Catalyst-Free Photoredox Addition-Cyclisations: Exploitation of Natural Synergy between Aryl Acetic Acids and Maleimide

Suitably functionalised carboxylic acids undergo a previously unknown photoredox reaction when irradiated with UVA in the presence of maleimide. Maleimide was found to synergistically act as a radical generating photoxidant and as a radical acceptor, negating the need for an extrinsic photoredox catalyst. Modest to excellent yields of the product chromenopyrroledione, thiochromenopyrroledione and pyrroloquinolinedione derivatives were obtained in thirteen preparative photolyses. In situ NMR spectroscopy was used to study each reaction. Reactant decay and product build-up were monitored, enabling reaction profiles to be plotted. A plausible mechanism, whereby photo-excited maleimide acts as an oxidant to generate a radical ion pair, has been postulated and is supported by UV/Vis. spectroscopy and DFT computations. The radical-cation reactive intermediates were also characterised in solution by EPR spectroscopy.

An Iron Complex of Dipyridophenazine as a Potent Photocytotoxic Agent in Visible Light

Ternary iron(III) complexes (FeL(B)] (1-3) of a trianionic tetradentate phenolate-based ligand (L) and henanthroline base (B), namely, 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), have been prepared and structurally characterized and their DNA binding, cleavage, and photocytotoxic properties studied. The complexes with a FeN3O3 core show the Fe(III)/Fe(II) redox couple near -0.6 V in DMF, a magnetic moment value of similar to 5.9 mu(B), and a binding propensity to both calf thymus DNA and bovine serum albumin (BSA) protein. They exhibit red-light-induced DNA cleavage activity following a metal-assisted photoredox pathway forming HO center dot radicals but do not show any photocleavage of BSA in UV-A light. Complex 3 displays photocytotoxicity in the human cervical cancer cell line (HeLa) and human keratinocyte cell line (HaCaT) with respective IC50 values of 3.59 mu M and 6.07 mu M in visible light and 251 nM and 751 nM in UV-A light of 365 nm. No significant cytotoxicity is observed in the dark. The photoexposed HeLa cells, treated prior with complex 3, have shown marked changes in nuclear morphology as demonstrated by Hoechst 33258 nuclear stain. Generation of reactive oxygen species has been evidenced from the fluorescence enhancement of dichlorofluorescein upon treatment with 3 followed by photoexposure. Nuclear chromatin cleavage has been observed in acridine orange/ethidium bromide dual staining of treated HeLa cells and from alkaline single-cell gel electrophoresis. Caspase 3/7 activity in HeLa cells has been found to be upregulated by only 4 fold after photoirradiation, signifying the fact that cell death through a caspase 3/7 dependent pathway may not be solely operative.

Ternary Iron(III) complex showing photocleavage of DNA in the photodynamic therapy window

A new ternary iron(III) complex [FeL(dpq)] containing dipyridoquinoxaline (dpq) and 2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)aminoacetic acid (H3L) is prepared and structurally characterized by X-ray crystallography. The high-spin complex with a FeN3O3 core shows a quasi-reversible iron(III)/iron(II) redox couple at -0.62 V (vs SCE) in DMF/0.1 M TBAP and a broad visible band at 470 nm in DMF/Tris buffer. Laser photoexcitation of this phenolate (L)-to-iron(III) charge-transfer band at visible wavelengths including red light of >= 630 nm leads to cleavage of supercoiled pUC19 DNA to its nicked circular form via a photoredox pathway forming hydroxyl radicals.

Structure-Activity Relationship of Photocytotoxic Iron(III) Complexes of Modified Dipyridophenazine Ligands

