Preclinical Evaluation of Zn(II) Self-Assemblies with Selective Cytotoxic Activity Against Cancer Cells In Vitro and In Ovo.

Dipodal pyridylthiazole amine ligands L1 and L2 both form different metallo-supramolecular self-assemblies with Zn2+ and Cu2+ and these are shown to be toxic and selective towards cancer cell lines in vitro. Furthermore, potency and selectivity are highly dependent upon the metal ions, ligand system and bound anion, with significant changes in chemosensitivity and selectivity dependent upon which species are employed. Importantly, significant anti-tumor activity was observed in ovo at doses that are non-toxic.

A Near-Infrared Luminescent Cr(III) N-Heterocyclic Carbene Complex.

Photoluminescent coordination complexes of Cr(III) are of interest as near-infrared spin-flip emitters. Here, we explore the preparation, electrochemistry, and photophysical properties of the first two examples of homoleptic N-heterocyclic carbene complexes of Cr(III), featuring 2,6-bis(imidazolyl)pyridine (ImPyIm) and 2-imidazolylpyridine (ImPy) ligands. The complex [Cr(ImPy)3]3+ displays luminescence at 803 nm on the microsecond time scale (13.7 µs) from a spin-flip doublet excited state, which transient absorption spectroscopy reveals to be populated within several picoseconds following photoexcitation. Conversely, [Cr(ImPyIm)2]3+ is nonemissive and has a ca. 500 ps excited-state lifetime.

Stereocontrolled synthesis of the aconitine D ring from D-glucose.

The synthesis of a fully oxygenated aconitine D ring precursor from (D)-(+)-glucose is described. The route features a highly diastereoselective alkynyl Grignard ketone addition and a base-mediated enelactone to 1,3-diketone rearrangement.

Direct Determination of the Rate of Intersystem Crossing in a Near-IR Luminescent Cr(III) Triazolyl Complex.

A detailed understanding of the dynamics of photoinduced processes occurring in the electronic excited state is essential in informing the rational design of photoactive transition-metal complexes. Here, the rate of intersystem crossing in a Cr(III)-centered spin-flip emitter is directly determined through the use of ultrafast broadband fluorescence upconversion spectroscopy (FLUPS). In this contribution, we combine 1,2,3-triazole-based ligands with a Cr(III) center and report the solution-stable complex [Cr(btmp)2]3+ (btmp = 2,6-bis(4-phenyl-1,2,3-triazol-1-yl-methyl)pyridine) (13+), which displays near-infrared (NIR) luminescence at 760 nm (τ = 13.7 µs, ϕ = 0.1%) in fluid solution. The excited-state properties of 13+ are probed in detail through a combination of ultrafast transient absorption (TA) and femtosecond-to-picosecond FLUPS. Although TA spectroscopy allows us to observe the evolution of phosphorescent excited states within the doublet manifold, more significantly and for the first time for a complex of Cr(III), we utilize FLUPS to capture the short-lived fluorescence from initially populated quartet excited states immediately prior to the intersystem crossing process. The decay of fluorescence from the low-lying 4MC state therefore allows us to assign a value of (823 fs)-1 to the rate of intersystem crossing. Importantly, the sensitivity of FLUPS to only luminescent states allows us to disentangle the rate of intersystem crossing from other closely associated excited-state events, something which has not been possible in the spectroscopic studies previously reported for luminescent Cr(III) systems.

Not All 3MC States Are the Same: The Role of 3MCcis States in the Photochemical N∧N Ligand Release from [Ru(bpy)2(N∧N)]2+ Complexes.

