continuum source atomic absorption spectrometry. Compound 1, and especially 2, showed very good uptake in cervical cancer cells (HeLa) with preferential nuclear accumulation. None of the compounds studied was found to be cytotoxic in the dark on both HeLa cells and, interestingly, on noncancerous MRC-5 cells (IC50 >100 μM). However, 1 and 2 showed very promising behavior with an increment of about 150 and 42 times, respectively, in their cytotoxicities upon light illumination at 420 nm in addition to a very good human plasma stability. As anticipated, the preferential nuclear accumulation of 1 and 2 and their very high DNA binding affinity resulted in very efficient DNA photocleavage, suggesting a DNA-based mode of phototoxic action.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich (Switzerland), WWW: www.gassergroup.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mari
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pierroz
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.forename: Malay
authors.initials: M
authors.lastname: Patra
authors.forename: Jeannine
authors.initials: J
authors.lastname: Hess
authors.forename: Bernhard
authors.initials: B
authors.lastname: Spingler
authors.forename: Luciano
authors.initials: L
authors.lastname: Oehninger
authors.forename: Julia
authors.initials: J
authors.lastname: Schur
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Luca
authors.initials: L
authors.lastname: Salassa
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055668:Photochemical Processes; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D007364:Intercalating Agents; D017319:Photosensitizing Agents; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D004247:DNA
keywords: DNA binding; density functional calculations; fluorescence microscopy; photodynamic therapy; singlet oxygen