Luminescent Pt(II) Complexes Using Unsymmetrical Bis(2-pyridylimino)isoindolate Analogues.

A series of ligands based upon a 1,3-diimino-isoindoline framework have been synthesized and investigated as pincer-type (N∧N∧N) chelates for Pt(II). The synthetic route allows different combinations of heterocyclic moieties (including pyridyl, thiazole, and isoquinoline) to yield new unsymmetrical ligands. Pt(L1-6)Cl complexes were obtained and characterized using a range of spectroscopic and analytical techniques: 1H and 13C NMR, IR, UV-vis and luminescence spectroscopies, elemental analyses, high-resolution mass spectrometry, electrochemistry, and one example via X-ray crystallography which showed a distorted square planar environment at Pt(II). Cyclic voltammetry on the complexes showed one irreversible oxidation between +0.75 and +1 V (attributed to Pt2+/3+ couple) and a number of ligand-based reductions; in four complexes, two fully reversible reductions were noted between -1.4 and -1.9 V. Photophysical studies showed that Pt(L1-6)Cl absorbs efficiently in the visible region through a combination of ligand-based bands and metal-to-ligand charge-transfer features at 400-550 nm, with assignments supported by DFT calculations. Excitation at 500 nm led to luminescence (studied in both solutions and solid state) in all cases with different combinations of the heterocyclic donors providing tuning of the emission wavelength around 550-678 nm.

Computational investigation of copper-mediated conformational changes in α-synuclein dimer.

We report molecular dynamics simulation of dimers of α-synuclein, the peptide closely associated with onset of Parkinson's disease, both as metal-free dimer and with inter-chain bridging provided by Cu(II) ions. Our investigation reveals that the presence of copper-induced inter-chain bridging not only stabilizes α-synuclein dimers, but also leads to enhanced ß-sheet formation at critical regions within the N-terminal and NAC regions of the protein. These contacts are larger and longer-lived in the presence of copper, and as a result each peptide chain is more extended and less flexible than in the metal-free dimer. The persistence of these inter-peptide contacts underscores their significance in stabilising the dimers, potentially influencing the aggregation pathway. Moreover, the increased flexibility in the two termini, as well as the absence of persistent contacts in the metal-free dimer, correlates with the presence of amorphous aggregates. This phenomenon is known to mitigate fibrillation, while their absence in the metal-bound dimer suggests an increased propensity to form fibrils in the presence of copper ions.

Welcoming Neighbour or Inhospitable Host? Selective Second Metal Binding in 5- and 6-Phospha-Substituted Bpy Ligands.

The controlled formation of mixed-metal bimetallics was realised through use of a fac-[Re(CO)3(N,N'-bpy-P)Cl] complex bearing an exogenous 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane donor at the 5-position of the bpy. The introduction of gold, silver, and rhodium with appropriate secondary ligands was readily achieved from established starting materials. Restricted rotation about the C(bpy)-P bond was observed in several of the bimetallic complexes and correlated with the relative steric bulk of the second metal moiety. Related chemistry with the 6-substituted derivative proved more limited in scope with only the bimetallic Re/Au complex being isolated.

Electron Density Analysis of Metal-Metal Bonding in a Ni4 Cluster Featuring Ferromagnetic Exchange.

We present a combined experimental and theoretical study of the nature of the proposed metal-metal bonding in the tetranuclear cluster Ni4(NPtBu3)4, which features four nickel(I) centers engaged in strong ferromagnetic coupling. High-resolution single-crystal synchrotron X-ray diffraction data collected at 25 K provide an accurate geometrical structure and a multipole model electron density description. Topological analysis of the electron density in the Ni4N4 core using the quantum theory of atoms in molecules clearly identifies the bonding as an eight-membered ring of type [Ni-N-]4 without direct Ni-Ni bonding, and this result is generally corroborated by an analysis of the energy density distribution. In contrast, the calculated bond delocalization index of ∼0.6 between neighboring Ni atoms is larger than what has been found for other bridged metal-metal bonds and implies direct Ni-Ni bonding. Similar support for the presence of direct Ni-Ni bonding is found in the interacting quantum atom approach, an energy decomposition scheme, which suggests the presence of stabilizing Ni-Ni bonding interactions with an exchange-correlation energy contribution approximately 50% of that of the Ni-N interactions. Altogether, while the direct interactions between neighboring Ni centers are too weak and sterically constrained to bear the signature of a topological bond critical point, other continuous measures clearly indicate significant Ni-Ni bonding. These metal-metal bonding interactions likely mediate direct ferromagnetic exchange, giving rise to the high-spin ground state of the molecule.