Iron(III) complexes FeL(B)] (1-5) of a tetradentate trianionic phenolate-based ligand (L) and modified dipyridophenazine bases (B), namely, dipyrido-6,7,8,9-tetrahydrophenazine (dpqC in 1), dipyrido3,2-a:2',3'-c]phenazine-2-carboxylic acid (dppzc in 2), dipyrido3,2-a:2',3'-c]phenazine-11-sulfonic acid (dppzs in 3), 7-aminodipyrido3,2-a:2',3'-c]phenazine (dppza in 4) and benzoi]dipyridro3,2-a:2',3'-c]phenazine (dppn in 5), have been synthesized, and their photocytotoxic properties studied along with their dipyridophenazine analogue (6). The complexes have a five. electron paramagnetic iron(III) center, and the Fe(III)/Fe(II) redox couple appears at about 0.69 V versus SCE in DMF-0.1 M TBAP. The physicochemical data also suggest that the complexes possess similar structural features as that of its parent complex FeL(dppz)] with FeO3N3 coordination in a distorted octahedral geometry. The DNA-complex and protein-complex interaction studies have revealed that the complexes interact favorably with the biomolecules, the degree of which depends on the nature of the substituents present on the dipyridophenazine ring. Photocleavage Of pUC19 DNA by the complexes has been studied using visible light of 476, 530, and 647 nm wavelengths. Mechanistic investigations with inhibitors show formation of HO center dot radicals via a photoredox pathway. Photocytotoxicity study of the complexes in HeLa cells has shown that the dppn complex (5) is highly active in causing cell death in visible light with sub micromolar IC50 value. The effect of substitutions and the planarity of the phenazine moiety on the cellular uptake are quantified by determining the total Cellular iron content using the inductively coupled plasma-optical emission spectrometry (ICP-OES) technique. The cellular uptake increases marginally with an increase in the hydrophobicity of the dipyridophenazine ligands whereas complex 3 with dppzs shows very high uptake. Insights into the cell death mechanism by the dppn complex 5, obtained through DAFT nuclear staining in HeLa cells, reveal a rapid programmed cell death mechanism following photoactivation of complex 5 with visible light. The effect of substituent on the DNA photocleavage activity of the complexes has been rationalized from the theoretical studies.

Impact of metal on the DNA photocleavage activity and cytotoxicity of ferrocenyl terpyridine 3d metal complexes

Ferrocenyl terpyridine 3d metal complexes and their analogues, viz. [M(Fc-tpy)(2)](ClO(4))(2) (1-4), [Zn(Ph-tpy)(2)](ClO(4))(2) (5) and [Zn(Fc-dpa)(2)]X(2) (X = ClO(4), 6; PF6, 6a), where M = Fe(II) in 1, Co(II) in 2, Cu(II) in 3 and Zn(II) in 4, Fc-tpy is 4'-ferrocenyl-2,2': 6', 2 `'-terpyridine, Ph-tpy is 4'-phenyl-2,2': 6', 2 `'-terpyridine and Fc-dpa is ferrocenyl-N,N-dipicolylmethanamine, are prepared and their DNA binding and photocleavage activity in visible light studied. Complexes 2, 4, 5 and 6a that are structurally characterized by X-ray crystallography show distorted octahedral geometry with the terpyridyl ligands binding to the metal in a meridional fashion, with Fc-dpa in 6a showing a facial binding mode. The Fc-tpy complexes display a charge transfer band in the visible region. The ferrocenyl (Fc) complexes show a quasi-reversible Fc(+)-Fc redox couple within 0.48 to 0.66 V vs. SCE in DMF-0.1 M TBAP. The DNA binding constants of the complexes are similar to 10(4) M(-1). Thermal denaturation and viscometric data suggest DNA surface binding through electrostatic interaction by the positively charged complexes. Barring the Cu(II) complex 3, the complexes do not show any chemical nuclease activity in the presence of glutathione. Complexes 1-4 exhibit significant plasmid DNA photocleavage activity in visible light via a photoredox pathway. Complex 5, without the Fc moiety, does not show any DNA photocleavage activity. The Zn(II) complex 4 shows a significant PDT effect in HeLa cancer cells giving an IC(50) value of 7.5 mu M in visible light, while being less toxic in the dark (IC(50) = 49 mu M).

Design and Synthesis of a Functional Derivative of the Triazinium Cation and Its Rhodium Complex that Shows Photoinduced DNA Cleavage Activity and Photocytotoxicity

The design and synthesis of an intensely blue rhodium(III) complex 3]+ of a new N,N-donor ligand, 8-(quinolin-8-ylamino)pyrido2,1-c]1,2,4]benzotriazin-11-ium, 2]+, which contains a planar pendant triazinium arm, is described. Structural characterization for 3]+ was carried out by using various spectroscopic techniques and single-crystal X-ray crystallography. The organometallic rhodium(III) compound shows a ligand-based reversible reduction at 0.65 V. The electrochemically reduced compound displays a single-line EPR spectrum that signifies the formation of ligand-based free radicals. Compound 3]+ shows a binding propensity to calf thymus DNA to give a Kapp value of 6.05X105 M1. The parent triazinium salt, pyrido2,1-c]1,2,4]benzotriazin-11-ium 1]+ and the ligand salt 2]+ exhibit photoinduced cleavage of DNA in UV-A light, whereas the reference Rh complex 3]+ photocleaves DNA with red light (647.1 nm). The compounds show photonuclease activities under both aerobic and anaerobic conditions. Mechanistic investigations under aerobic conditions with several inhibitors indicate the formation of hydroxyl radicals by means of a photoredox pathway. Under anaerobic conditions, it is believed that a photoinduced oxidation of DNA mechanism is operative. Compound 3]+ exhibits photocytotoxicity in HeLa cervical cancer cells to give IC50 values of (12+/-0.9) mu M in UV-A light at 365 nm and (31.4+/-1.1) mu M in the dark.

