A cisplatin-based platinum(IV) prodrug, [Pt(NH3)2Cl2(OH)(L1)], having L1 as red-light active boron-dipyrromethene (BODIPY) pendant, was synthesized, characterized and its application as a chemo-cum-photodynamic therapy agent studied. Me-L1 as the ligand precursor...
The bioessential nature of cobalt and the rich photochemistry of its coordination complexes can be exploited to develop potential next-generation photochemotherapeutics. A series of six novel mixed-ligand cobalt(III) complexes of the formulation [Co(B)2(L)]ClO4 (1–6), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1 and 4), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2 and 5), and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3 and 6), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat2–, in 1–3) or esculetin (6,7-dihydoxycoumarin, esc2–, in 4–6), have been prepared and characterized, and their light-triggered cytotoxicity has been studied in cancer cells. The single-crystal X-ray diffraction structures of complexes 1 (as PF6 – salt, 1a) and 2 show distorted octahedral geometries around the cobalt(III) center formed by the set of N4O2 donor atoms. The low-spin and 1:1 electrolytic complexes 1–6 display a d–d transition around 700 nm. Complexes 4–6 with a coordinated esc2– ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes 4–6 possessing a naturally occurring and photoactive esc2– ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC50 values while being much less toxic under dark conditions. Control complexes 1–3 possessing the photoinactive cat2– ligand show significantly less cytotoxicity either in the presence of light or in the dark. The complex-induced cell death is apoptotic in nature caused by the formation of reactive oxygen species via a type 1 photoredox pathway. Fluorescence microscopy of HeLa cells treated with complex 6 reveals mitochondrial localization of the complex. A significant decrease in the dark toxicity of free esculetin and dppz base is observed upon coordination to cobalt(III). Complexes bind to calf-thymus DNA with significant affinity, but 6 binds with the greatest affinity. Complex 6 efficiently photocleaves supercoiled DNA to its nicked circular form when irradiated with visible light via a photoredox type 1 pathway involving hydroxyl radicals (HO•). Thus, complex 6 showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.
Iron(III) complexes of a vitamin B 6 Schiff base and NNN-donor ligands with pendant boron-dipyrromethene (BODIPY) moieties; namely, [Fe(L 1-3 )(L 4,5 )](NO 3 ) (1-4), where L 1 is benzyl-bis[(pyridin-2-yl)methyl]methanamine (bzdpa in 1), L 2 is a noniodinated BODIPY-appended dipicolylamine ligand (in 2, 3), L 3 is the diiodinated BODIPY analogue in 4, L 4 is a vitamin B 6 Schiff base, namely 3-hydroxy-5(hydroxymethyl)-4-{[(2hydroxyphenyl)imino]methyl}-2-methylpyridine (in 1, 3, and 4), and L 5 is 2-[(2-hydroxyphenylimino)-methyl]phenol (in 2) as a nonpyridoxal Schiff base, were prepared, characterized, and their cellular localization and cytotoxic activity in light and in the dark were studied. The diiodo-BODIPY complex 4 displays remarkable photoinduced cytotoxicity in visible light (400- [a]
Iron(III) complexes of curcumin (Hcur) having a tridentate NNN‐donor dipicolylamine‐based ligand L1 and its biotinylated analogue L2, namely, [Fe(L1)(cur)Cl] (1) and [Fe(L2)(cur)Cl] (2), were prepared, characterized and their photo‐induced cytotoxicity studied. The complexes exhibited curcumin‐based absorption band near 430 nm and emission maxima at 520 nm. Complex 2 with a biotin moiety showed enhanced cellular uptake and higher cytotoxicity compared to its non‐biotin analogue 1. The visible light induced cytotoxicity was studied in HeLa, MCF‐7 and HepG2 cell lines. Complex 2 displayed photodynamic effect (400–700 nm, 10 J cm−2) giving an IC50 value of ∼4 μM in HeLa and MCF‐7 cells, while being significantly non‐toxic in the dark (IC50>100 μM). A 5‐fold increase in cytotoxicity was observed in HepG2 cells (IC50∼0.7 μM) for the biotin‐appended complex 2. In vitro generation of reactive oxygen species (ROS) was observed from dichlorofluorescein diacetate (DCFDA) assay. The mode of cell death was apoptotic. Formation of hydroxyl radicals as the ROS was evidenced from the plasmid pUC19 DNA photo‐cleavage studies. The complexes demonstrated the ability to act as targeted PDT (photodynamic therapy) drugs.
