Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren’t sufficient for long-term treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms

Mechanisms Underlying Emergence of a Sub-G1 Population of Cells in a Mutant Xenopus laevis Line Lacking AHR1α

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds. In the absence of xenobiotics, AHR also plays roles in development and physiology, including promoting cell cycle progression through the G1/S checkpoint. Unlike humans and rodents, the frog Xenopus laevis expresses two paralogous AHR proteins, AHR1α and AHR1β, the result of a genome duplication approximately 17-18 million years ago. We recently generated mutant derivatives of the XLK-WG cell line lacking a functional version of either AHR1α or AHR1β. Growth of each strain was measured using colony formation assays and the water-soluble tetrazolium (WST-8) method, each demonstrating that AHR1α-/- cells proliferate approximately 30% more slowly than wild-type or the AHR1β-/- line. To investigate a potential mechanism underlying the slow growth phenotype, cell cycle distribution of each line was determined by propidium iodide staining and flow cytometry. AHR1β-/- cells and wild-type lines exhibited similar distributions of cells in the various stages. In contrast, AHR1α-/- cells exhibited a unique sub-G1 population. This indicates breakdown of genomic DNA and suggests that this mutant line has a heightened propensity for apoptosis. We tested this hypothesis directly using two approaches: Annexin V staining with flow cytometry for fixed cells and a caspase-3/7 assay in live cells. Neither approach detected increased apoptosis in AHR1α-/- cells. We next tested the hypothesis that AHR1α-/- cells in the sub-G1 population undergo pyroptosis, a distinct pathway of programmed cell death that resembles apoptosis in the breakdown of genomic DNA. A luminescent caspase-1 inflammasome assay revealed no increased pyroptosis, even in wild-type cells treated with talabostat, resiquimod, or PAM3CSK4, inducers of the pyroptosis pathway. We tentatively conclude that the slow growth and apparent degradation of genomic DNA in AHR1α-/- mutants occurs by a unique mechanism, as yet undetermined

Metrology of Sheet Metal Distortion and Effects of Spot-Welding Sequences on Sheet Metal Distortion

Refill friction stir spot welding (RFSSW) is an emerging solid-state welding technology that demonstrates an outstanding ability to join aerospace aluminum alloys. The thermomechanical processing of RFSSW may cause variations in the workpiece in the form of distortion. This study aims to establish a metrology method for sheet metal distortion with the intent to investigate the effects of RFSSW sequences on sheet metal distortion. The approach employs a robotic metrology system and the least squares method to measure and estimate the flatness of sheet metal before RFSSW and after RFSSW. The RFSSW experimentation produces five 10-spot-weld panels with five different RFSSW sequences, whereas the RFSSW sequences are based on the common practice of making sheet metal assemblies. A panel consists of two lap-welded sheets where the top sheet, a 6013-T6 aluminum alloy, is refill friction stir spot welded onto the bottom sheet, a 2029-T8 aluminum alloy. The results suggest that RFSSW sequences do have effects on sheet metal distortion. The panel with the worst distortion has a root-mean-square error of 0.8 mm as an average deviation from the ideal flatness

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner

Ligand activation and DNA-binding dictate the outcome of glucocorticoid receptor (GR)-mediated transcriptional regulation by inducing diverse receptor conformations that interact differentially with coregulators. GR recruits many coregulators via the well-characterized AF2 interaction surface in the GR ligand-binding domain, but Lin11, Isl-1, Mec-3 (LIM) domain coregulator Hic-5 (TGFB1I1) binds to the relatively uncharacterized tau2 activation domain in the hinge region of GR. Requirement of hydrogen peroxide-inducible clone-5 (Hic-5) for glucocorticoid-regulated gene expression was defined by Hic-5 depletion and global gene-expression analysis. Hic-5 depletion selectively affected both activation and repression of GR target genes, and Hic-5 served as an on/off switch for glucocorticoid regulation of many genes. For some hormone-induced genes, Hic-5 facilitated recruitment of Mediator complex. In contrast, many genes were not regulated by glucocorticoid until Hic-5 was depleted. On these genes Hic-5 prevented GR occupancy and chromatin remodeling and thereby inhibited their hormone-dependent regulation. Transcription factor binding to genomic sites is highly variable among different cell types; Hic-5 represents an alternative mechanism for regulating transcription factor-binding site selection that could apply both within a given cell type and among different cell types. Thus, Hic-5 is a versatile coregulator that acts by multiple gene-specific mechanisms that influence genomic occupancy of GR as well transcription complex assembly