ORCID Profile
0000-0003-4090-3960
Current Organisation
University of Nottingham
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2019
DOI: 10.1101/602474
Abstract: Multiscale Genomics (MuG) Virtual Research Environment (MuGVRE) is a cloud-based computational infrastructure created to support the deployment of software tools addressing the various levels of analysis in 3D/4D genomics. Integrated tools tackle needs ranging from high computationally demanding applications (e.g. molecular dynamics simulations) to high-throughput data analysis applications (like the processing of next generation sequencing). The MuG Infrastructure is based on openNebula cloud systems implemented at the Institute for research in Biomedicine, and the Barcelona Supercomputing Center, and has specific interfaces for users and developers. Interoperability of the tools included in MuGVRE is maintained through a rich set of metadata allowing the system to associate tools and data in a transparent manner. Execution scheduling is based in a traditional queueing system to handle demand peaks in applications of fixed needs, and an elastic and multi-scale programming model (pyCOMPSs, controlled by the PMES scheduler), for complex workflows requiring distributed or multi-scale executions schemes. MuGVRE is available at vre.multiscalegenomics.eu and documentation and general information at www.multiscalegenomics.eu . The infrastructure is open and freely accessible.
Publisher: Informa UK Limited
Date: 08-2004
DOI: 10.1080/00498250400003463
Abstract: 1. The O-dealkylation of 7-alkoxycoumarins is widely used as an assay to characterize cytochrome P450 (CYP) activity. These substrates can also undergo oxidative attack at additional sites on the coumarin nucleus, which may influence their apparent selectivity for particular CYP forms. 2. Accordingly, the effect of blockade of these additional sites was investigated on the selectivity towards rat hepatic CYP forms, with emphasis on the CYP1A and 2B forms. 3. Blockade of the 3-/4- and 6-positions resulted in substrates for which the CYP1A1/2 selectivity of the unsubstituted 7-alkoxycoumarins was altered to a CYP2B selectivity this was achieved with little overall change in the molecular dimensions of the substrate. Limited analysis of other inducible CYP forms indicated at most only small effects of structure modification on activity. 4. The findings suggest that the sensitivity of probe substrates for CYP forms may be limited by the occurrence of competing side reactions of the substrate, and that better probes may be derived by blocking the sites of these side reactions.
Publisher: American Chemical Society (ACS)
Date: 07-03-2023
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-10-2015
Abstract: ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL-77 displays potent growth inhibitory activity in vitro (GI50 < 1μM against HCT-116 cells), demonstrating 3- to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Charles Laughton.