Exploring the excited-state charge transfer fluorescence profile of 7-hydroxycoumarin and 2-methylimidazole - a combined X-ray diffraction and theoretical approach.

This study investigated the effect of 2-methylimidazole (2-MIM) addition on the fluorescence of ethyl-7-hydroxy-2-oxo-2H-chromene-3-carboxylate using low-cost density functional theory (DFT) and Time-Dependent DFT calculations on single crystal X-ray geometries of ethyl-7-hydroxy-2-oxo-2H-chromene-3-carboxylate hydrate (1), 2-MIM (2), and the 1 : 1 co-crystal of (1) and (2), (3). At low concentrations (1 : 1-1 : 10) of 2-MIM, the fluorophore shows a decrease in the fluorescence intensity, but at higher concentrations (above 1 : 10) the fluorescence excitation maximum shifted from 354 nm to 405 nm, with a significant emission intensity increase. The changed excitation and emission profile at high concentrations is due to the deprotonation of the coumarin's phenolic group, which was confirmed by the increased shielding of the aromatic protons in the titration 1H NMR spectra. The experimental fluorescence data between the 1 : 1 and 1 : 10 ratios agreed with the theoretical fluorescence data, with a redshift and decreased intensity when comparing (1) and (3). The data indicated that combining the fluorophore with 2-MIM increased levels of vibronic coupling between 2-MIM and the fluorophore decreasing de-excitation efficiency. These increased vibronic changes were due to charge transfer between the fluorophore and 2-MIM in (3). The subtle movement of the proton, H(5) toward N(2') (0.07 Å) caused a significant decrease in fluorescence due to electron density distribution (EDD) changes. This was identified by comparison of the EDD in the excited (S1) and ground (S0) states plotted as an isosurface of EDD difference. For the higher concentrations, an alternative excitation pathway was explored by modifying the crystal geometry of (3) based on 1H NMR spectroscopy data to resemble excitoplexes. Theses excitoplex geometries reflected the fluorescence profile of the fluorophore with high concentrations of 2-MIM; there were dramatic changes in the theoretical fluorescence pathway, which was 100% vibronic coupling compared to 15.31% in the free fluorophore. At this concentration, the de-excitation pathway causes remodelling of the lactone ring via stretching/breaking the CO bond in the S1 causing increased fluorescence by movement of the transition dipole moment. These results reflect previous studies, but the methods used are less experimentally and computationally expensive. This study is among the first to explain charge transfer fluorescence using crystalline geometries. This study will be of interest to the fields of crystal engineering and fluorescence spectroscopy.

Photochemical Oxidation of Pt(IV)Me3(1,2-diimine) Thiolates to Luminescent Pt(IV) Sulfinates.

We report the formation of dinuclear complexes from, and photochemical oxidation of, (CH3)3-Pt(IV)(N^N) (N^N = 1,2-diimine derivatives) complexes of thiophenolate ligands to the analogous sulfinates (CH3)3Pt(N^N)(SO2Ph) and structural, spectroscopic, and theoretical studies of the latter revealing tunable photophysics depending upon the 1,2-diimine ligands. Electron-rich thiolate and conjugated 1,2-diimines encourage formation of thiolate-bridged dinuclear complexes; smaller 1,2-diimines or electron-poor thiolates favor mononuclear complexes. Photooxidation of the thiolate ligand yields hitherto unreported Pt(IV)-SO2R complexes, promoted by electron-deficient thiolates such as 4-nitrothiophenol, which exclusively forms the sulfinate complex. Such complexes exhibit expected absorptions due to π-π* ligand transitions of the 1,2-diimines mixed with spin-allowed singlet MLCT (d-π*) at relatively high energy (270-290 nm), as well as unexpected broad, lower energy absorptions between 360 and 490 nm. DFT data indicate that these low energy absorption bands result from excitation of Pt-S and Pt-C σ-bonding electrons to π* orbitals on sulfinate and 1,2-diimine, the latter of which gives rise to emission in the visible range.