Ruthenium(II) complexes feature prominently in the development of agents for photoactivated chemotherapy; however, the excited-state mechanisms by which photochemical ligand release operates remain unclear. We report here a systematic experimental and computational study of a series of complexes [Ru(bpy)2(N∧N)]2+ (bpy = 2,2'-bipyridyl; N∧N = bpy (1), 6-methyl-2,2'-bipyridyl (2), 6,6'-dimethyl-2,2'-bipyridyl (3), 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole (4), 1-benzyl-4-(6-methylpyrid-2-yl)-1,2,3-triazole (5), 1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl (6)), in which we probe the contribution to the promotion of photochemical N∧N ligand release of the introduction of sterically encumbering methyl substituents and the electronic effect of replacement of pyridine by 1,2,3-triazole donors in the N∧N ligand. Complexes 2 to 6 all release the ligand N∧N on irradiation in acetonitrile solution to yield cis-[Ru(bpy)2(NCMe)2]2+, with resultant photorelease quantum yields that at first seem counter-intuitive and span a broad range. The data show that incorporation of a single sterically encumbering methyl substituent on the N∧N ligand (2 and 5) leads to a significantly enhanced rate of triplet metal-to-ligand charge-transfer (3MLCT) state deactivation but with little promotion of photoreactivity, whereas replacement of pyridine by triazole donors (4 and 6) leads to a similar rate of 3MLCT deactivation but with much greater photochemical reactivity. The data reported here, discussed in conjunction with previously reported data on related complexes, suggest that monomethylation in 2 and 5 sterically inhibits the formation of a 3MCcis state but promotes the population of 3MCtrans states which rapidly deactivate 3MLCT states and are prone to mediating ground-state recovery. On the other hand, increased photochemical reactivity in 4 and 6 seems to stem from the accessibility of 3MCcis states. The data provide important insights into the excited-state mechanism of photochemical ligand release by Ru(II) tris-bidentate complexes.

Synthesis of novel isoflavone/benzo-δ-sultam hybrids as potential anti-inflammatory drugs.

A small series of novel isoflavone/benzo-δ-sultam hybrids was synthesised and evaluated as potential anti-inflammatory and neuroprotective drugs in LPS-activated BV2 microglia. The benzo-δ-sultam core was constructed in a two-step reaction by coupling 2-halobenzenesulfonamide derivatives with terminal alkynes, followed by a 6-endo-dig cyclisation. The synthesised compounds, including precursors and hybrids, were tested for their ability to inhibit NO and TNF-α production in LPS-stimulated BV2 microglial cells, and the results are promising. The most potent hybrid reduces the NO production to 41%, and the TNF-α to 34% at 20 µM final concentration in the well.

Photochemistry of Heteroleptic 1,4,5,8-Tetraazaphenanthrene- and Bi-1,2,3-triazolyl-Containing Ruthenium(II) Complexes.

Diimine metal complexes have significant relevance in the development of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) applications. In particular, complexes of the TAP ligand (1,4,5,8-tetraazaphenanthrene) are known to lead to photoinduced oxidation of DNA, while TAP- and triazole-based complexes are also known to undergo photochemical ligand release processes relevant to PACT. The photophysical and photochemical properties of heteroleptic complexes [Ru(TAP)n(btz)3-n]2+ (btz = 1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl, n = 1 (1), 2 (2)) have been explored. Upon irradiation in acetonitrile, 1 displays analogous photochemistry to that previously observed for [Ru(bpy)(btz)2]2+ (bpy = 2,2'-bipyridyl) and generates trans-[Ru(TAP)(btz)(NCMe)2]2+ (5), which has been crystallographically characterized, with the observation of the ligand-loss intermediate trans-[Ru(TAP)(κ2-btz)(κ1-btz)(NCMe)]2+ (4). Complex 2 displays more complicated photochemical behavior with not only preferential photorelease of btz to form cis-[Ru(TAP)2(NCMe)2]2+ (6) but also competitive photorelease of TAP to form 5. Free TAP is then taken up by 6 to form [Ru(TAP)3]2+ (3) with the proportion of 5 and 3 observed to progressively increase during prolonged photolysis. Data suggest a complex set of reversible photochemical ligand scrambling processes in which 2 and 3 are interconverted. Computational DFT calculations have enabled optimization of geometries of the pro-trans 3MCcis states with repelled btz or TAP ligands crucial for the formation of 5 from 1 and 2, respectively, lending weight to recent evidence that such 3MCcis states play an important mechanistic role in the rich photoreactivity of Ru(II) diimine complexes.

Unravelling the Mechanism of Excited-State Interligand Energy Transfer and the Engineering of Dual Emission in [Ir(C∧N)2(N∧N)]+ Complexes.

