DNA Binding and Photocleavage in Vitro by New Dirhodium(II) dppz Complexes:  Correlation to Cytotoxicity and Photocytotoxicity

Abstract

Two new dirhodium(II) complexes possessing the intercalating dppz ligand (dppz = dipyrido[3,2-a:2',3'-c]phenazine), cis-[Rh(2)(mu-O(2)CCH(3))(2)(dppz)(eta(1)-O(2)CCH(3))(CH(3)OH)](+) (1) and cis-[Rh(2)(mu-O(2)CCH(3))(2)(dppz)(2)](2+) (2), were synthesized and characterized as potential agents for photochemotherapy. Various techniques show that 1 binds to DNA through intercalation, although some aggregation of the complex on the DNA surface is also present. In contrast, 2 does not intercalate between the DNA bases; however, strong hypochromic behavior is observed in the presence of DNA, which can be attributed to intermolecular pi-stacking of 2 enhanced by the polyanion. The apparent DNA binding constants determined using optical titrations are compared to those from dialysis experiments. Both complexes photocleave pUC18 plasmid in vitro under irradiation with visible light (lambda(irr) >or= 395 nm, 15 min), resulting in the nicked, circular form. Greater photocleavage is observed for 1 relative to 2, which may be due to the ability of 1 to intercalate between the DNA bases. The cytotoxicity toward human skin cells (Hs-27) measured as the concentration at which 50% cell death is recorded, LC(50), was found to be 135 +/- 8 microM for 2 in the dark (30 min), which is significantly lower than those of 1 (LC(50) = 27 +/- 2 microM) and Rh(2)(O(2)CCH(3))(4) (LC(50) = 15 +/- 2 microM). Irradiation of cell cultures containing 1 and Rh(2)(O(2)CCH(3))(4) with visible light (400-700 nm, 30 min) has little effect on their cytotoxicity, with LC(50) values of 21 +/- 3 and 13 +/- 2 microM, respectively. Interestingly, a 3.4-fold increase in the toxicity of 2 is observed when the cell cultures are irradiated (400-700 nm, 30 min), resulting in LC(50) = 39 +/- 1 microM. The greater toxicity of 1 compared to 2 in the dark may be related to the ability of the former compound to intercalate between the DNA bases. The lower cytotoxicity of 2, together with its significantly greater photocytotoxicity, makes this complex a potential agent for photodynamic therapy (PDT). These results suggest that intercalation or strong DNA binding may not be a desirable property of a potential PDT agent.

Photochemistry and DNA photocleavage by a new unsupported dirhodium(II,II) complex

“…The recovered product was 0.11 g which is an overall yield of 75 per cent based on rhodium. Recrystallization of [Rh 2 (phen) 2 [65] and cis-[Rh 2 (μ-OAc) 2 (dppz) 2 (CH 3 OH)(OAc)] + [68].…”

“…In H 2 O, the lowest energy absorption band of 1 red-shifts to 540 nm (300 M −1 cm −1 ), while the higher energy band remains at a similar energy with maximum at 366 nm (4500 M −1 cm −1 , figure 2). The lowest energy transition in d 7 -d 7 dirhodium(II,II) complexes is known to involve promotion of an electron to the unoccupied metal-metal σ * orbital; the energy of this molecular orbital (MO) is sensitive to the identity of the axial ligands [66,68]. Therefore, a shift in the lowest energy band is expected as a function of solvent.…”

Interactions of Metal—Metal‐Bonded Antitumor Active Complexes with DNA Fragments and DNA

“…Dirhodium complexes are being investigated by the Turro group at The Ohio State University as potential antitumor agents in photochemotherapy, which involves triggering the toxicity of a compound by irradiation of the affected Figure 16), 60 effect direct pUC18 plasmid photocleavage in vitro upon irradiation with visible light (λ irr g 395 nm) resulting in nicked circular DNA. An enhancement of photocleavage is observed for cis-[Rh 2 (µ-O 2 CCH 3 ) 2 (dppz)(η 1 -O 2 CCH 3 )-(CH 3 OH)] + , which may be due to its ability to intercalate DNA bases.…”

“…An enhancement of photocleavage is observed for cis-[Rh 2 (µ-O 2 CCH 3 ) 2 (dppz)(η 1 -O 2 CCH 3 )-(CH 3 OH)] + , which may be due to its ability to intercalate DNA bases. 60 The species cis-[Rh 2 (µ-O 2 CCH 3 ) 2 (dppz) 2 ] 2+ exhibits relatively low cytotoxicity toward human skin cells in the dark, but its toxicity increases 3.4-fold upon irradiation of the cell cultures with visible light. 60 Likewise, the cytotoxicity of the heteroleptic species cis-[Rh 2 -(µ-O 2 CCH 3 ) 2 (bpy)(dppz)] 2+ ( Figure 17) increases 5-fold upon irradiation, with the advantage of 10-fold lower toxicity than hematoporphyrin (key component in Photofrin) in the dark.…”

“…60 The species cis-[Rh 2 (µ-O 2 CCH 3 ) 2 (dppz) 2 ] 2+ exhibits relatively low cytotoxicity toward human skin cells in the dark, but its toxicity increases 3.4-fold upon irradiation of the cell cultures with visible light. 60 Likewise, the cytotoxicity of the heteroleptic species cis-[Rh 2 -(µ-O 2 CCH 3 ) 2 (bpy)(dppz)] 2+ ( Figure 17) increases 5-fold upon irradiation, with the advantage of 10-fold lower toxicity than hematoporphyrin (key component in Photofrin) in the dark. 61 These results render the aforementioned compounds promising candidates for photochemotherapy.…”