Understanding Hygroscopicity of Theophylline via a Novel Cocrystal Polymorph: A Charge Density Study.

The charge density distribution in a novel cocrystal (1) complex of 1,3-dimethylxanthine (theophylline) and propanedioic acid (malonic acid) has been determined. The molecules crystallize in the triclinic, centrosymmetric space group P1̅, with four independent molecules (Z = 4) in the asymmetric unit (two molecules each of theophylline and malonic acid). Theophylline has a notably high hygroscopic nature, and numerous cocrystals have shown a significant improvement in stability to humidity. A charge density study of the novel polymorph has identified interesting theoretical results correlating the stability enhancement of theophylline via cocrystallization. Topological analysis of the electron density highlighted key differences (up to 17.8) in Laplacian (∇2ρ) between the experimental (EXP) and single-point (SP) models, mainly around intermolecular-bonded carbonyls. Further investigation via molecular electrostatic potential maps reaffirmed that the charge redistribution enhanced intramolecular hydrogen bonding, predominantly for N(2') and N(2) (61.2 and 61.8 kJ mol-1, respectively). An overall weaker lattice energy of the triclinic form (-126.1 kJ mol-1) compared to that of the monoclinic form (-133.8 kJ mol-1) suggests a lower energy threshold to overcome to initiate dissociation. Future work via physical testing of the novel cocrystal in both dissolution and solubility will further solidify the correlation between theoretical and experimental results.

Insights into the Mechanisms of Aquaporin-3 Inhibition by Gold(III) Complexes: the Importance of Non-Coordinative Adduct Formation.

Following our recent reports on the inhibition of the water and glycerol channel aquaglyceroporin-3 (AQP3) by the coordination complex [AuIII(1,10-phenanthroline)Cl2] (Auphen), a series of six new Au(III) complexes featuring substituted 1,10-phenanthroline ligands (1-6) have been synthesized and characterized. The speciation of the compounds studied in buffered solution by UV-visible spectrophotometry showed that most of the complexes remain stable for several hours. Quantum mechanics (QM) studies of the hydrolysis processes of the compounds suggest that they are thermodynamically less prone to exchange the chlorido ligands with H2O or OH- in comparison to Au(III) bipyridyl complexes. Preliminary data on the antiproliferative activity against A549 human lung cancer cells indicate that the compounds are able to inhibit cell proliferation in vitro. Stopped-flow spectroscopy showed that these complexes potently inhibit glycerol permeation in human red blood cells (hRBC) through AQP3 blockage. The QM investigation of the ligand exchange with methanethiol, used as a model of Cys40 of AQP3, was carried out for some derivatives and showed that the affinity of the compounds' binding for thiols is higher in comparison to the Aubipy complex ([AuIII(bipy)Cl2]PF6, bipy = 2,2'-bipyridine). In addition, both noncovalent and coordinative binding of complex 3 ( [AuIII(5-chloro-1,10-phenanthroline)Cl2]PF6) to the protein channel has been investigated in comparison to the benchmark Auphen and Aubipy using a computational workflow, including QM, molecular dynamics (MD), and quantum mechanics/molecular mechanics (QM/MM) approaches. Finally, atoms in molecules (AIM) and natural bond orbital (NBO) analyses corroborate the MD predictions, providing quantification of the noncoordinative interactions between the compounds and AQP3. AQP3 inhibition is the result of protein conformational changes, upon coordinative gold binding, which induce pore closure. The importance of noncoordinative adducts in modulating the AQP3 inhibition properties of the investigated Au(III) compounds has been elucidated, and these interactions should be further considered in the future design of isoform-selective AQP inhibitors.

Pseudohalide Tectons within the Coordination Sphere of the Uranyl Ion: Experimental and Theoretical Study of C-H···O, C-H···S, and Chalcogenide Noncovalent Interactions.

