Fr Francium

Follow my lead! NSC 670224, previously shown to be toxic to Saccharomyces cerevisiae at low micromolar concentrations, potentially acts via a mechanism of action related to that of tamoxifen (NSC 180973), breast cancer drug. The structure of NSC 670224, previously thought to be a 2,4-dichloro arene, was established as the 3,4-dichloro arene, and a focused library of analogues were synthesized and biologically evaluated.

The ability of small molecules to target DNA forms the basis of many clinically used antitumour agents. This study examines the effects of novel 9-aminoacridine carboxamides, synthesised by click chemistry based upon the reactions of either 9-(2-azidoethyl)amino or 9-propargylaminoacridine compounds, on various types of DNA tertiary structures. This gave either monomeric or dimeric compounds, the dimeric derivatives being the first unsymmetrical acridine dimers to be described. The compounds were assayed for duplex DNA, quadruplex DNA and four-way junction DNA binding. Their antiproliferative activity in the Human promyelocytic leukaemia cell line, HL60, was also assessed. Although for some of the compounds, notably the acridine 4-carboxamides, activity correlated with DNA binding affinity, for others it did not, with the rigidly linked dimers in particular showing a complicated relationship between 3- and 4-carboxamide structure and biological activity. The monomeric 3-carboxamides were more effective at stabilising G-quadruplex structures and also gave more hits in the four-way junction stabilisation assay. There is clear evidence from the binding of the 3-carboxamides that these compounds destabilise the open X form of the junction at lower concentrations and stabilise the X-stacked at higher concentrations. This might have implications for the biological activity of these compounds against proteins that bind to the Holliday junction (HJ).

Click and you′re on Holliday! Click chemistry has been used to generate a small library of 9-aminoacridines. These novel analogues were evaluated for cytotoxicity, and duplex, quadruplex and Holliday junction (HJ) DNA binding. For some compounds, there was a direct correlation between activity and DNA binding, while for others a more complicated relationship exists. The acridine 3-carboxamides proved the most interesting, stabilising both quadruplex and HJ DNA.

The endogenous neuropeptide galanin has anticonvulsant and analgesic properties mediated by galanin receptors expressed in the central and peripheral nervous systems. Our previous work showed that by combining truncation of the galanin peptide with N- and C-terminal modifications afforded analogues that suppress seizures or pain upon intraperitoneal (i.p.) administration. To generate orally active galanin analogues, the previously reported lead compound Gal-B2 (NAX 5055) was redesigned by 1) central truncation, (2) introduction of D-amino acids, and 3) addition of backbone spacers. Analogue D-Gal(7-Ahp)-B2, containing 7-aminoheptanoic acid as a backbone spacer and an oligo-D-lysine motif at the C terminus, exhibits anticonvulsant and analgesic activity post-i.p. administration. Oral administration of D-Gal(7-Ahp)-B2 demonstrates analgesic activity with decreases in both acute and inflammatory pain in the mouse formalin model of pain at doses as low as 8 mg kg⁻¹.

Gallant pain relief:D-Gal(7-Ahp)-B2 is an analgesic peptide that incorporates a central truncation of the galanin neuropeptide, the addition of a backbone spacer, and the introduction of D-amino acids. Oral administration of this galanin-based peptide demonstrates analgesic activity in the formalin model of acute and inflammatory pain in mice.

There is a demand for new and robust Pd^II extractants due to growing recycling rates. Chelating dithioethers are promising substances for solvent extraction as they form stable square-planar complexes with Pd^II. We have modified unsaturated dithioethers, which are known to coordinate Pd^II, and adapted them to the requirements of industrial practice. The ligands are analogues of 1,2-dithioethene with varying electron-withdrawing backbones and polar end-groups. The crystal structures of several ligands and their palladium complexes were determined as well as their electro- and photochemical properties, complex stability and behaviour in solution. Solvent extraction experiments showed the superiority of some of our ligands over conventionally used extractants in terms of their very fast reaction rates. With highly selective 1,2-bis(2-methoxyethylthio)benzene (4) it is possible to extract Pd^II from a highly acidic medium in the presence of other base and palladium-group metals.

Unsaturated dithioethers based on o-dithiobenzene units and substituted with polar side arms, such as 1,2-bis(2-methoxyethylthio)benzene, are selective ligands for Pd^II with fast extraction kinetics and a high oxidation resistance. Solvent extraction experiments demonstrate their good performance even in HCl-containing media and the advantages of these extractants over commonly used ones.

Zeolites, clays, and mesoporous silica materials offer the possibility to be loaded with Ln³⁺ ions either by means of ion exchange of the cations that are balancing the negative charge of the framework or by grafting of Ln³⁺ chelates to the framework. In this Microreview, the structures of the materials used up to now are described and related to their stabilities and relaxometric behavior. The possible exploitation of the unique features of these materials as both positive and negative MRI contrast agents in multimodal probes and in theranostics are discussed.

Various strategies for the loading of porous, nanosized materials with lanthanides for use as positive or negative contrast agents for MRI have been described. The diverse structural features of these materials with large pore volumes and various domains that can be functionalized independently enable multimodal and theranostic applications.

