Ionophoric properties of a tetra-tetrazole functionalised calix[4]arene

© 2015 Taylor & Francis. The synthesis and characterisation of p-t-butylcalix[4]arene functionalised at the lower rim with four tetrazole moieties is reported. The macrocycle is found to be a poorer ionophore for lanthanoid cations than the bis-tetrazole-substituted analogue. Solution-phase photophysical studies strongly suggested that the cations interacted only weakly with the calixarene ligand. A mixed sodium/triethylammonium salt of the calixarene ligand was crystallised in the presence of lanthanoid cations and structurally characterised. Strong intramolecular interactions are hypothesised to be the cause of the observed behaviour

Pulsed gradient spin-echo NMR

In this chapter, the fundamentals of translational diffusion and PGSE NMR diffusion measurements and the solutions of the common artefacts in PGSE experiments (such as background gradients, huge solvent (e.g., water) signal, and thermal convection) are discussed and the practical issues of PGSE measurements (including sample preparation, selection of pulse sequences, and parameter settings) are considered; the fundamentals of the application of PGSE NMR to the study of ligand-macromolecule interactions and supramolecular assembly are examined

Drug delivery devices and targeting agents for platinum (II) anticancer complexes

An ideal platinum-based delivery device would be one that selectively targets cancerous cells, can be systemically delivered, and is non-toxic to normal cells. Itwould be beneficial to provide drug delivery devices for platinum-based anticancer agents that exhibit high drug transport capacity, good water solubility, stability during storage, reduced toxicity, and enhanced anticancer activity in vivo. However, the challenges for developing drug delivery devices include carrier stability in vivo, the method by which extracellular or intracellular drug release is achieved, overcoming the various mechanisms of cell resistance to drugs, controlled drug release to cancer cells, and platinum drug bioavailability. There are many potential candidates under investigation including cucurbit[n]urils, cyclodextrins, calix[n]arenes, and dendrimers, with the most promising being those that are synthetically adaptable enough to attach to targeting agents

Spectroscopic investigations on the interactions of potent platinum(II) anticancer agents with bovine serum albumin

The interactions of three platinum(II)-based anticancer complexes [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane)platinum(II)]2+, [(5,6-dimethyl- 1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum( II)]2+, and [(5,6-dimethyl-1,10-phenanthroline)(1,2- diaminoethane)platinum(II)]2+ (56MEEN) with BSA have been examined by circular dichroism (CD), fluorescence and 1H pulsed gradient spin–echo (PGSE) diffusion NMR spectroscopy. The number of association constants and sites differed depending upon the spectroscopic method. This may be because each technique monitors different types of interaction/s and/or as a consequence of the different concentration ranges required for each technique. The titration of BSA with the achiral 56MEEN as monitored by CD indicates a reduction in the α-helical nature of the albumin, with the association constant calculated to be ~5×106 M−1 for one site. Due to the chiral nature of the other two complexes, their association with albumin was not monitored using CD but was examined using fluorescence and PGSE diffusion NMR. Titration of BSA with any of the three metal complexes resulted in quenching of fluorescence, with the number of association sites calculated to be ~1.1, with an association constant of ~2×105 M−1. PGSE diffusion NMR provided insights into interactions occurring with the BSA in its entirety, rather than with individual regions. Metal complex binding sites were estimated (~10 equivalent) from the diffusion data, with the average association constant for all sites ~102–103M−1. These experiments highlight the information that can be elucidated from complementary spectroscopic techniques and demonstrate the usefulness of PGSE diffusion NMR in monitoring multiple weak binding sites, which is of great importance in studying drug-biomolecule interactions

Copper(ii) and palladium(ii) complexes with cytotoxic and antibacterial activity

The synthesis of eight square pyramidal copper complexes with general structure [Cu(IL)(AL)H2O]2þ, where IL represents various methylated 1,10-phenanthrolines, andAL represents either 1S,2S- or 1R,2R-diaminocyclohexane, is reported, with the complexes synthesised as both the perchlorate and chloride salts. The crystal structures of [Cu(1,10-phenanthroline) (1S,2S-diaminocyclohexane](ClO4)2_H2Oand [Cu(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane](ClO4)2_1.5H2O are reported. Four square planar palladium complexes with general structure [Pd(IL)(AL)]Cl2 have also been synthesised. These complexes were synthesised in order to investigate the structure–activity relationship against both cancer cell lines and bacterial cultures. The copper complexes display anticancer activity similar to cisplatin and 1,10-phenanthroline (phen) in the L1210 murine leukaemia cell line. Methylation of the phen increased the copper complex cytotoxicity by approximately four-fold, compared with the non-methylated complex. No significant difference in activity was observed by altering the chirality of the diaminocyclohexane ligand. The copper complexes demonstrated antibacterial activity against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli; however, high levels of toxicity (30–60%of death) were observed in the nematode Caenorhabditis elegans. The copper complexes have also been shown to act as DNA nucleases, with the ability to cleave plasmid DNA in the presence of hydrogen peroxide. The palladium complexes all have half maximal inhibitory concentration (IC50) values of,10 mMin the L1210 cell line, with no significant difference in the cytotoxicity of any of the compounds tested. Minimal antibacterial activity of the palladium complexes was observed

