Dual-action platinum(II) Schiff base complexes : photocytotoxicity and cellular imaging

Nine photo-stable Pt(II) Schiff base complexes [Pt(O^N^N^O)] (Pt1–Pt9) containing tetradentate salicylaldimine chelating ligands have been synthesized and characterized as potential photosensitisers for photodynamic therapy (PDT). The effects of electron-withdrawing versus electron-donating substituents on their electronic spectral properties are investigated. Pt1–Pt9 show broad absorption bands between 400–600 nm, which makes them useful for green-light photodynamic therapy. The complexes showed intense phosphorescence with emission maxima at ca. 625 nm. This emission was used to track their cellular localization in cancer cells. Confocal cellular imaging showed that the complexes localized mostly in the cytoplasm. In the dark, the complexes were non-toxic to A549 human lung cancer cells, but exhibited high photo-toxicity upon low-dose green light (520 nm, 7.02 J/cm2) irradiation via photo-induced singlet oxygen generation. Thus, these photoactive Pt(II) complexes have the potential to overcome the problem of drug resistance and side effects of current clinical Pt(II) drugs, and to act as both theranostic as well as therapeutic agents

Vitamin-B6 Schiff base dioxovanadium(V) complex for targeted visible light-induced anticancer activity

A dioxovanadium(V) complex of vitamin-B6 Schiff base [VO2L] (1) (where H2L·HCl is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-1-ium chloride) has been prepared and structurally characterized. Its photo-induced cytotoxicity and mechanism of cell death has been studied. Single crystal X-ray structure shows five-coordinate square-pyramidal geometry of the complex having the dianionic O,N,O-donor tridentate vitamin-B6 Schiff base and two cis-oriented oxo ligands bound to V(V). DFT study shows the HOMO located on the amino-phenolic moiety, while the LUMO is on the protonated aromatic unit, i.e., the pyridiniumphenolate moiety. Vitamin-B6 transporting membrane carrier (VTC) pathway seems to be responsible for the higher cellular uptake and activity of the complex into the cervical HeLa and breast cancer MCF-7 cells in preference to the normal embryonic fibroblast 3T3 cells. The complex exhibits reactive oxygen species (ROS) mediated apoptotic photocytotoxicity in visible light of 400–700 nm in the cancer cells (IC50: ~16 μM), while being essentially non-toxic in the dark. Alkaline Comet assay shows damage of the nuclear DNA.

Generation of maghemite nanocrystals from iron–sulfur centres

Iron oxide nano-crystals 0.1–1.1 μm in diameter were generated on sulfur-doped amorphous carbon surfaces by electron beam irradiation of the novel 13e− high-spin complex [Fe(4-methyl-1,2-benzenedithiolate)2][NHEt3] encapsulated in a triblock copolymer. Possible relevance to iron nano-mineralization from Fe–S ferredoxin proteins and iron dysregulation in neurological disorders is discussed. Graphical abstract: Generation of maghemite nanocrystals from iron–sulfur centres Iron is an essential element for mammals and, amongst many other functions, plays an important role in the human brain.1 Recent research has indicated a strong association between iron dysregulation and Alzheimer's disease (AD), although it is unknown how the chemical and magnetic state of iron is linked to AD pathogenesis.2–4 Reports from Collingwood et al., and Dobson et al., for example, have shown the presence of iron oxide as the mixed oxidation state mineral, magnetite (Fe3O4) in AD tissue, a possible source of redox-active iron, but it remains unclear how this kind of iron mineral forms in the tissue.5,6 These unsolved and important questions have led us to consider how atomic resolution microscopy might provide new insight into nanoscale iron mineralization. Recently we reported methodology for studies of the nano-mineralisation of osmium, gold, ruthenium and iridium from their respective 1,2-dicarba-closo-dodecarborane-1,2-dithiolate complexes encapsulated in polymer micelles upon electron beam irradiation.7–9 Here we report the synthesis and characterization of the novel 13e− iron(iii) complex [Fe(4-methyl-1,2-benzenedithiolate)2][NHEt3] (1), containing Fe–S bonds analogous to those in the ubiquitous iron–sulfur ferredoxin proteins. Importantly, recent research has indicated a strong relationship between neurodegenerative disorders and defective Fe–S clusters.10,11 We have characterized complex 1 using Mössbauer, Raman and far-infra red spectroscopy, and investigated the generation of iron nanocrystals from 1 encapsulated in a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer (Scheme 1) by electron beam irradiation, and used electron energy-loss spectra (EELS) to identify the oxidation state of iron and its coordination environment in the nanocrystals

New activation mechanism for half-sandwich organometallic anticancer complexes

The Cpx C–H protons in certain organometallic RhIII half-sandwich anticancer complexes [(η5-Cpx)Rh(N,N′)Cl]+, where Cpx = Cp*, phenyl or biphenyl-Me4Cp, and N,N′ = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh–hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular ‘twisters’. The calculations reveal the crucial role of pπ orbitals of N,N′-chelated ligands in stabilizing deprotonated Cpx ligands, and also the accessibility of RhI–fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)RhIII(en)Cl]+ and [(Cp*)IrIII(bpy)Cl]+ do not have activated Cp* rings. The thiol tripeptide glutathione (γ-L-Glu-L-Cys-Gly, GSH) and the activated dienophile N-methylmaleimide, (NMM) did not undergo addition reactions with the proposed RhI–fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized RhI–fulvene intermediates by Diels–Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9Z,11E)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels–Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action

Kinetics and mechanism of sequential ring methyl C–H activation in cyclopentadienyl rhodium(iii) complexes