A series of uranyl thiocyanate and selenocyanate of the type [R4N]3[UO2(NCS)5] (R4 = nBu4, Me3Bz, Et3Bz), [Ph4P][UO2(NCS)3(NO3)] and [R4N]3[UO2(NCSe)5] (R4 = Me4, nPr4, Et3Bz) have been prepared and structurally characterized. The resulting noncovalent interactions have been examined and compared to other examples in the literature. The nature of these interactions is determined by the cation so that when the alkyl groups are small, chalcogenide···chalcogenide interactions are present, but this "switches off" when R = nPr and charge assisted U═O···H-C and S(e)···H-C hydrogen bonding remain the dominant interaction. Increasing the size of the chain to nBu results in only S···H-C interactions. The spectroscopic implications of these chalcogenide interactions have been explored in the vibrational and photophysical properties of the series [R4N]3[UO2(NCS)5] (R4 = Me4, Et4, nPr4, nBu4, Me3Bz, Et3Bz), [R4N]3[UO2(NCSe)5] (R4 = Me4, nPr4, Et3Bz) and [Et4N]4[UO2(NCSe)5][NCSe]. The data suggest that U═O···H-C interactions are weak and do not perturb the uranyl moiety. While the chalcogenide interactions do not influence the photophysical properties, a coupling of the U═O and δ(NCS) or δ(NCSe) vibrational modes is observed in the 77 K solid state emission spectra. A theoretical examination of representative examples of Se···Se, C-H···Se, and C-H···O═U by molecular electrostatic potentials and NBO and AIM methodologies gives a deeper understanding of these weak interactions. C-H···Se are individually weak but C-H···O═U interactions are even weaker, supporting the idea that the -yl oxo's are weak Lewis bases. An Atoms in Molecules study suggests that the chalcogenide interaction is similar to lone pair···π or fluorine···fluorine interactions. An oxidation of the NCS ligands to form [(UO2)(SO4)2(H2O)4]·3H2O was also noted.

Non-covalent interactions of uranyl complexes: a theoretical study.

We report a set of theoretical calculations designed to examine the potential of model uranyl complexes to participate in hydrogen- and halogen-bonding. Potential energy scans for the interaction of [UO2Cl2(H2O)3] and [UO2(NCSe)2(H2O)3] with a single water molecule demonstrate that uranyl is a weak hydrogen bond acceptor, but that equatorially coordinated water is a strong hydrogen bond donor. These predictions are supported by a survey of contacts reported in the Cambridge Structural Database. At the minima of each scan, we show that the interaction energy is only weakly dependent on the choice of the theoretical method, with standard density functional theory methods comparing well with coupled-cluster, MP2 and double-hybrid DFT predictions. Geometry optimisation of a 1 : 1 uranyl : water complex results in a cyclic structure, in which vibrational frequencies, atoms-in-molecules and natural bond orbital analysis support the weakness of U-Oyl as an acceptor. The origin of this behaviour is traced to the electronic structure of uranyl, and in particular covalency in the U-Oyl bonds resulting from donation into formally empty 5f and 6d orbitals on U.

Exploring the Binding of Barbital to a Synthetic Macrocyclic Receptor. A Charge Density Study.

Experimental charge density distribution studies, complemented by quantum mechanical theoretical calculations, of a host-guest system composed of a macrocycle (1) and barbital (2) in a 1:1 ratio (3) have been carried out via high-resolution single-crystal X-ray diffraction. The data were modeled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. The asymmetric unit of macrocycle 1 contained an intraannular ethanol molecule and an extraannular acetonitrile molecule, and the asymmetric unit of 3 also contained an intraannular ethanol molecule. Visual comparison of the conformations of the macrocyclic ring shows the rotation by 180° of an amide bond attributed to competitive hydrogen bonding. It was found that the intraannular and extraannular molecules inside were orientated to maximize the number of hydrogen bonds present, with the presence of barbital in 3 resulting in the greatest stabilization. Hydrogen bonds ranging in strength from 4 to 70 kJ mol-1 were the main stabilizing force. Further analysis of the electrostatic potential among 1, 2, and 3 showed significant charge redistribution when cocrystallization occurred, which was further confirmed by a comparison of atomic charges. The findings presented herein introduce the possibility of high-resolution X-ray crystallography playing a more prominent role in the drug design process.