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

Lanthanide complexes Ln(DTPAAQ)(DMF)] (1-3) (Ln - Pr (1), Eu (2), Tb (3), H(3)DTPAAQ - N, N `'-bis(3-amidoquinolyl) diethylenetriamine-N, N', N `'-triacetic acid, DMF - N, N-dimethylformamide) were studied for their structures, photophysical properties, DNA and protein binding, DNA photocleavage, photocytotoxicity and cellular internalization. The crystal structures of complexes Ln(DTPAAQ)(DMF)] (1-3) display a discrete mononuclear nine-coordinate {LnN(3)O(6)} tricapped-trigonal prism (TTP) coordination geometry. The europium and terbium complexes show strong luminescence properties in the visible region having a long luminescence lifetime (tau = 0.51-0.64 ms). The conjugated 3-aminoquinoline moieties act as efficient light harvesting antennae, which upon photoexcitation transfer their energy to Eu(III) or Tb(III) for their characteristic D-5(0) -> F-7(J) or D-5(4) -> F-7(J) f-f transitions respectively. The complexes display efficient binding affinity to DNA (K-b = 3.4 x 10(4) - 9.8 x 10(4) M-1) and BSA (KBSA = 3.03 x 10(4) - 6.57 x 10(4) M-1). Europium and terbium complexes give enhanced luminescence upon interacting with CT-DNA suggesting possible luminescence-based sensing applications for these complexes. Complexes 1-3 show moderate cleavage of supercoiled (SC) DNA to its nicked circular (NC) form on exposure to UV-A light of 312 nm involving formation of singlet oxygen (O-1(2)) and hydroxyl radicals (cOH) in type-II and photoredox pathways. Eu(III) and Tb(III) complexes exhibit remarkable photocytotoxicity with human cervical cancer cell line (HeLa) (IC50 = 20.7-28.5 mM) while remaining essentially noncytotoxic up to 150 mM in the dark. Complexes are nontoxic in nature thus suitable for designing cellular imaging agents. Fluorescence microscopy data reveal primarily cytosolic localization of the Eu(III) and Tb(III) complexes in HeLa cells.

Synthesis, structure, and photophysics of polypyridophenazine transition-metal complexes

The condensation of phenanthroline-5,6-dione (phendione) with polyamines is a versatile synthetic route to a wide variety of chelating ligands. Condensation with 2,3- napthalene diamine gives benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (bdppz) a ligand containing weakly-coupled orbitals of benzophenazine (bpz) and 2,2' -bipyridinde(bpy) character. The bpy character gives Re and Ru complexes excited-state redox properties; intramolecular electron transfer (ET) takes place to the bpz portion of the ligand. The charge-separated state so produced has an extraordinarily-long 50 µs lifetime. The slow rate of charge recombination arises from a combination of extremely weak coupling between the metal center and the bpz acceptor orbital and Marcus "inverted region" behavior. Molecular orbital calculations show that only 3% the electron density in the lowest unoccupied molecular orbital lies on the bpy atoms of bdppz, effectively trapping the transferred electron on the bpz portion. The rate of charge recombination decreases with increasing driving force, showing that these rates lie in the inverted region. Comparison of forward and back ET rates shows that donor-acceptor coupling is four orders of magnitude greater for photoinduced electron transfer than it is for thermal charge recombination.

Condensation of phendione with itself or tetramines gives a series of binucleating tetrapyridophenazine ligands of incrementally-varying coordination-site separation. When a photoredox-active metal center is attached, excited-state energy and electron transfer to an acceptor metal center at the other coordination site can be studied as a function of distance. A variety of monometallic and homo- and heterodimetallic tetrapyridophenazine complexes has been synthesized. Electro- and magnetochemistry show that no ground-state interaction exists between the metals in bimetallic complexes. Excited-state energy and electron transfer, however, takes place at rates which are invariant with increasing donor-acceptor separation, indicating that a very efficient coupling mechanism is at work. Theory and experiment have suggested that such behavior might exist in extended π-systems like those presented by these ligands.

