Samya Banerjee

Metal Complexes of Curcumin for Cellular Imaging, Targeting, and Photoinduced Anticancer Activity

Curcumin is a polyphenolic species. As an active ingredient of turmeric, it is well-known for its traditional medicinal properties. The therapeutic values include antioxidant, anti-inflammatory, antiseptic, and anticancer activity with the last being primarily due to inhibition of the transcription factor NF-κB besides affecting several biological pathways to arrest tumor growth and its progression. Curcumin with all these positive qualities has only remained a potential candidate for cancer treatment over the years without seeing any proper usage because of its hydrolytic instability involving the diketo moiety in a cellular medium and its poor bioavailability. The situation has changed considerably in recent years with the observation that curcumin in monoanionic form could be stabilized on binding to a metal ion. The reports from our group and other groups have shown that curcumin in the metal-bound form retains its therapeutic potential. This has opened up new avenues to develop curcumin-based metal complexes as anticancer agents. Zinc(II) complexes of curcumin are shown to be stable in a cellular medium. They display moderate cytotoxicity against prostate cancer and neuroblastoma cell lines. A similar stabilization and cytotoxic effect is reported for (arene)ruthenium(II) complexes of curcumin against a variety of cell lines. The half-sandwich 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (RAPTA)-type ruthenium(II) complexes of curcumin are shown to be promising cytotoxic agents with low micromolar concentrations for a series of cancer cell lines. In a different approach, cobalt(III) complexes of curcumin are used for its cellular delivery in hypoxic tumor cells using intracellular agents that reduce the metal and release curcumin as a cytotoxin. Utilizing the photophysical and photochemical properties of the curcumin dye, we have designed and synthesized photoactive curcumin metal complexes that are used for cellular imaging by fluorescence microscopy and damaging the cancer cells on photoactivation in visible light while being minimally toxic in darkness. In this Account, we have made an attempt to review the current status of the chemistry of metal curcumin complexes and present results from our recent studies on curcumin complexes showing remarkable in vitro photocytotoxicity. The undesirable dark toxicity of the complexes can be reduced with suitable choice of the metal and the ancillary ligands in a ternary structure. The complexes can be directed to specific subcellular organelles. Selectivity by targeting cancer cells over normal cells can be achieved with suitable ligand design. We expect that this methodology is likely to provide an impetus toward developing curcumin-based photochemotherapeutics for anticancer treatment and cure.

BODIPY appended copper(II) complexes of curcumin showing mitochondria targeted remarkable photocytotoxicity in visible light

Copper(II) complexes of BODIPY (borondipyrromethene) derivatives (L-1, L-2) and curcumin (Hcur), viz. Cu(L-1)(cur)]Cl (1) and Cu(L-2)(cur)]Cl (2), where L-1 and L-2 are the non-iodinated and diiodinated BODIPY appended dipicolylamine ligands, are prepared and characterized and their photocytotoxic activity in visible light studied. Binding to copper(II) has rendered stability to curcumin from its hydrolytic degradation in buffer medium. The complexes show mitochondrial localization in HeLa cells emphasizing the findings that both 1 and 2 are mitochondria-targeting complexes and induce cancer cell death. Complex 1 with a fluorophoric BODIPY moiety in L-1 gave IC50 values of 7.9(+/- 0.3) mu M in visible light (400-700 nm) and 29.1(+/- 0.5) mu M in the dark. Complex 2 having a diiodo BODIPY moiety in L-2 as a photosensitizer gave IC50 values of 3.8(+/- 0.2) mu M in visible light and 32.1(+/- 0.4) mu M in the dark. The PDT effect of 2 is comparable to that of Photofrin (R), an FDA approved PDT drug. Cell death follows an apoptotic pathway with the formation of reactive oxygen species (ROS).