The synthesis of platinum(II) intercalators

The pharmacological properties of any drug are largely dependent on binding interactions with biomolecules. The investigation of such interactions is essential to gain some understanding of the mechanisms of drug action, and to determine which structural characteristics influence the pharmacological properties. Of particular interest are the interactions between anticancer agents and DNA, as DNA is considered to be the major cellular target for a large number of compounds that are effective in the treatment of various types of cancers. It has been reported that the binding of such drugs to DNA can inhibit cellular processes such as DNA replication and transcription, which are vital for the proliferation of cells. The inhibition or prevention of cell division is the primary objective for drug design as it most markedly affects rapidly dividing cells such as tumour cells, and ultimately prevents their spread throughout the body

Substituted β-cyclodextrin and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators

The encapsulation of three platinum(II)-based anticancer complexes, [(5,6-dimethyl-1,10-phenanthroline)(1S,2Sdiaminocyclohexane) platinum(II)]2+ (56MESS), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum( II)]2+ (56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)]2+ (56MEEN), with carboxylated-β-cyclodextrin (c-β-CD) and p-sulfonatocalix[4]arene (s-CX[4]) has been examined by one- and twodimensional 1H nuclear magnetic resonance (NMR) spectroscopy, pulsed gradient spin-echo NMR, ultraviolet spectrophotometry, glutathione degradation experiments, and growth inhibition assays. Titration of any of the three metal complexes with c-β-CD resulted in 1:1 encapsulation complexes with the cyclodextrin located over the intercalating ligand of the metal complexes, with a binding constant of 104-105 M-1. In addition to binding over the phenanthroline ligand of 56MEEN, c-β-CD was also found to portal bind to the ethylenediamine ligand, with fast exchange kinetics on the NMR timescale between the two binding sites. In contrast, the three metal complexes all formed 2:2 inclusion complexes with s-CX[4] where the two metal complexes stacked in a head-to-tail configuration and were capped by the s-CX[4] molecules. Interestingly, the 56MEEN-s-CX[4] complex appeared to undergo a thermodynamically controlled rearrangement to a less soluble complex over time. Encapsulation of the metal complexes in either c-β-CD or s-CX[4] significantly decreased the metal complexes’ rate of diffusion, consistent with the formation of larger particle volumes. Encapsulation of 56MESS within s-CX[4] or c-β-CD protected the metal complex from degradation by reduced L-glutathione, with a reaction half-life greater than 9 days. In vitro growth inhibition assays using the LoVo human colorectal cancer cell line showed no significant change in the cytotoxicity of 56MESS when encapsulated by either s-CX[4] or c-β-CD

Membrane Protein Structures in Lipid Bilayers; Small-Angle Neutron Scattering With Contrast-Matched Bicontinuous Cubic Phases

. Deuterated vesicles can be used to obtain the radius of gyration of membrane proteins, but protein-protein interference effects within the vesicles severely limits this method such that the protein structure cannot be modeled. We show herein that different membrane protein conformations can be distinguished within the lipid bilayer of the bicontinuous cubic phase using contrast-matching. Time-resolved studies performed using SANS illustrate the complex phase behavior in lyotropic liquid crystalline systems and emphasize the importance of this development. We believe that studying membrane protein structures and phase behavior in contrast-matched lipid bilayers will advance both biological and pharmaceutical applications of membrane-associated proteins, biosensors and food science

Substituted beta-cyclodextrin and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators

The encapsulation of three platinum(II)-based anticancer complexes, [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2+ (56MESS), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)]2+ (56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)]2+ (56MEEN), with carboxylated-β-cyclodextrin (c-β-CD) and p-sulfonatocalix[4]arene (s-CX[4]) has been examined by one- and two-dimensional 1H nuclear magnetic resonance (NMR) spectroscopy, pulsed gradient spin−echo NMR, ultraviolet spectrophotometry, glutathione degradation experiments, and growth inhibition assays. Titration of any of the three metal complexes with c-β-CD resulted in 1:1 encapsulation complexes with the cyclodextrin located over the intercalating ligand of the metal complexes, with a binding constant of 104−105 M−1. In addition to binding over the phenanthroline ligand of 56MEEN, c-β-CD was also found to portal bind to the ethylenediamine ligand, with fast exchange kinetics on the NMR timescale between the two binding sites. In contrast, the three metal complexes all formed 2:2 inclusion complexes with s-CX[4] where the two metal complexes stacked in a head-to-tail configuration and were capped by the s-CX[4] molecules. Interestingly, the 56MEEN-s-CX[4] complex appeared to undergo a thermodynamically controlled rearrangement to a less soluble complex over time. Encapsulation of the metal complexes in either c-β-CD or s-CX[4] significantly decreased the metal complexes' rate of diffusion, consistent with the formation of larger particle volumes. Encapsulation of 56MESS within s-CX[4] or c-β-CD protected the metal complex from degradation by reduced L-glutathione, with a reaction half-life greater than 9 days. In vitro growth inhibition assays using the LoVo human colorectal cancer cell line showed no significant change in the cytotoxicity of 56MESS when encapsulated by either s-CX[4] or c-β-CD