Paramagnetic magnetic resonance imaging (MRI) contrast agents are the compounds most used in clinical studies. Among these, the derivatives of Gd-DTPA (gadoliniumdiethylenetriaminepentaacetic acid, Magnevist^®, Bayer HealthCare) have been extensively studied. The first part of this work consists of a comparison of various derivatives of Gd-DTPA [mono-, bis- or pentaamides; C-functionalised (C₂, C₄, C₅, N₆) or diester derivatives] according to their synthesis and to the most important parameters that regulate their efficacy. The synthesis of bis(amide)s consists of only one step and is thus easier than the synthesis of the C₄ derivatives, which needs several steps and requires a tedious purification. These last compounds are, however, more stable against transmetallation with another ion such as zinc [more than 50 % of the gadolinium complex remains after 4300 min while this percentage falls under 40 % for most of the bis(amide) compounds] and generally have higher relaxivities. Moreover, the residence time of the water molecule in the first coordination sphere of the gadolinium complex (τ_M) is shorter for the C₄ derivatives and does not limit the relaxivity. In the second part of this work, an overview of different kinds of recently developed paramagnetic contrast agents is presented: new systems to improve the relaxivity, like fullerenol compounds, apoferritin or zeolite complexes, lipophilic complexes (in structures like micelles or liposomes), macromolecular products as well as small complexes interacting with human serum albumin (HSA).

Derivatives of Gd-DTPA (gadolinium diethylenetriaminepentaacetic acid) are compared with regard to their synthesis and to the most important parameters that regulate their efficacy.

In a molecular frame rigidly bound to the contrast agent, the instantaneous zero-field splitting (ZFS) Hamiltonian acting on the Gd³⁺ electronic spin, S, has a constant mean value, named static ZFS (Hamiltonian). Expressed in the laboratory frame, the static ZFS has a random variation with time, which stems from the Brownian rotation of the complex and can be the source of a fast electronic spin relaxation that significantly quenches the relaxivity at low field. Except in a few cases, the static ZFS is too large and the Brownian rotation is too slow for the electronic relaxation to be described by Redfield analytical equations. Here, we present a formalism for simulating the quantum time correlation functions (TCFs) of the electronic spin operators, which properly account for relaxivity quenching by electronic relaxation. Though the formalism can be used at all field values, the interpretation of the high-field relaxivity with the help of simple justified analytical equations is recommended. The simulation procedure is illustrated by the case study of a model of the complex Gddtpa {[Gd³⁺(dtpa)(H₂O)]^2– (dtpa^5– = diethylenetriamine pentaacetate)}. The numerical implementation of the simulation at several levels of parallel computing is examined.

Simulated time correlation functions of the fluctuating intramolecular local dipolar field created by Gd³⁺ in a Gddtpa-like complex giving rise to inner sphere relaxivity at 0 and 1.25 T.

The current work reports single-phase, terbium-doped sodium dysprosium fluoride (NaDyF₄:Tb³⁺) nanocrystals with green luminescence and good T₂ contrast in 7.0-T MRI phantom and animal imaging. The current nanocrystals demonstrate good potential as a dual modal contrast agent for high-field magnetic resonance (MR) and fluorescence imaging.

Dual-mode NaDyF₄:Tb³⁺ nanocrystals were synthesized by the thermal decomposition method. The nanocrystals showedgreen fluorescence and good negative T₂ contrast in 7-T MR phantom and animal imaging.

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of β-amyloid (Aβ) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of Aβ oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF₃-C-OH and CF₃-C-NH groups that were proposed to be binding units in our previous studies. A broad range of potential small-molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy for monitoring fibril formation, biotinyl Aβ_1–42 single-site streptavidin-based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either Aβ fibril or oligomer formation. A detailed analysis of the structure–activity relationship of anti-fibril and ‒oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the Aβ peptide with chiral small molecules is not stereospecific in nature.

Aβ blockers: A diverse library of compounds with the same binding moiety was generated, and the general structural features that characterize inhibitors of β-amyloid oligomer and fibril formation were observed. The ultimate goal of this project was to identify lead structures for further focused inhibitor design.

Using [Ln(L)₈]³⁺ [Ln = Tb, Y; L = dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF)] cations as templating reagents, the syntheses and crystal structures of the following new metal organic–inorganic hybrid complexes based on either discrete clusters or 1D chains of an iodoplumbate or -bismuthate moiety are reported: [Tb(DMSO)₈]₂[(DMSO)₂Pb₅I₁₆] (1), [Tb(DMF)₈][Pb₃I₉]_1∞·DMF (2) and [Ln(DMF)₈][Bi₂I₉] [Ln = Y (3), Tb (4)]. These derivatives were characterized by thermogravimetric analysis (TGA), diffuse-reflectance spectroscopy, luminescence spectroscopy and magnetic studies. TGA studies show that the thermal stability of these complexes decreases in the order 2 > 3 ≈ 4 > 1. An optical band-gap in the range 1.90–2.15 eV in the diffuse-reflectance spectra of 1–4 indicate their potential use as semiconductors, 3 and 4 being the most promising because of their low band gap values. Compared to the precursors [Tb(DMSO)₈]I₃ and [Tb(DMF)₈]I₃, the high energy transitions in the excitation spectra of 1, 2 and 4 are quenched by a process that is best attributed to the autoionization of the carriers in the material. The temperature dependence of the magnetic susceptibilities of 1, 2 and 4 was reproduced well by a Curie–Weiss plot at 2–300 K.

New hybrid complexes composed of metal–organic cations with a magnetic/luminescent terbium centre and iodometallate anions derived from the neutral semiconductor PbI₂ and BiI₃ are reported, and the solvent-induced interconversion among the iodoplumbate derivatives is described.