A Multi-Level Theoretical Study to Disclose the Binding Mechanisms of Gold(III)-Bipyridyl Compounds as Selective Aquaglyceroporin Inhibitors.

Structural studies have paved the avenue to a deeper understanding of aquaporins (AQPs), small ancient proteins providing efficient transmembrane pathways for water, small uncharged solutes such as glycerol, and possibly gas molecules. Despite the numerous studies, their roles in health and disease remain to be fully disclosed. The recent discovery of AuIII complexes as potent and selective inhibitors of aquaglyceroporin isoforms paves the way to their possible therapeutic application. The binding of the selective human AQP3 inhibitor, the cationic complex [Au(bipy)Cl2 ]+ (Aubipy), to the protein channel has been investigated here by means of a multi-level theoretical workflow that includes QM, MD and QM/MM approaches. The hydroxo complex was identified as the prevalent form of Aubipy in physiological media and its binding to AQP3 studied by MD. Both non-covalent and coordinative Aubipy-AQP3 adducts were simulated to probe their role in the modulation of water channel functionality. The electronic structures of representative Aubipy-AQP3 adducts were then analysed to unveil the role played by the metal moiety in their stabilisation. This study spotlights the overall importance of three key aspects for AQP3 inhibition: 1) water speciation of the AuIII complex, 2) stability of non-covalent adducts and 3) conformational changes induced within the pore by the coordinative binding of AuIII . The obtained results are expected to orient future developments in the design of isoform-selective AuIII inhibitors.

From Ligand to Phosphor: Rapid, Machine-Assisted Synthesis of Substituted Iridium(III) Pyrazolate Complexes with Tuneable Luminescence.

A first-generation machine-assisted approach towards the preparation of hybrid ligand/metal materials has been developed. A comparison of synthetic approaches demonstrates that incorporation of both flow chemistry and microwave heating can be successfully applied to the rapid synthesis of a range of new phenyl-1H-pyrazoles (ppz) substituted with electron-withdrawing groups (-F, -CF3 , -OCF3 , and -SF5 ). These, in turn, can be translated into heteroleptic complexes, [Ir(ppz)2 (bipy)]BF4 (bipy=2,2'-bipyridine). Microwave-assisted synthesis for the IrIII complexes allows isolation of spectroscopically pure species in less than 1 h of reaction time starting from IrCl3 . All of the new complexes have been characterised photophysically (including nanosecond time-resolved transient absorption spectroscopy), electrochemically, and by TD-DFT studies. The complexes exhibit ligand-dependent, tuneable, green-yellow luminescence (500-560 nm), with quantum yields in the range 5-15 %.

Understanding the Coordination Modes of [Cu(acac)2(imidazole)n=1,2] Adducts by EPR, ENDOR, HYSCORE, and DFT Analysis.

The interaction of imidazole with a [Cu(acac)2] complex was studied using electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), hyperfine sublevel correlation spectroscopy (HYSCORE), and density functional theory (DFT). At low Im ratios (Cu:Im 1:10), a 5-coordinate [Cu(acac)2Imn=1] monoadduct is formed in frozen solution with the spin Hamiltonian parameters g1 = 2.063, g2 = 2.063, g3 = 2.307, A1 = 26, A2 = 15, and A3 = 472 MHz with Im coordinating along the axial direction. At higher Im concentrations (Cu:Im 1:50), a 6-coordinate [Cu(acac)2Imn=2] bis-adduct is formed with the spin Hamiltonian parameters g1 = 2.059, g2 = 2.059, g3 = 2.288, A1 = 30, A2 = 30, and A3 = 498 MHz with a poorly resolved 14N superhyperfine pattern. The isotropic EPR spectra revealed a distribution of species ([Cu(acac)2], [Cu(acac)2Imn=1], and [Cu(acac)2Imn=2]) at Cu:Im ratios of 1:0, 1:10, and 1:50. The superhyperfine pattern originates from two strongly coordinating N3 imino nitrogens of the Im ring. Angular selective 14N ENDOR analysis revealed the NA tensor of [34.8, 43.5, 34.0] MHz, with e2qQ/h = 2.2 MHz and η = 0.2 for N3. The hyperfine and quadrupole values for the remote N1 amine nitrogens (from HYSCORE) were found to be [1.5, 1.4, 2.5] MHz with e2qQ/h = 1.4 MHz and η = 0.9. 1H ENDOR also revealed three sets of HA tensors corresponding to the nearly equivalent H2/H4 protons in addition to the H5 and H1 protons of the Im ring. The spin Hamiltonian parameters for the geometry optimized structures of [Cu(acac)2Imn=2], including cis-mixed plane, trans-axial, and trans-equatorial, were calculated. The best agreement between theory and experiment indicated the preferred coordination is trans-equatorial [Cu(acac)2Imn=2]. A number of other Im derivatives were also investigated. 4(5)-methyl-imidazole forms a [Cu(acac)2(Im-3)n=2] trans-equatorial adduct, whereas the bulkier 2-methyl-imidazole (Im-2) and benzimidazole (Im-4) form the [Cu(acac)2(Im-2,4)n=1] monoadduct only. Our data therefore show that subtle changes in the substrate structure lead to controllable changes in coordination behavior, which could in turn lead to rational design of complexes for use in catalysis, imaging, and medicine.

