[Pt(cur)(NH3)2](NO3) (1), a curcumin-bound cis-diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5'-GMP and ct-DNA indicated formation of platinum-bound DNA adducts upon exposure to visible light (λ=400-700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC50 ≈ 15 μM), thus forming (⋅)OH, while remaining passive in the darkness (IC50 >200 μM). A comet assay and platinum estimation suggest Pt-DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo- and phototherapeutic agent.
Platinum(II) complexes [Pt(L)(R-BODIPY)]Cl (1) and [Pt(L)(R-BODIPY)]Cl (2), where R-BODIPY is 8-(4-ethynylphenyl)-distyryl-4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3, L is 4'-phenyl-2,2':6',2″-terpyridine, and L is (2,2':6',2″-terpyridin-4'-oxy)ethyl-β-d-glucopyranoside, were synthesized and characterized, and their photocytotoxicity was studied. The phenylacetylide complex [Pt(L)(C≡CPh)]Cl (3) was prepared and used as a control. Complexes 1 and 2 showed near-IR absorption bands at 713 nm (ε = 3.47 × 10 M cm) and 715 nm (3.2 × 10 M cm) in 10% dimethyl sulfoxide (DMSO)-Dulbecco's Modified Eagle's Medium (DMEM) (pH 7.2). The BODIPY complexes are emissive in 10% DMSO-DMEM at pH 7.2 with λ (λ, Φ) = 822 nm (710 nm, 0.022) for complex 1 and λ (λ, Φ) = 825 nm (710 nm, 0.026) for complex 2. They generated singlet oxygen (O) in red light as evidenced from 1,3-diphenylisobenzofuran (DPBF) titration experiments. The singlet oxygen quantum yield (Φ) values for 1 and 2 were ∼0.6 signifying their photosensitizing ability. They were remarkably photodynamic therapy (PDT) active in red light showing significant red light-induced cytotoxicity in cervical HeLa, lung cancer A549, and breast cancer MCF-7 cells (IC: 2.3-24.7 μM in light) with negligible dark toxicity (IC > 100 μM). A significant enhancement in cellular uptake was observed for 2 having glucose-appended terpyridine ligand compared to 1. The confocal microscopy showed significant mitochondrial localization of the complexes as evidenced from the JC-1 assay. The complexes released the photoactive R-BODIPY ligand upon red light-irradiation as evidenced from the mass and H NMR spectral studies. Complex 2 is remarkable in satisfying the essential requirements of targeted PDT in red light.
Monofunctional pyriplatin analogues cis-[Pt-(NH 3 ) 2 (L)Cl](NO 3 ) (1−3) having boron-dipyrromethene (BODIPY) pendants (L) with 1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4′-difluoroboradiazaindacene moieties were designed and synthesized, and their photocytotoxic properties were studied. The Pt-BODIPY conjugates displayed an absorption band within 505−550 nm and a green emissive band near 535 nm in 1% DMSO/DMEM (Dulbecco's modified Eagle's medium) buffer. Complex cis-[Pt(NH 3 ) 2 (4-Me-py)Cl](NO 3 ) (4) was used as a control for determining the structural aspects by X-ray crystallography. The mono-and diiodinated BODIPY complexes 2 and 3 showed generation of singlet oxygen on light activation as evidenced from the 1,3-diphenylisobenzofuran (DPBF) titration experiments. The cytotoxicity of the BODIPY complexes was tested against A549 (human lung cancer), MCF-7 (human breast cancer), and HaCaT (human skin keratinocyte) cells in dark and visible light (400−700 nm, 10 J cm −2 ). While complexes 2 and 3 showed excellent photocytotoxicity (IC 50 ≈ 0.05 μM), they remained essentially nontoxic in the dark (IC 50 > 100 μM). The emissive bands of 1 and 2 were used for cellular imaging by confocal microscopy study, which showed their mitochondrial localization. This was further supported by platinum estimation from isolated mitochondria and mitochondrial depolarization through a JC-1 assay. The photomediated apoptotic cell death was evidenced from flow cytometric assays, annexin-V/FITC-PI (fluorescein isothiocyanate-propidium iodide) and cell cycle arrest in sub-G1 and G2/M phases. The complexes bind to 9-ethylguanine as a model nucleobase to form monoadducts. A mechanistic study on DNA photocleavage activity using pUC19 DNA showed singlet oxygen as the reactive oxygen species (ROS). The combination of photodynamic therapy with DNA cross-linking property enhanced the anticancer potential of the monofunctional BODIPY-conjugates of pyriplatins.
Monofunctional platinum(II) complexes of formulation cis-[Pt(NH)(L)Cl](NO), where L is an imidazole base conjugated to 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) with emissive (L in 1) and nonemissive (L in 2) moieties were prepared and characterized, and their singlet oxygen-mediated photoinduced cytotoxicity was studied. The 1-methylimidazole (1-MeIm) complex 3 was prepared as a control and for structural characterization by X-ray crystallography. Complexes 1 and 2 showed strong visible absorption bands at 500 nm (ε = 2.7 × 10 M cm) and 540 nm (1.4 × 10 M cm). Complex 1 is emissive with a band at 510 nm (Φ = 0.09) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH 7.2). Singlet oxygen generation upon photoirradiation with visible light (400-700 nm) was evidenced from 1,3-diphenylisobenzofuran titration experiments showing significant photosensitizing ability of the BODIPY complexes. Both 1 and 2 were remarkably photocytotoxic in visible light (400-700 nm, 10 J cm) in skin keratinocyte HaCaT and breast cancer MCF-7 cells giving IC values in nanomolar concentration. The complexes were, however, essentially nontoxic to the cells in the dark (IC > 80 μM). Complex 2 having a diiodo-BODIPY unit is nonemissive but an efficient photosensitizer with high singlet oxygen generation ability in visible light (400-700 nm). Confocal microscopy using the emissive complex 1 showed significant mitochondrial localization of the complex. Cell death via apoptotic pathway was observed from the Annexin-V-FITC/PI assay. The formation of Pt-DNA adducts was evidenced from the binding experiments of the complexes 1 and 2 with 9-ethylguanine as a model nucleobase from H NMR and mass spectral studies.
Three platinum(II) complexes of curcumin, [Pt(NH 3 ) 2 -(cur)](NO 3 ) (1), [Pt(en)(cur)](NO 3 ) (2) and [Pt(dach)(cur)](NO 3 ) (3), where Hcur is curcumin, en is ethylenediamine and dach is 1R,2R-(-)-1,2-diaminocyclohexane, were synthesized, characterized and their photocytotoxic properties were explored. The acetylacetone (Hacac) analogue of 1, [Pt(NH 3 ) 2 (acac)]NO 3 (4), was prepared to investigate the role of photoactive curcumin. The crystal structure of [Pt(NH 3 ) 2 (acac)]CF 3 SO 3 (4a) revealed square-planar geometry of the platinum(II) centre. Complexes 1-3 displayed an intense absorption band at 450 nm (ε = 22500 M -1 cm -1 ). The curcumin in metal-bound form showed
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