Condensation of three equivalents of 4,5-dimethyl-1,2-phenylenediamine with hexaketocyclohexane gives the trinucleating ligand hexaazahexamethyltrinapthalene (hhtn). Attaching two photredox-active metal centers and a third catalytic center to hhtn provides means by which multielectron photocatalyzed reactions might be carried out. The coordination properties of hhtn have been examined; X-ray crystallographic structure determination shows that the ligand's constricted coordination pocket leads to distorted geometries in its mono- and dimetallic derivatives.

Modification of Fluorescent Photoinduced Electron Transfer (PET) Sensors/Switches To Produce Molecular Photo-Ionic Triode Action

The fluorophore-spacer₁-receptor₁-spacer₂-receptor₂ system (where receptor₂ alone is photoredox-inactive) shows ionically tunable proton-induced fluorescence off-on switching, which is reminiscent of thermionic triode behavior. This also represents a new extension to modular switch systems based on photoinduced electron transfer (PET) towards the emulation of analogue electronic devices.

Réaction de photocyclodéshydrogénation par catalyse photorédox

Cette thèse présente une nouvelle méthode pour accomplir la réaction de Mallory en utilisant la lumière visible. Pour atteindre ce but, la chimie photorédox qui s'est développée ces dernières années permettra une utilisation efficace de la lumière visible. De plus, la chimie en flux continu sera utilisé afin d'augmenter la surface irradiée du mélange réactionnel. Au cours de ces travaux, une nouvelle méthodologie photochimique utilisant un photocatalyseur de cuivre avec la lumière visible a été efficace pour la synthèse du 5hélicène. Un mécanisme de désactivation oxydante est proposé pour cette réaction. Par ailleurs, cette nouvelle méthodologie a été utilisée pour la synthèse d'un dérivé du 5hélicène et d'un 4hélicène-pyrène hybride. Par la suite, la méthodologie photochimique utilisant un photocatalyseur de cuivre avec la lumière visible a servi à la synthèse de divers carbazoles substitués au niveau de l'azote par des groupements aryles et alkyles. Au cours de cette synthèse, la réaction a révélé un problème de régiosélectivité. Ce dernier a été étudié par la synthèse de nouvelles triarylamines. Finalement, il a été découvert que l'utilisation d'un photocatalyseur de fer peut remplacer le photocatalyseur de cuivre en utilisant l'oxygène comme oxydant pour la synthèse de 9-phénylcarbazole.

Molecular mixed-valence cyanide bridged Co-III-Fe-II complexes

Cyano-bridged mixed-valence compounds have been known for a long time, i.e., Prussian Blue polymeric solids. Nevertheless, the interest in discrete complexes having a well-defined molecular nuclearity has emerged more recently. There are numerous examples of cyano-bridged mixed-valence complexes in the recent literature, as they show promising and useful applications in electrochromism, molecular magnetism and molecular electronics. In this paper, the reactivity, synthetic and structural chemistry, as well as some physical and chemical properties, of a series of discrete dinuclear mixed-valence cyano-bridged complexes of general formulae [LnCoIII(mu NC)Fe-II(CN)(5)](-) (L = pentadentate macrocyclic ligand) are reviewed. Special emphasis is given to the synthetic strategy, redox properties and metal-to-metal-charge-transfer (MMCT) band energy. Tuning the MMCT transition energy has been possible by changing the redox potential of the metal centers, both through structural and outer-sphere changes. The redox processes that involve the appearance and disappearance of these MMCT bands in the visible region have been dealt with in relation to the possible uses of the complexes. (c) 2004 Elsevier B.V. All rights reserved.

Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids

A metal-free dehydrogenative lactonization of 2-arylbenzoic acids at room temperature was developed. This work illustrates the first application of visible-light photoredox catalysis in the preparation of benzo-3,4-coumarins, an important structural motif in bioactive molecules. The combination of photocatalyst [Acr+-Mes] with (NH4)2S2O8 as a terminal oxidant provides an economical and environmentally benign entry to different substituted benzocoumarins. Preliminary mechanistic studies suggest that this reaction most likely occurs through a homolytic aromatic substitution pathway.