Fundamental insights into the mechanism of triplet-excited-state interligand energy transfer dynamics and the origin of dual emission for phosphorescent iridium(III) complexes are presented. The complexes [Ir(C∧N)2(N∧N)]+ (HC∧N = 2-phenylpyridine (1a-c), 2-(2,4-difluorophenyl)pyridine (2a-c), 1-benzyl-4-phenyl-1,2,3-triazole (3a-c); N∧N = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole (pytz, a), 1-benzyl-4-(pyrimidin-2-yl)-1,2,3-triazole (pymtz, b), 1-benzyl-4-(pyrazin-2-yl)-1,2,3-triazole (pyztz, c)) are phosphorescent in room-temperature fluid solutions from triplet metal-to-ligand charge transfer (3MLCT) states admixed with either ligand-centered (3LC) (1a, 2a, and 2b) or ligand-to-ligand charge transfer (3LL'CT) character (1c, 2c, and 3a-c). Particularly striking is the observation that pyrimidine-based complex 1b exhibits dual emission from both 3MLCT/3LC and 3MLCT/3LL'CT states. At 77 K, the 3MLCT/3LL'CT component is lost from the photoluminescence spectra of 1b, with emission exclusively arising from its 3MLCT/3LC state, while for 2c switching from 3MLCT/3LL'CT- to 3MLCT/3LC-based emission is observed. Femtosecond transient absorption data reveal distinct spectral signatures characteristic of the population of 3MLCT/3LC states for 1a, 2a, and 2b which persist throughout the 3 ns time frame of the experiment. These 3MLCT/3LC state signatures are apparent in the transient absorption spectra for 1c and 2c immediately following photoexcitation but rapidly evolve to yield spectral profiles characteristic of their 3MLCT/3LL'CT states. Transient data for 1b reveals intermediate behavior: the spectral features of the initially populated 3MLCT/3LC state also undergo rapid evolution, although to a lesser extent than that observed for 1c and 2c, behavior assigned to the equilibration of the 3MLCT/3LC and 3MLCT/3LL'CT states. Density functional theory (DFT) calculations enabled minima to be optimized for both 3MLCT/3LC and 3MLCT/3LL'CT states of 1a-c and 2a-c. Indeed, two distinct 3MLCT/3LC minima were optimized for 1a, 1b, 2a, and 2b distinguished by upon which of the two C∧N ligands the excited electron resides. The 3MLCT/3LC and 3MLCT/3LL'CT states for 1b are very close in energy, in excellent agreement with experimental data demonstrating dual emission. Calculated vibrationally resolved emission spectra (VRES) for the complexes are in excellent agreement with experimental data, with the overlay of spectral maxima arising from emission from the 3MLCT/3LC and 3MLCT/3LL'CT states of 1b convincingly reproducing the observed experimental spectral features. Analysis of the optimized excited-state geometries enable the key structural differences between the 3MLCT/3LC and 3MLCT/3LL'CT states of the complexes to be identified and quantified. The calculation of interconversion pathways between triplet excited states provides for the first time a through-space mechanism for a photoinduced interligand energy transfer process. Furthermore, examination of structural changes between the possible emitting triplet excited states reveals the key bond vibrations that mediate energy transfer between these states. This work therefore provides for the first time detailed mechanistic insights into the fundamental photophysical processes of this important class of complexes.

Self-Assembled Anion-Binding Cryptand for the Selective Liquid-Liquid Extraction of Phosphate Anions.

The ligands L1 and L2 form trinuclear self-assembled complexes with Cu2+ (i.e. [(L1 )2 Cu3 ]6+ or [(L2 )2 Cu3 ]6+ ) both of which act as a host to a variety of anions. Inclusion of long aliphatic chains on these ligands allows the assemblies to extract anions from aqueous media into organic solvents. Phosphate can be removed from water efficiently and highly selectively, even in the presence of other anions.

Synthesis and photochromism of some mono and bis (thienyl) substituted oxathiine 2,2-dioxides.

1,2-Oxathiine 2,2-dioxides have been obtained from their respective 3,4-dihydro-4-dimethylamino precursors, for the first time, by a mild Cope elimination of the 4-dimethylamino function. The application of the 1,2-oxathiine 2,2-dioxide scaffold in materials chemistry is exemplified by the efficient P-type photochromism of the 5,6-bis(2,5-dimethyl-3-thienyl) substituted oxathiine 2,2-dioxides.

Expedient synthesis of highly substituted 3,4-dihydro-1,2-oxathiine 2,2-dioxides and 1,2-oxathiine 2,2-dioxides: revisiting sulfene additions to enaminoketones.

Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.

Photophysical and Cellular Imaging Studies of Brightly Luminescent Osmium(II) Pyridyltriazole Complexes.