We have studied activation of the methyl C–H bonds in the cyclopentadienyl ligands of half-sandwich Rh(III) complexes [η5-CpXRh(N,N′)Cl]+ by observing the dependence of sequential H/D exchange on variations in CpX = Cp* (complexes 1 and 2), Me4PhCp (CpXPh, 3) or Me4PhPhCp (CpXPhPh, 4), and chelated ligand N,N′ (bpy, 1; phen, 2–4). H/D exchange was fastest in d4-MeOD (t1/2 = 10 min, 37 °C, complex 1), no H/D exchange was observed in DMSO/D2O, and d4-MeOD enhanced the rate in CD3CN. The proposed Rh(I)–fulvene intermediate was trapped by [4 + 2] Diels–Alder reactions with conjugated dienes and characterized. The Rh(I) oxidation state was confirmed by X-ray photoelectron spectroscopy (XPS). Influence of solvent on the mechanisms of activation and Diels–Alder adduct formation was modelled using DFT calculations with the CAM-B3LYP functional and CEP-31 g basis set, and influence on the reaction profile of the dimiine ligand and phenyl substituent using the larger qzvp basis set. The Rh(III)–OH intemediate is stabilised by H-bonding with methanol and a Cp* CH3 hydrogen. The Rh(I)(Me4fulvene) species, stabilised by interaction of methanol with a coordinated water, again by two H-bonds H2O–HOMe (1.49 Å) and fulvene CH2 (1.94 Å), arises from synchronous transfer of the methanol OH proton to a Rh(III)–OH ligand and Cp* methyl hydrogen to the methanol oxygen. Additionally, the observed trend in catalytic activity for complexes 1–4 was reproduced by DFT calculations. These complexes form a novel class of catalytic molecular motors with a tunable rate of operation that can be stalled in a given state. They provide a basis for elucidation of the effects of ligand design on the contributions of electronic, rotational and vibrational energies to each step in the reaction pathway at the atomic level, consideration of which will enhance the design principles for the next generation of molecular machines

Ligand-controlled reactivity and cytotoxicity of cyclometalated rhodium(III) complexes

We report the synthesis, characterization and cytotoxicity of six cyclometalated rhodium(III) complexes [CpXRh(C^N)Z]0/+, in which CpX = Cp*, Cpph, or Cpbiph, C^N = benzo[h]quinoline, and Z = chloride or pyridine. Three X‐ray crystal structures showing the expected “piano‐stool” configurations have been determined. The chlorido complexes hydrolyzed faster in aqueous solution, and reacted preferentially with 9‐ethyl guanine or glutathione compared to their pyridine analogues. The 1‐biphenyl‐2,3,4,5‐tetramethylcyclopentadienyl complex [CpbiphRh(benzo‐[h]quinoline)Cl] (3a) was the most efficient catalyst in coenzyme reduced nicotinamide adenine dinucleotide (NADH) oxidation to NAD+ and induced an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [CpbiphRh(benzo[h]quinoline)py]+ (3b) was the most potent against A549 lung and A2780 ovarian cancer cell lines, being 5‐fold more active than cisplatin towards A549 cells, and acted as a ROS scavenger. This work highlights a ligand‐controlled strategy to modulate the reactivity and cytotoxicity of cyclometalated rhodium anticancer complexes

Effect of cysteine thiols on the catalytic and anticancer activity of Ru(ii) sulfonyl-ethylenediamine complexes

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1–8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The ‘piano-stool’ structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The Image ID:d1dt03856g-t1.gif values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1–8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5–9.7 h−1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2− or [(η6-biph)2Ru2(NAC-H)3]2−, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex

Acute onset movement disorders in diabetes mellitus: A clinical series of 59 patients

Background and purpose: No previous study has assessed the frequency and clinical– radiological characteristics of patients with diabetes mellitus (DM) and acute onset non-choreic and nonballistic movements. We conducted a prospective study to investigate the spectrum of acute onset movement disorders in DM.Methods: We recruited all the patients with acute onset movement disorders and hyper-glycemia who attended the wards of three hospitals in West Bengal, India from August 2014 to July 2021.Results: Among the 59 patients (mean age = 55.4± 14.3 years, 52.5% men) who were included, 41 (69.5%) had choreic or ballistic movements, and 18 (30.5%) had nonchoreic and nonballistic movements. Ballism was the most common movement disorder (n= 18, 30.5%), followed by pure chorea (n= 15, 25.4%), choreoathetosis (n= 8, 13.6%), tremor (n= 5, 8.5%), hemifacial spasm (n= 3, 5.1%), parkinsonism (n= 3, 5.1%), myoclonus (n= 3, 5.1%), dystonia (n= 2, 3.4%), and restless leg syndrome (n= 2, 3.4%). The mean duration of DM was 9.8 ± 11.4 years (89.8% of the patients had type 2 DM). Nonketotic hypergly-cemia was frequently (76.3%) detected. The majority (55.9%) had no magnetic resonance imaging (MRI) changes; the remaining showed striatal hyperintensity. Eight patients with MRI changes exhibited discordance with sidedness of movements. Most of the patients (76.3%) recovered completely.Conclusions: This is the largest clinical series depicting the clinical–radiological spectrum of acute onset movement disorders in DM. Of note was that almost one third of patients had nonchoreic and nonballistic movements. Our findings highlight the importance of a capillary blood glucose measurement in patients with acute or subacute onset movement disorders, irrespective of their past glycemic status

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

CONSPECTUS: 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-kappa B 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