Structural Variability of 4f and 5f Thiocyanate Complexes and Dissociation of Uranium(III)-Thiocyanate Bonds with Increased Ionicity.

A series of complexes [Et4N][Ln(NCS)4(H2O)4] (Ln = Pr, Tb, Dy, Ho, Yb) have been structurally characterized, all showing the same structure, namely a distorted square antiprismatic coordination geometry, and the Ln-O and Ln-N bond lengths following the expected lanthanide contraction. When the counterion is Cs+, a different structural motif is observed and the eight-coordinate complex Cs5[Nd(NCS)8] isolated. The thorium compounds [Me4N]4[Th(NCS)7(NO3)] and [Me4N]4[Th(NCS)6(NO3)2] have been characterized, and high coordination numbers are also observed. Finally, attempts to synthesize a U(III) thiocyanate compound has been unsuccessful; from the reaction mixture, a heterocycle formed by condensation of five MeCN solvent molecules, possibly promoted by U(III), was isolated and structurally characterized. To rationalize the inability to isolate U(III) thiocyanate compounds, thin-layer cyclic voltammetry and IR spectroelectrochemistry have been utilized to explore the cathodic behavior of [Et4N]4[U(NCS)8] and [Et4N][U(NCS)5(bipy)2] along with a related uranyl compound [Et4N]3[UO2(NCS)5]. In all examples, the reduction triggers a rapid dissociation of [NCS]- ions and decomposition. Interestingly, the oxidation chemistry of [Et4N]3[UO2(NCS)5] in the presence of bipy gives the U(IV) compound [Et4N]4[U(NCS)8], an unusual example of a ligand-based oxidation triggering a metal-based reduction. The experimental results have been augmented by a computational investigation, concluding that the U(III)-NCS bond is more ionic than the U(IV)-NCS bond.

Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP83-96) Epitope to Function as T-Cell Receptor Antagonists.

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83-96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83-96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83-99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS.

A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of piroxicam.

Experimental charge density distribution studies of two polymorphic forms of piroxicam, ß-piroxicam (1) and piroxicam monohydrate (2), were carried out via high-resolution single crystal X-ray diffraction experiments and multipole refinement. The asymmetric unit of (2) consists of two discrete piroxicam molecules, (2a) and (2b), and two water molecules. Geometry differs between (1) and (2) due to the zwitterionic nature of (2) which results in the rotation of the pyridine ring around the C(10)-N(2) bond by approximately 180°. Consequently, the pyridine and amide are no longer co-planar and (2) forms two exclusive, strong hydrogen bonds, H(3)O(4) and H(2)O(3), with bond energies of 66.14 kJ mol-1 and 112.82 kJ mol-1 for (2a), and 58.35 kJ mol-1 and 159.51 kJ mol-1 for (2b), respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified by the calculation of atomic charges in the zwitterion that shows the formally positive charge of the pyridyl nitrogen which is redistributed over the whole of the pyridine ring instead of concentrating at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazine carboxamide moiety. The multipole derived lattice energy for (1) is -304 kJ mol-1 and that for (2) is -571 kJ mol-1, which is in agreement with the experimentally determined observations of higher solubility and dissolution rates of (1) compared to (2).