Selective and Sensitive Turn-on Chemosensor for Arsenite Ion at the ppb Level in Aqueous Media Applicable in Cell Staining

A newly designed and structurally characterized cell permeable diformyl-p-cresol based receptor (HL) selectively senses the AsO3(3-) ion up to ca. 4.1 ppb in aqueous media over the other competitive ions at biological pH through an intermolecular H-bonding induced CHEF (chelation-enhanced fluorescence) process, established by detailed experimental and theoretical studies. This biofriendly probe is highly competent in recognizing the existence of AsO3(3-) ions in a living organism by developing an image under a fluorescence microscope and useful to estimate the amount of arsenite ions in various water samples.

Significant photocytotoxic effect of an iron(III) complex of a Schiff base ligand derived from vitamin B6 and thiosemicarbazide in visible light

Iron(III)–Schiff base complexes, namely, [Fe(tsc-py)2](NO3) (1), [Fe(tsc-acpy)2](NO3) (2) and [Fe(tsc-VB6)2](NO3) (3), where tsc-py, tsc-acpy and tsc-VB6 are the respective Schiff bases derived from thiosemicarbazide (tsc) and pyridine-2-aldehyde (tsc-py), 2-acetyl pyridine (tsc-acpy) and vitamin B6 (pyridoxal, tsc-VB6), have been prepared, structurally characterized and their photocytotoxicity studied in cancer HeLa cells. The single crystal X-ray structures of the complexes 1 and 2 show a distorted octahedral geometry formed by the FeN4S2 core. The low-spin and 1:1 electrolytic complexes display a broad absorption band in the visible region. Complexes 1 and 2, without any VB6 moiety are not cytotoxic under light or dark conditions. Complex 3 is significantly photocytotoxic under visible light of 400–700 nm giving an IC50 value of 22.5 μM in HeLa cells with no dark toxicity (IC50 > 100 μM). The photo-induced cell death is attributable to apoptotic pathways involving photo-assisted generation of intracellular ROS. The observed photocytotoxicity of complex 3 could be the result of its better photosensitizing property combined with its enhanced uptake into cancer cells via a VB6 transporting membrane carrier (VTC) mediated diffusion pathway due to the presence of the VB6 moiety compared to the two non-vitamin B6 analogues, complexes 1 and 2.

Remarkable visible light-triggered cytotoxicity of mitochondria targeting mixed-ligand cobalt(III) complexes of curcumin and phenanthroline bases binding to human serum albumin

Six new mixed-ligand cobalt(III) complexes of formulation [Co(N–N)2(O–O)](ClO4)2 (1–6), where N–N is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 5, 6), O–O is acetylacetonate (acac in 1, 3, 5) or curcumin (bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, cur in 2, 4, 6), have been synthesized and characterized. The X-ray crystal structures of complex 1 (as PF6− salt, 1a) and 3 show distorted octahedral geometries formed by the CoN4O2 core. The complexes 1, 3 and 5 having the simple acac ligand are prepared as control species to understand the role of curcumin. The optimized geometries and the frontier orbitals of the curcumin complexes 2, 4, and 6 are obtained from the DFT calculations. The complexes 2, 4, and 6 having the photoactive curcumin moiety display an absorption band in the visible region near 420 nm and show remarkable photocytotoxicity in HeLa cancer cells with respective IC50 values of 7.4 μM, 5.1 μM and 1.6 μM while being much less toxic in dark. MTT assay using complex 6 shows that it is not significantly photocytotoxic to MCF-10A normal cells. The control complexes having the acac ligand are non-toxic both in the presence and absence of light. The cell death is apoptotic in nature and triggered by the photogeneration of reactive oxygen species. Fluorescence imaging experiments on HeLa cells reveals that complex 6 accumulated primarily inside the mitochondria. Human serum albumin (HSA) binding experiments show that the complexes bind HSA with good affinity, but 6 binds with the highest affinity, with a Kb value of 9.8 × 105 M−1. Thus, complex 6 with its negligible toxicity in the dark and in normal cells but remarkable toxicity in visible light holds significant photochemotherapeutic potential.