The series of complexes [Os(bpy)3- n(pytz) n][PF6]2 (bpy = 2,2'-bipyridyl, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, 1 n = 0, 2 n = 1, 3 n = 2, 4 n = 3) were prepared and characterized and are rare examples of luminescent 1,2,3-triazole-based osmium(II) complexes. For 3 we present an attractive and particularly mild preparative route via an osmium(II) η6-arene precursor circumventing the harsh conditions that are usually required. Because of the high spin-orbit coupling constant associated with the Os(II) center the absorption spectra of the complexes all display absorption bands of appreciable intensity in the range of 500-700 nm corresponding to spin-forbidden ground-state-to-3MLCT transitions (MLCT = metal-to-ligand charge transfer), which occur at significantly lower energies than the corresponding spin-allowed 1MLCT transitions. The homoleptic complex 4 is a bright emitter (λmaxem = 614 nm) with a relatively high quantum yield of emission of ∼40% in deoxygenated acetonitrile solutions at room temperature. Water-soluble chloride salts of 1-4 were also prepared, all of which remain emissive in aerated aqueous solutions at room temperature. The complexes were investigated for their potential as phosphorescent cellular imaging agents, whereby efficient excitation into the 3MLCT absorption bands at the red side of the visible range circumvents autofluorescence from biological specimens, which do not absorb in this region of the spectrum. Confocal microscopy reveals 4 to be readily taken up by cancer cell lines (HeLa and EJ) with apparent lysosomal and endosomal localization, while toxicity assays reveal that the compounds have low dark and light toxicity. These complexes therefore provide an excellent platform for the development of efficient luminescent cellular imaging agents with advantageous photophysical properties that enable excitation and emission in the biologically transparent region of the optical spectrum.

Self-Assembly of an Anion-Binding Cryptand for the Selective Encapsulation, Sequestration, and Precipitation of Phosphate from Aqueous Systems.

The self-assembled trimetallic species [L2 Cu3 ]6+ contains a cavity that acts as a host to many different anions. By using X-ray crystallography, ESI-MS, and UV/Vis spectroscopy we show that these anions are encapsulated both in the solid state and aqueous systems. Upon encapsulation, the anions Br- , I- , CO32- , SiF62- , IO63- , VO43- , WO42- , CrO42- , SO42- , AsO43- , and PO43- are all precipitated from aqueous solution and can be removed by filtration. Furthermore, the cavity can be tuned to be selective to either phosphate or sulfate anions by variation of the pH. Phosphate anions can be removed from water, even in the presence of other common anions, reducing the concentration from 1000 to <0.1 ppm and recovering approximately 99 % of the phosphate anions.

Ruthenium-Containing Linear Helicates and Mesocates with Tuneable p53-Selective Cytotoxicity in Colorectal Cancer Cells.

The ligands L1 and L2 both form separable dinuclear double-stranded helicate and mesocate complexes with RuII . In contrast to clinically approved platinates, the helicate isomer of [Ru2 (L1 )2 ]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53-/- ), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+ . Other structurally similar RuII -containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be "tuned" to either genotype. In the search for compounds that can target difficult-to-treat tumours that lack the p53 tumour suppressor gene, [Ru2 (L1 )2 ]4+ is a promising compound for further development.

Catalytic sp3 -sp3 Functionalisation of Sulfonamides: Late-Stage Modification of Drug-Like Molecules.

A new application of Pd-catalysed allylation is reported that enables the synthesis of a range of branched sp3 -functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and base at room temperature, direct allylation was efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction was performed under mild conditions and could be applied to nanomolar sigma-receptor binders, thus enabling a late-stage functionalisation and efficient expansion of drug-like chemical space.

Photochemistry of [Ru(pytz)(btz)2](2+) and Characterization of a κ(1)-btz Ligand-Loss Intermediate.

We report the synthesis, characterization, and photochemical reactivity of the triazole-containing complex [Ru(pytz)(btz)2](2+) (1, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, btz = 1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl). The UV-vis absorption spectrum of 1 exhibits pytz- and btz-centered (1)MLCT bands at 365 and 300 nm, respectively. Upon photoexcitation, acetonitrile solutions of 1 undergo conversion to the ligand-loss intermediate, trans-[Ru(pytz)(κ(2)-btz)(κ(1)-btz)(NCMe)](2+) (2, Φ363 = 0.013) and ultimately to the ligand-loss product trans-[Ru(pytz)(btz)(NCMe)2](2+) (3), both of which are observed and characterized by (1)H NMR spectroscopy. Time-dependent density functional theory calculations reveal that the S1 state of the complex has primarily HOMO → LUMO pytz-based (1)MLCT character. Data show that the (3)MLCT and (3)MC states are in close energetic proximity (≤0.11 eV to 2 d.p.) and that the T1 state from a single-point triplet state calculation at the S0 geometry suggests (3)MC character. Optimization of the T1 state of the complex starting from the ground state geometry leads to elongation of the two Ru-N(btz) bonds cis to the pytz ligand to 2.539 and 2.544 Å leading to a pseudo-4-coordinate (3)MC state rather than the (3)MLCT state. The work therefore provides additional insights into the photophysical and photochemical properties of ruthenium triazole-containing complexes and their excited state dynamics.