Computational evidence for structural consequences of kiteplatin damage on DNA.

The reaction of the potential anticancer drug kiteplatin, cis-[PtCl2(cis-1,4-DACH)], with oligomers of single- and double-stranded DNA ranging from 2 to 12 base pairs in length was performed as a model for DNA interaction. The potential for conformational flexibility of single-stranded adducts was examined with density functional theory (DFT) and compared with data from (1)H-NMR 1D and 2D spectroscopy. This indicates the presence of multiple conformations of an adduct with d(GpG), but only one form of the adduct with d(TGGT). The importance of a suitable theoretical model, and in particular basis set, in reproducing experimental data is demonstrated. The DFT theoretical model was extended to platinated base pair step (GG/CC), allowing a comparison to the related compounds cisplatin and oxaliplatin. Adducts of kiteplatin with larger fragments of double-stranded DNA, including tetramer, octamer, and dodecamer, were studied theoretically using hybrid quantum mechanics/molecular mechanics methods. Structural parameters of all the base-paired models were evaluated and binding energies calculated in gas phase and in solution; these are compared across the series and also with the related complexes cisplatin and oxaliplatin, thus revealing insights into how kiteplatin binds to DNA and similarities and differences between this and related compounds.

Phosphorescent, Cyclometalated Cinchophen-Derived Platinum Complexes: Syntheses, Structures, and Electronic Properties.

The syntheses of nine new monometallic heteroleptic platinum complexes [Pt(L1-4)(acac)], [Pt(L1)(hmacac/hfacac)], [PtCl(L1)(py)], [Pt(L1)(8-Q)], [Pt(L1)(bpy)](PF6) (where L1 = 2-phenyl-4-ethyl-quinolinecarboxylate; L2/L3 = N-functionalization of 2-phenyl-N-aryl/alkyl-quinoline-4-carboxamides; L4 = 2-phenyl-4-quinolinecarboxylic acid (cinchophen); acac = acetylacetonato; hmacac =2,2,6,6-tetramethyl-3,5-heptanedionate; hfacac = hexafluoroacetylacetonate; py = pyridine; 8-Q = 8-quinolinato; bpy =2,2'-bipyridine) are described from precursor dimeric Pt(II) species via an intermediate DMSO adduct of the general form [PtCl(L1-4)(DMSO)]. Single crystal X-ray diffraction studies were undertaken on three complexes, [Pt(L1)(acac)], [PtCl(L1)(DMSO)], and [Pt(L1)(bpy)](PF6). The structures show that the complexes each adopt a distorted square planar geometry (most severely in the case of [Pt(L1)(bpy)](PF6)) with indications of intermolecular Pt-Pt interactions in one example. The complexes were investigated using (195)Pt{(1)H} NMR spectroscopy, revealing varied chemical shifts that were strongly dependent upon the specific coordination environment of Pt(II). Luminescence studies showed the complexes possess a phosphorescent character with tunable emission wavelengths between 605 and 641 nm and luminescent lifetimes up to ∼450 ns. Supporting TD-DFT studies provided descriptions of the HOMO and LUMO energy levels of the key complex types, confirming an MLCT contribution to the lowest energy absorption that generally correlated well with the experimental spectra. The contribution of the Pt(5d) center to the calculated HOMOs was strongly ligand dependent, whereas the LUMOs are generally localized over the quinoline component of the cyclometalated ligand.

Improving catalyst activity in secondary amine catalysed transformations.

The effect on catalyst performance of altering substituents at the 2-position of the Macmillan imidazolidinone has been examined. Condensation of L-phenylalanine N-methyl amide with acetophenone derivatives results in a series of imidazolidinones whose salts can be used to accelerate the Diels-Alder cycloaddition. Electron withdrawing groups significantly increase the overall rate of cycloaddition without compromise in selectivity. The most effective catalyst was shown to be efficient for a variety of substrates and the applicability of this catalyst to alternative secondary amine catalysed transformations is also discussed.