BODIPY appended copper(II) complexes for cellular imaging and singlet oxygen mediated anticancer activity in visible light

Copper(II) complexes of N,N,N-donor dipicolylamine ligands, viz. [Cu(L1)Cl2] (1), [Cu(L2)Cl2] (2) and [Cu(L3)Cl2] (3) with L2 and L3 having BODIPY (borondipyrromethene) moieties were synthesized, characterized and their photocytotoxicity studied. Complex 1 was structurally characterized by X-ray crystallography. It has copper(II) in a distorted square-pyramidal geometry (τ = 0.11) with two chloride ligands in axial-equatorial cis-disposition. The one-electron paramagnetic and redox active complexes are non-electrolytic in DMF. They behave as 1 : 1 and 1 : 2 electrolytes in 1 : 1 and 1 : 9 (v/v) DMF–H2O. The BODIPY complexes 2 and 3 show respective visible bands at 501 nm and 535 nm in DMF. Complex 2 displays an emission band at 515 nm in DMF (λex = 465 nm) with a quantum yield (ΦF) value of 0.14. This complex, as a fluorogenic probe for cellular imaging, shows cytosolic localisation of the complex in HeLa and MCF-7 cancer cells. Complex 3 having a diiodo BODIPY unit in L3 is non-emissive but acts as an efficient photosensitizer showing a significant PDT effect with apoptotic cell death forming singlet oxygen as ROS (ϕΔ = 0.53) and giving respective IC50 values of 0.15 ± 0.02 and 0.17 ± 0.03 μM in HeLa and MCF-7 cancer cells in visible light of 400–700 nm, while being less toxic in the dark.

Substituent effect on fluorescence signaling of the cell permeable HSO4- receptors through single point to ratiometric response in green solvent

Two new 2-(2-aminophenyl)benzimidazole-based HSO4− ion selective receptors, 6-(4-nitrophenyl)-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (L1H) and 6-(4-methoxyphenyl)-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (L2H), and their 1 : 1 molecular complexes with HSO4− were prepared in a facile synthetic method and characterized by physicochemical and spectroscopic techniques along with the detailed structural analysis of L1H by single crystal X-ray crystallography. Both receptors (L1H and L2H) behave as highly selective chemosensor for HSO4− ions at biological pH in ethanol–water HEPES buffer (1/5) (v/v) medium over other anions such as F−, CI−, Br−, I−, AcO−, H2PO4−, N3− and ClO4−. Theoretical and experimental studies showed that the emission efficiency of the receptors (L1H and L2H) was tuned successfully through single point to ratiometric detection by employing the substituent effects. Using 3σ method the LOD for HSO4− ions were found to be 18.08 nM and 14.11 nM for L1H and L2H, respectively, within a very short responsive time (15–20 s) in 100 mM HEPES buffer (ethanol–water: 1/5, v/v). Comparison of the utility of the probes (L1H and L2H) as biomarkers for the detection of intracellular HSO4− ions concentrations under a fluorescence microscope has also been included and both probes showed no cytotoxic effect.

A quinazoline derivative as quick-response red-shifted reporter for nanomolar Al3+ and applicable to living cell staining

A newly synthesized and structurally characterized quinazoline derivative (L) has been shown to act as a quick-response chemosensor for Al3+ with a high selectivity over other metal ions in water-DMSO. In the presence of Al3+, L shows a red-shifted ratiometric enhancement in fluorescence as a result of internal charge transfer and chelation-enhanced fluorescence through the inhibition of a photo-induced electron transfer mechanism. This probe detects Al3+ at concentrations as low as 1.48 nM in 100 mM HEPES buffer (DMSO-water, 1 : 9 v/v) at biological pH with a very short response time (15-20 s). L was applied to biological imaging to validate its utility as a fluorescent probe for monitoring Al3+ ions in living cells, illustrating its value in practical environmental and biological systems.

Photocytotoxic ternary copper(II) complexes of histamine Schiff base and pyridyl ligands

AbstractTernary copper(II) complexes of salicylaldehyde-histamine Schiff base (HL) and pyridyl ligands, viz. [Cu(bpy)(L)](ClO4) (1) and [Cu(dppz)(L)](ClO4) (2), where bpy is 2,2′

Photocytotoxic luminescent lanthanide complexes of DTPA–bisamide using quinoline as photosensitizer

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