title: π-Expansive Heteroleptic Ruthenium(II) Complexes as Reverse Saturable Absorbers and Photosensitizers for Photodynamic Therapy.
abstract: Five heteroleptic tris-diimine ruthenium(II) complexes [RuL(N^N)2](PF6)2(where L is 3,8-di(benzothiazolylfluorenyl)-1,10-phenanthroline and N^N is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), 1,4,8,9-tetraazatriphenylene (tatp) (3), dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4), or benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) (5), respectively) were synthesized. The influence of π-conjugation of the ancillary ligands (N^N) on the photophysical properties of the complexes was investigated by spectroscopic methods and simulated by density functional theory (DFT) and time-dependent DFT. Their ground-state absorption spectra were characterized by intense absorption bands below 350 nm (ligand L localized1π,π* transitions) and a featureless band centered at ∼410 nm (intraligand charge transfer (1ILCT)/1π,π* transitions with minor contribution from metal-to-ligand charge transfer (1MLCT) transition). For complexes 4 and 5 with dppz and dppn ligands, respectively, broad but very weak absorption (ε < 800 M-1cm-1) was present from 600 to 850 nm, likely emanating from the spin-forbidden transitions to the triplet excited states. All five complexes showed red-orange phosphorescence at room temperature in CH2Cl2solution with decreased lifetimes and emission quantum yields, as the π-conjugation of the ancillary ligands increased. Transient absorption (TA) profiles were probed in acetonitrile solutions at room temperature for all of the complexes. Except for complex 5 (which showed dppn-localized3π,π* absorption with a long lifetime of 41.2 μs), complexes 1-4 displayed similar TA spectral features but with much shorter triplet lifetimes (1-2 μs). Reverse saturable absorption (RSA) was demonstrated for the complexes at 532 nm using 4.1 ns laser pulses, and the strength of RSA decreased in the order: 2 ≥ 1 ≈ 5 > 3 > 4. Complex 5 is particularly attractive as a broadband reverse saturable absorber due to its wide optical window (430-850 nm) and long-lived triplet lifetime in addition to its strong RSA at 532 nm. Complexes 1-5 were also probed as photosensitizing agents for in vitro photodynamic therapy (PDT). Most of them showed a PDT effect, and 5 emerged as the most potent complex with red light (EC50= 10 μM) and was highly photoselective for melanoma cells (selectivity factor, SF = 13). Complexes 1-5 were readily taken up by cells and tracked by their intracellular luminescence before and after a light treatment. Diagnostic intracellular luminescence increased with increased π-conjugation of the ancillary N^N ligands despite diminishing cell-free phosphorescence in that order. All of the complexes penetrated the nucleus and caused DNA condensation in cell-free conditions in a concentration-dependent manner, which was not influenced by the identity of N^N ligands. Although the mechanism for photobiological activity was not established, complexes 1-5 were shown to exhibit potential as theranostic agents. Together the RSA and PDT studies indicate that developing new agents with long intrinsic triplet lifetimes, high yields for triplet formation, and broad ground-state absorption to near-infrared (NIR) in tandem is a viable approach to identifying promising agents for these applications.
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Acadia University , 6 University Avenue, Wolfville, NS B4P 2R6, Canada.
authors.forename: Huimin
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Jabed
authors.affiliation: Department of Chemistry, Acadia University , 6 University Avenue, Wolfville, NS B4P 2R6, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Hetu
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Chengzhe
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Acadia University , 6 University Avenue, Wolfville, NS B4P 2R6, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Monro
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Svetlana
authors.identifier: http://orcid.org/0000-0003-1350-2790
authors.initials: S
authors.lastname: Kilina
authors.affiliation: Department of Chemistry, Acadia University , 6 University Avenue, Wolfville, NS B4P 2R6, Canada.|Department of Chemistry and Biochemistry, University of North Carolina at Greensboro , Greensboro, North Carolina 27402-6170, United States.
authors.forename: Sherri A
authors.initials: SA
authors.lastname: McFarland
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108-6050, United States.
authors.forename: Wenfang
authors.identifier: http://orcid.org/0000-0003-3608-611X
authors.initials: W
authors.lastname: Sun
mesh_terms: D065966:Absorption, Physicochemical; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D017319:Photosensitizing Agents; D012428:Ruthenium