X-ray studies of the crystal structures of some biologically significant molecules

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A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer

Accuracy of alcohol and breast cancer risk information on Drinkaware's website

A recent paper in Drug and Alcohol Review analysed the information on cancer disseminated by 27 alcohol industry funded organisations. The independent UK alcohol education charity Drinkaware was among the organisations whose information was studied, and based on the analysis claims were made of misrepresentation of evidence about the alcohol-related risk of cancer and alcohol industry influence. This commentary challenges the validity of these findings in respect to the evidence relating to the Drinkaware information, as the analysis is found to be misrepresenting the information by both disregarding the wider information content provided and the order and prominence with which alcohol-related cancer risk is presented. Furthermore, it is argued that the public has a right to be provided with relevant evidence-based information about cancer risk. It is critical that Drinkaware's important public health function is not compromised by unjustified allegations of inaccuracy and by unwarranted attacks on its independence and integrity.</p

On Water Arrangements in Right- and Left-Handed DNA Structures

DNA requires hydration to maintain its structural integrity. Crystallographic analyses have enabled patterns of water arrangements to be visualized. We survey these water motifs in this review, focusing on left- and right-handed duplex and quadruplex DNAs, together with the i-motif. Common patterns of linear spines of water organization in grooves have been identified and are widely prevalent in right-handed duplexes and quadruplexes. By contrast, a left-handed quadruplex has a distinctive wheel of hydration populating the almost completely circular single groove in this structure

The relationship of potential G-quadruplex sequences in cis-upstream regions of the human genome to SP1-binding elements

We have carried out a survey of potential quadruplex structure sequences (PQSS), which occur in the immediate upstream region (500 bp) of human genes. By examining the number and distribution of these we have established that there is a clear link between them and the occurrence of the SP1-binding element ‘GGGCGG’, such that a large number of upstream PQSS incorporate the SP1-binding element

Atomic Force Microscopy and Voltammetric Investigation of Quadruplex Formation between a Triazole-Acridine Conjugate and Guanine-Containing Repeat DNA Sequences

The interactions of the Tetrahymena telomeric repeat sequence d(TG4T) and the polyguanylic acid (poly(G)) sequence with the quadruplex-targeting triazole-linked acridine ligand GL15 were investigated using atomic force microscopy (AFM) at a highly oriented pyrolytic graphite and voltammetry at a glassy carbon electrode. GL15 interacted with both sequences, in a time dependent manner, and G-quadruplex formation was detected. AFM showed the adsorption of quadruplexes as small d(TG4T) and poly(G) spherical aggregates and large quadruplex-based poly(G) assemblies, and voltammetry showed the decrease and disappearance of GL15 and guanine oxidation peak currents and appearance of the G-quadruplex oxidation peak. The GL15 molecule strongly stabilized and accelerated G-quadruplex formation in both Na+ and K+ ion-containing solution, although only K+ promoted the formation of perfectly aligned tetra-molecular G-quadruplexes. The small-molecule complex with the d(TG4T) quadruplex is discrete and approximately globular, whereas the G-quadruplex complex with poly(G) is formed at a number of points along the length of the polynucleotide, analogous to beads on a string.Financial support from Fundação para a Ciência e Tecnologia (FCT), Grant SFRH/BPD/92726/2013 (A.-M. Chiorcea-Paquim), Project Grant (A.D.R. Pontinha), projects PTDC/SAU-BMA/118531/2010, PTDC/QEQ-MED/0586/2012, PEst-C/EME /UI0285/2013 and CENTRO-07-0224-FEDER-002001 (MT4MOBI) (co-financed by the European Community Fund FEDER), FEDER funds through the program COMPETE - Programa Operacional Factores de Competitividade is gratefully acknowledged. Work in the S.N. laboratory was supported by Programme Grant No. C129/A4489, from Cancer Research UK, and by the FP6 framework grant “Molecular Cancer Medicine” from the EU. S.S. was a Maplethorpe Fellow of The University of London.Peer reviewe

Highly prevalent putative quadruplex sequence motifs in human DNA

We report here the results of a systematic search for the existence and prevalence of potential intramolecular G-quadruplex forming sequences in the human genome. We have also examined the tendency for particular sequences of ‘loop’ regions to occur in particular positions with respect to the G-tracts in a quadruplex. Using arithmetic ratio and probability techniques we have discovered frequent and systematic occurrence of certain sequence types, the most prominent being a potential quadruplex containing CCTGT in the first ‘loop’ position. Being able to highlight types of potential quadruplex sequences in G-rich regions is an important step in searching for biologically relevant sequences and finding their function

QN-302 demonstrates opposing effects between i-motif and G-quadruplex DNA structures in the promoter of the S100P gene

GC-rich sequences can fold into G-quadruplexes and i-motifs and are known to control gene expression in many organisms. The potent G-quadruplex experimental anticancer drug QN-302 down-regulates a number of cancer-related genes, in particular S100P. Here we show this ligand has strong opposing effects with i-motif DNA structures and is one of the most potent i-motif destabilising agents reported to date. QN-302 down-regulates the expression of numerous cancer-related genes by pan-quadruplex targeting. QN-302 exhibits exceptional combined synergistic effects compared to many other G-quadruplex and i-motif interacting compounds. This work further emphasises the importance of considering G-quadruplex and i-motif DNA structures as one dynamic system

Comment on MaaniHessari, N.; van Schalkwyk, M.C.; Thomas, S.; Petticrew, M. Alcohol Industry CSR Organisations:What Can Their Twitter Activity Tell Us about Their Independence and Their Priorities? A Comparative Analysis. Int. J. Environ. Res. Public Health 2019, 16, 892

We noted with concern that you published recently (12 March 2019) an article about so-called &ldquo;Alcohol industry CSR Organisations&rdquo;, which selectively targets criticism of Drinkaware [...

Synthesis, characterisation and photochemistry of PtIV pyridyl azido acetato complexes

PtII azido complexes [Pt(bpy)(N3)2] (1), [Pt(phen)(N3)2] (2) and trans-[Pt(N3)2(py)2] (3) incorporating the bidentate diimine ligands 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N3–Pt–N3 angle 146.7°) as a result of steric congestion at the Pt centre. The novel PtIV complexes trans, cis-[Pt(bpy)(OAc)2(N3)2] (4), trans, cis-[Pt(phen)(OAc)2(N3)2] (5), trans, trans, trans-[Pt(OAc)2(N3)2(py)2] (6), were obtained from 1–3via oxidation with H2O2 in acetic acid followed by reaction of the intermediate with acetic anhydride. Complexes 4–6 exhibit interesting structural and photochemical properties that were studied by X-ray, NMR and UV-vis spectroscopy and TD-DFT (time-dependent density functional theory). These PtIV complexes exhibit greater absorption at longer wavelengths (ε = 9756 M−1 cm−1 at 315 nm for 4; ε = 796 M−1 cm−1 at 352 nm for 5; ε = 16900 M−1 cm−1 at 307 nm for 6, in aqueous solution) than previously reported PtIV azide complexes, due to the presence of aromatic amines, and 4–6 undergo photoactivation with both UVA (365 nm) and visible green light (514 nm). The UV-vis spectra of complexes 4–6 were calculated using TD-DFT; the nature of the transitions contributing to the UV-vis bands provide insight into the mechanism of production of the observed photoproducts. The UV-vis spectra of 1–3 were also simulated by computational methods and comparison between PtII and PtIV electronic and structural properties allowed further elucidation of the photochemistry of 4–6