Anticancer Water-Soluble Organoruthenium Complexes: Synthesis and Preclinical Evaluation.

The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''-trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.

Poly(acrylic acid) interpolymer complexes.

Interpolymer complex formation of poly(acrylic acid) with other macromolecules can occur via several mechanisms that vary depending on the pH. At low pH the protonated acid functional group can form bonds with both donor and acceptor moieties, resulting in desolvated structures consisting of two polymers. Complexes were formed in dilute solutions of PAA, functionalised with acenaphthylene, with a range of other polymers including: poly(NIPAM); poly(ethylene oxide) (PEO); poly(dimethylacrylamide) (PDMA); poly(diethyl acrylamide) (PDEAM) poly(vinyl alcohol) (PVA) and poly(vinyl pyrolidinone) (PVP). Fluorescence anisotropy was used to demonstrate complex formation in each case by monitoring the reductions in segmental motion of the chain as the complexes formed. Considerations of the molecular structures of the complexing moieties suggest that solvation energies and pKas play an important role in complex formation.

Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics?

Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.

Complete colloidal synthesis of Cu2SnSe3 nanocrystals with crystal phase and shape control.

Here we report an investigation of systematic control of crystal phase in the ternary nanocrystal system, dicopper tin triselenide. Optimizing the synthetic parameters allows modulation between nucleation and growth in either the hexagonal or cubic phase. In addition to size controlled single crystals, the particles can be tuned to occur as 1D linear heterostructures or 3D tetrapods with growth in one phase and termination in the alternate.

Proton transfer and hydrogen bonding in the organic solid state: a combined XRD/XPS/ssNMR study of 17 organic acid-base complexes.

The properties of nitrogen centres acting either as hydrogen-bond or Brønsted acceptors in solid molecular acid-base complexes have been probed by N 1s X-ray photoelectron spectroscopy (XPS) as well as (15)N solid-state nuclear magnetic resonance (ssNMR) spectroscopy and are interpreted with reference to local crystallographic structure information provided by X-ray diffraction (XRD). We have previously shown that the strong chemical shift of the N 1s binding energy associated with the protonation of nitrogen centres unequivocally distinguishes protonated (salt) from hydrogen-bonded (co-crystal) nitrogen species. This result is further supported by significant ssNMR shifts to low frequency, which occur with proton transfer from the acid to the base component. Generally, only minor chemical shifts occur upon co-crystal formation, unless a strong hydrogen bond is formed. CASTEP density functional theory (DFT) calculations of (15)N ssNMR isotropic chemical shifts correlate well with the experimental data, confirming that computational predictions of H-bond strengths and associated ssNMR chemical shifts allow the identification of salt and co-crystal structures (NMR crystallography). The excellent agreement between the conclusions drawn by XPS and the combined CASTEP/ssNMR investigations opens up a reliable avenue for local structure characterization in molecular systems even in the absence of crystal structure information, for example for non-crystalline or amorphous matter. The range of 17 different systems investigated in this study demonstrates the generic nature of this approach, which will be applicable to many other molecular materials in organic, physical, and materials chemistry.

Creation of ternary multicomponent crystals by exploitation of charge-transfer interactions.

Four new ternary crystalline molecular complexes have been synthesised from a common 3,5-dinitrobenzoic acid (3,5-dnda) and 4,4'-bipyridine (bipy) pairing with a series of amino-substituted aromatic compounds (4-aminobenzoic acid (4-aba), 4-(N,N-dimethylamino)benzoic acid (4-dmaba), 4-aminosalicylic acid (4-asa) and sulfanilamide (saa)). The ternary crystals were created through the application of complementary charge transfer and hydrogen-bonding interactions. For these systems a dimer was created through a charge-transfer interaction between two of the components, while hydrogen bonding between the third molecule and this dimer completed the construction of the ternary co-crystal. All resulting structures display the same acid⋅⋅⋅pyridine interaction between 3,5-dnba and bipy. However, changing the third component causes the proton of this bond to shift from neutral OH⋅⋅⋅N to a salt form, O(-) ⋅⋅⋅HN(+) , as the nature of the group hydrogen bonding to the carboxylic acid was changed. This highlights the role of the crystal environment on the level of proton transfer and the utility of ternary systems for the study of this process.

Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria.