Mixed-ligand oxidovanadium(IV) β-diketonates having NNN-donor dipicolylamine-conjugated to boron-dipyrromethene (BOD-IPY in L 1 ) and diiodo-BODIPY (in L 2 ) moieties, namely, [VO(L 1 )(acac)] Cl (1), [VO(L 2 )(acac)]Cl (2), and [VO(L 1 )(dbm)]Cl (3), where acac and dbm are monoanionic O,O-donor acetylacetone and 1,3-diphenyl-1,3propanedione, were prepared, characterized, and tested for their photoinduced anticancer activity in visible light. Complexes 1 and 2 were structurally characterized as their PF 6 − salts (1a and 2a) by X-ray crystallography. They showed V IV N 3 O 3 six-coordinate geometry with dipicolylamine base as the facial ligand. The non-iodinated BODIPY complexes displayed absorption maxima at ∼501 nm, while it is ∼535 nm for the di-iodinated 2 in 10% DMSO−PBS buffer medium (pH = 7.2). Complexes 1 and 3 being green emissive (λ em , ∼512 nm; λ ex , 470 nm; Φ F , ∼0.10) in 10% aqueous DMSO were used for cellular imaging studies. Complex 3 localized primarily in the mitochondria of the cervical HeLa cells with a co-localization coefficient value of 0.7. The nonemissive diiodo-BODIPY complex 2 showed generation of singlet oxygen (Φ Δ ≈ 0.47) on light activation. Annexin-V assay showed singlet oxygen-mediated cellular apoptosis, making this complex a targeted PDT agent.
Cis-dichloro-oxovanadium(IV) complexes [VO(L 1 /L 2)Cl 2 ], where L 1 is N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4ʎ 4 ,5ʎ 4-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl) methanamine in 1 and L 2 is N-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4ʎ 4 ,5ʎ 4-dipyrrolo[1,2-c:2′,1′f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 2) having 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene as boron-dipyrromethene (BODIPY) appended dipicolylamine bases were prepared, characterized and their photocytotoxicity studied. X-ray crystal structure of 1 showed distorted octahedral geometry with a V IV ON 3 Cl 2 core having Cl-V-Cl angle of 91.93(4)°. The complexes showed variable solution conductivity properties. They were non-electrolytes in dry DMF at 25°C but showed 1:1 electrolytic behavior in an aqueous medium due to dissociation of one chloride ligand as evidenced from the mass spectral study. Complexes 1 and 2 showed absorption bands at 500 and 535 nm, respectively. The calf thymus DNA melting study revealed their interaction through DNA crosslinking on exposure to light which was further confirmed from the alkaline agarose gel electrophoresis using plasmid supercoiled pUC19 DNA. Complex 2 showed disruption of the mitochondrial membrane potential in the JC-1 (1,1′,3,3′-tetraethyl-5,5′,6,6′-tetrachloroimidacarbocyanine iodide) assay. The complexes were photocytotoxic in visible light (400-700 nm, power: 10 J cm −2) in cervical cancer HeLa and breast cancer MCF-7 cells. Complex 2 having a photoactive diiodo-boron-dipyrromethene moiety gave a singlet oxygen quantum yield (Φ Δ) value of~0.6. It showed singlet oxygen mediated apoptotic photodynamic therapy activity with remarkably low IC 50 (half maximal inhibitory concentration) value of~0.15 μM. The cis-disposition of chlorides gave a cis-divacant 4-coordinate intermediate structure from the density functional theory (DFT) study thus mimicking the DNA crosslinking property of cisplatin.
Two multichromophoric homoleptic ruthenium(II) complexes [Ru(tpy-BODIPY)2]Cl2 (complexes 1 and 2, tpy = 4-phenyl-2,2:6,2-terpyridine, BODIPY = boron-dipyrromethene) were prepared, characterized and their phototherapeutic activity and bioimaging properties studied. The complexes having...
A perceived drawback of ruthenium(II) polypyridyl photosensitizers for phototherapeutic applications is their inadequate absorption in the visible region. Ru(II) dyads attached to lightharvesting organic chromophores are studied to address this issue. Biotin-appended compounds having one chromophore, namely BODIPY (boron-dipyrromethene) (1) and Ru(II)-(tpy) 2 (2), or a dyad system containing BODIPY linked to Ru(II)-(tpy) 2 via a diphenylacetylene linker (3) were prepared and studied as photodetection agent and photosensitizes for Photodynamic Therapy (PDT) applications. The bichromophoric 3 with a strong absorption profile (ɛ � 71000 M À 1 cm À 1 at λ max = 503 nm) and high singlet oxygen quantum yield (Φ Δ = 0.63 in DMSO) was studied for PDT activity. This complex produced a superoxide anion radical via type-I and singlet oxygen via type-II photosensitization processes on light exposure, as evidenced from DNA photo-cleavage experiments and in vitro DCFDA assay using reactive oxygen species scavengers/quenchers. Dyad 3 displayed an apoptotic photo-cytotoxic effect against HeLa and H1299 cancer cells with a photocytotoxicity index (PI) value of > 625 in HeLa cells with a PDT efficacy much superior to those of its monochromophoric analogs 1 and 2. The intrinsic emission of complex 3, utilized for cellular imaging, showed selectivity towards lysosomes. Finally, the remarkable potential of complex 3 was evidenced using a clinically relevant 3D multicellular tumor spheroid model.
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