Labilizing the Photoinert: Extraordinarily Facile Photochemical Ligand Ejection in an [Os(N

Whilst [Os(N^N)3 ](2+) complexes are supposed to be photochemically inert to ligand loss, the complex [Os(btz)3 ](2+) (btz=1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl) undergoes unprecedented photolytic reactivity to liberate free btz (Φ363 ≈1.2 %). Further, both cis and trans isomers of the photodechelated ligand-loss solvento intermediate [Os(κ(2) -btz)2 (κ(1) -btz)(NCMe)](2+) are unambiguously observed and characterized by NMR spectroscopy and mass spectrometry.

Photochemistry of RuII 4,4'-bi-1,2,3-triazolyl (btz) complexes: crystallographic characterization of the photoreactive ligand-loss intermediate trans-[Ru(bpy)(κ2-btz)(κ1-btz)(NCMe)]2+.

We report the unprecedented observation and unequivocal crystallographic characterization of the meta-stable ligand loss intermediate solvento complex trans-[Ru(bpy)(κ(2) -btz)(κ(1) -btz)(NCMe)](2+) (1 a) that contains a monodentate chelate ligand. This and analogous complexes can be observed during the photolysis reactions of a family of complexes of the form [Ru({NN})(btz)(2)](2+) (1 a-d: btz=1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl; {NN}=a) 2,2'-bipyridyl (bpy), b) 4,4'-dimethyl-2,2'-bipyridyl (dmbpy), c) 4,4'-dimethoxy-2,2'-bipyridyl (dmeobpy), d) 1,10-phenanthroline (phen)). In acetonitrile solutions, 1 a-d eventually convert to the bis-solvento complexes trans-[Ru({NN})(btz)(NCMe)(2)](2+) (3 a-d) along with one equivalent of free btz, in a process in which the remaining coordinated bidentate ligands undergo a new rearrangement such that they become coplanar. X-ray crystal structure of 3 a and 3 d confirmed the co-planar arrangement of the {NN} and btz ligands and the trans coordination of two solvent molecules. These conversions proceed via the observed intermediate complexes 2 a-d, which are formed quantitatively from 1 a-d in a matter of minutes and to which they slowly revert back on being left to stand in the dark over several days. The remarkably long lifetime of the intermediate complexes (>12 h at 40 °C) allowed the isolation of 2 a in the solid state, and the complex to be crystallographically characterized. Similarly to the structures adopted by complexes 3 a and d, the bpy and κ(2) -btz ligands in 2 a coordinate in a square-planar fashion with the second monodentate btz ligand coordinated trans to an acetonitrile ligand.

Formation of a dimer of trinuclear helicates which encapsulates an array of six hydrogen-bonded anions.

The amine-containing ligand L, composed of two bidentate pyridyl-thiazole moieties linked by a 1,3-diaminophenylene unit, reacts with copper(II) ions to form a dinuclear double helicate [Cu2 L2 ](4+) . Reaction of [Cu2 L2 ](4+) with dihydrogen phosphate (0.5 equivalents) gives the unsaturated dinuclear double helicate [Cu2 L2 (OPO3 H2 )](3+) . [Cu2 L2 (OPO3 H2 )](3+) further reacts with another 0.5 equivalents of dihydrogen phosphate to give a trinuclear circular helicate which then self-assembles into a hexameric cluster [{Cu3 L3 (OPO3 H2 )3 }](26+) .

Tri-carbonyl-chlorido-(6',7'-di-hydro-5'H-spiro-[cyclo-pentane-1,6'-dipyrido[3,2-d:2',3'-f][1,3]diazepine]-κ(2) N (1),N (11))rhenium(I).

In the title compound, [ReCl(C15H16N4)(CO)3], the Re(I) ion is coordinated in a distorted octa-hedral geometry by one Cl atom, two N atoms of the bidentate ligand and three carbonyl groups. The cyclo-pentane group is orientated in a transoid fashion with respect to the chloride ligand. The dihedral angle between the pryridine rings is 10.91 (12)°. In the crystal, N-H⋯Cl hydrogen bonds link complex mol-ecules, forming a two-dimensional network parallel to (001).