Antimicrobial resistant (AMR) bacteria are emerging and spreading globally, threatening our ability to treat common infectious diseases. The development of new classes of antibiotics able to kill or inhibit the growth of such AMR bacteria through novel mechanisms of action is therefore urgently needed. Here, a new family of indole-containing arene ruthenium organometallic compounds are screened against several bacterial species and drug resistant strains. The most active complex [(p-cym)Ru(O-cyclohexyl-1H-indole-2-carbothioate)Cl] (3) shows growth inhibition and bactericidal activity against different organisms (Acinetobacter baumannii, Mycobacterium abscessus, Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica serovar Typhi and Escherichia coli), demonstrating broad-spectrum inhibitory activity. Importantly, this compound series exhibits low toxicity against human cells. Owing to the novelty of the antibiotic family, their moderate cytotoxicity, and their inhibitory activity against Gram positive, Gram negative and acid-fast, antibiotic resistant microorganisms, this series shows significant promise for further development.

Crystallography aided by atomic core-level binding energies: proton transfer versus hydrogen bonding in organic crystal structures.

Ionic bond or hydrogen bridge? Brønsted proton transfer to nitrogen acceptors in organic crystals causes strong N1s core-level binding energy shifts. A study of 15 organic cocrystal and salt systems shows that standard X-ray photoelectron spectroscopy (XPS) can be used as a complementary method to X-ray crystallography for distinguishing proton transfer from H-bonding in organic condensed matter.

Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides.

The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1-3 and a dimethylsulfoxide (DMSO) solvate of 2 (2-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH3)2 hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in 1-3. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity. The chemosensitivity results highlight that modification of the terminal group from Ac to Boc in 1 and 2 leads to a 3-fold increase in antiproliferative activity against the cisplatin-sensitive ovarian carcinoma cell line, A2780. The presence of the amine termini in 3 gave the only member of the series to display activity against the cisplatin-resistance ovarian carcinoma cell line, A2780cisR. Compound 2 is the lead candidate of this series, displaying high selectivity towards A2780 cancer cells when compared to non-malignant PNT-2 cells, with a selectivity index value >4.2. Importantly, this compound is more selective towards A2780 (cf. PNT-2) than the clinical platinum drugs oxaliplatin by > 2.6-fold and carboplatin by > 1.6-fold.

Stabilisation of metastable polymorphs: the case of paracetamol form III.

The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of ß-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph.

Differential evolution: crystal structure determination of a triclinic polymorph of adipamide from powder diffraction data.

The crystal structure of a previously unknown triclinic polymorph of adipamide has been solved from laboratory X-ray powder diffraction data using a new direct space global optimisation method based on differential evolution.

Creation of a ternary complex between a crown ether, 4-aminobenzoic acid and 3,5-dinitrobenzoic acid.

The creation of ternary multi-component crystals through the introduction of 18-crown-6 to direct the hydrogen-bonding motifs of the other molecular components was investigated for 3,5-dinitrobenzoic acid (3,5-dnba) with 4-aminobenzoic acid (4-aba). The creation of a binary complex between 18-crown-6 and 4-aba (C12H24O6·2C7H7NO2)2 and a ternary salt between 3,5-dnba, 18-crown-6 and 4-aba (C12H24O6·C7H8NO2(+)·C7H3N2O6(-)·C7H4N2O6) were confirmed by single-crystal structure determination. In both structures, the amino molecules bind to the crown ether through N-H...O hydrogen bonds, leaving available only a single O atom site on the crown with restricted geometry to potentially accept a hydrogen bond from 3,5-dnba. While 3,5-dnba and 4-aba form a binary co-crystal containing neutral molecules, the shape-selective nature of 18-crown-6 preferentially binds protonated amino molecules, thereby leading to the formation of the ternary salt, despite the predicted low concentration of the protonated species in the crystallizing solution. Thus, through the choice of crown ether it may be possible to control both location and nature of the available bonding sites for the designed creation of ternary crystals.

The isolation of a metastable conglomerate using a combined computational and controlled crystallization approach.

While the use of additives to control the crystallization of polymorphs is well known, similar methodology to promote the crystallization of a metastable conglomerate over a stable racemic compound in enantiomeric systems has not been reported. Here we demonstrate this phenomenon in the case of 2-chloromandelic acid.

Solubility, metastable zone width measurement and crystal growth of the 1:1 benzoic acid/isonicotinamide cocrystal in solutions of variable stoichiometry.

The solubility and crystal growth of the 1:1 cocrystal between benzoic acid and isonicotinamide from 95% ethanol was studied through the creation of a ternary phase diagram at differing temperatures and turbidity measurements. From the solubility measurements thermodynamic properties of the system were evaluated, which indicate little solution binding of the two components supported by in situ FT-IR spectra. Cooling crystallisation from solutions of differing composition suggests differing crystal growth characteristics. An excess of benzoic acid appears to increase the metastable zone width and reduce the crystal size through interactions along the fastest growth axis, while an excess of isonicotinamide decreases the metastable zone width with increased crystal size.

Molecular versus crystal symmetry in tri-substituted triazine, benzene and isocyanurate derivatives.

The crystal structures of triethyl-1,3,5-triazine-2,4,6-tricarboxylate (I), triethyl-1,3,5-benzenetricarboxylate (II) and tris-2-hydroxyethyl isocyanurate (III) have been determined from conventional laboratory X-ray powder diffraction data using the differential evolution structure solution technique. The determination of these structures presented an unexpectedly wide variation in levels of difficulty, with only the determination of (III) being without complication. In the case of (I) structure solution resulted in a Rietveld refinement profile that was not ideal, but was subsequently rationalized by single-crystal diffraction as resulting from disorder. Refinement of structure (II) showed significant variation in side-chain conformation from the initial powder structure solution. Further investigation showed that the structure solution optimization had indeed been successful, and that preferred orientation had a dramatic effect on the structure-solution R-factor search surface. Despite the presence of identical side chains in (I) and (II), only the triazine-based system retains threefold molecular symmetry in the crystal structure. The lack of use of the heterocyclic N atom as a hydrogen-bond acceptor in this structure results in the formation of a similar non-centrosymmetric network to the benzene-based structure, but with overall three-dimensional centrosymmetry. The hydrogen-bonded layer structure of (III) is similar to that of other isocyanurate-based structures of this type.

Structures of three substituted arenesulfonamides from X-ray powder diffraction data using the differential evolution technique.

The structures of three substituted arenesulfonamides have been solved from laboratory X-ray powder diffraction data, using a new direct-space structure solution method based on a differential evolution algorithm, and refined by the Rietveld method. In 2-toluenesulfonamide, C(7)H(9)NO(2)S (I) (tetragonal I4(1)/a, Z = 16), the molecules are linked by N-H...O=S hydrogen bonds into a three-dimensional framework. In 3-nitrobenzenesulfonamide, C(6)H(6)N(2)O(4)S (II) (monoclinic P2(1), Z = 2), N-H...O=S hydrogen bonds produce molecular ladders, which are linked into sheets by C-H...O=S hydrogen bonds: the nitro group does not participate in the hydrogen bonding. Molecules of 4-nitrobenzenesulfonamide, C(6)H(6)N(2)O(4)S (III) (monoclinic P2(1)/n, Z = 4), are linked into sheets by four types of hydrogen bond, N-H...O=S, N-H...O(nitro), C-H...O=S and C-H...O(nitro), and the sheets are weakly linked by aromatic pi...pi stacking interactions.

Characterization of complicated new polymorphs of chlorothalonil by X-ray diffraction and computer crystal structure prediction.

A simultaneous experimental and computational search for polymorphs of chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile) has been conducted, leading to the first characterization of forms 2 and 3. The crystal structure prediction study, using a specifically developed anisotropic atom-atom potential for chlorothalonil, gave as the global minimum in the lattice energy a structure that was readily refined against powder diffraction data to the known form 1 (P2(1)/a). The structure of form 2 was solved and refined from powder diffraction data, giving a disordered structure in the Rm (166) space group (Z = 3). It could also be refined against a P1 ordered model, starting from a low-energy hypothetical sheet structure found in the computational search. This shows that the disorder could be associated with the stacking of ordered sheets. The disordered structure for form 2 was later confirmed by single-crystal X-ray diffraction. The structure of form 3, determined from single-crystal diffraction, contains three independent molecules in the asymmetric unit in P2(1) (4) (Z = 6). Powder diffraction showed that this single-herringbone structure was similar to two low-energy structures found in the search. Further analysis confirmed that form 3 has a similar lattice energy and contains elements from both these predicted structures, which can be considered as good approximations to the form 3 structure.