Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

YesThe duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation in solid phase synthesis. The synthesis was performed on a large scale and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers. Application to solid phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine but this had no beneficial effects on biological activity.MJS was funded by Novartis and UEA. We thank the EPSRC Mass Spectrometry Service, Swansea. We thank Richard Robinson and Julia Hatto at Novartis for help in the large scale synthesis

Intramolecular thermal stepwise [2 + 2] cycloadditions: investigation of a stereoselective synthesis of [n.2.0]-bicyclolactones

YesFused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity.The work was funded by Yorkshire Cancer Researc

Understanding causality and uncertainty in volcanic observations: an example of forecasting eruptive activity on Soufrière Hills Volcano, Montserrat

Following a cessation in eruptive activity it is important to understand how a volcano will behave in the future and when it may next erupt. Such an assessment can be based on the volcano's long-term pattern of behaviour and insights into its current state via monitoring observations. We present a Bayesian network that integrates these two strands of evidence to forecast future eruptive scenarios using expert elicitation. The Bayesian approach provides a framework to quantify the magmatic causes in terms of volcanic effects (i.e., eruption and unrest). In October 2013, an expert elicitation was performed to populate a Bayesian network designed to help forecast future eruptive (in-)activity at Soufrière Hills Volcano. The Bayesian network was devised to assess the state of the shallow magmatic system, as a means to forecast the future eruptive activity in the context of the long-term behaviour at similar dome-building volcanoes. The findings highlight coherence amongst experts when interpreting the current behaviour of the volcano, but reveal considerable ambiguity when relating this to longer patterns of volcanism at dome-building volcanoes, as a class. By asking questions in terms of magmatic causes, the Bayesian approach highlights the importance of using short-term unrest indicators from monitoring data as evidence in long-term forecasts at volcanoes. Furthermore, it highlights potential biases in the judgements of volcanologists and identifies sources of uncertainty in terms of magmatic causes rather than scenario-based outcomes

The impact of nature on children’s wellbeing

Engaging with nature has been found to be associated with various benefits, including benefits for physical health and self-reported well-being (e.g. Rogerson, Barton, Bragg, & Pretty, 2017). However, most of the research to date has been undertaken with adults and much less is known about the benefits to children. Here we report on a project funded by The Wildlife Trusts in which we undertook research to investigate what children felt they got from participating in outdoor activities

Primary children’s views about appreciating, supporting, and learning about nature

Biology education aims to inspire interest, curiosity, and understanding about the natural world, foster children’s interests and orientations towards supporting and protecting nature, and support children towards biology-related careers (including those involving nature and animals). However, it remains less clear how these views might associate with different aspects of education and life. In order to gain new insights, 679 children in England (between 7 and 10 years old) were surveyed. The questionnaire included established measures for views about nature and learning, alongside new areas. The analysis applied predictive modelling to reveal independent associations between the children’s views. The children’s appreciation of nature and affinities towards animals were two of the strongest positive predictors of their interest in learning about nature, which was the strongest positive predictor of their aspirations towards careers involving nature or animals. Other findings highlighted the importance of nature-related activities and also children’s wider educational contexts and views. Watching nature-related media positively predicted children’s interest in learning about nature, while reading books about nature or wildlife positively predicted children’s aspirations towards careers involving nature or animals. Children’s confidence and enjoyment in their schoolwork positively predicted their appreciation of nature and also their interest in learning about nature

Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents

Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alphav beta6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery programme. Compounds 33S and 43E1 are pan alphav antagonists having ca 100 nM potency against alphav beta3, alphav beta5, alphav beta6 and alphav beta8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for alphav beta3 and alphav beta5

Synthetic efforts towards the phenyl glycosidic class of lignin-carbohydrate complex models

Within biomass as a whole, the linkages which are present have been largely identified and elucidated, one of the key types off linkages and functionalities which have been identified are lignin-carbohydrate complexes (LCC). These are the major bonding patterns found in biomass between the carbohydrate (cellulose & hemicellulose) and lignin functionalities from extracted portions of biomass. One of the main bonding patterns within LCCs is phenyl glycosidic, where the C1 of the carbohydrate is bonded through an ether bond to an aromatic ring. The synthesis of such compounds which represent extracted portions of biomass have a carbohydrate portion and therefore will allow for water solubility and negates the need for organic solvents when probing depolymerisation studies

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

A three-dimensional crustal seismic velocity model for southern California from a composite event method

We present a new crustal seismic velocity model for southern California derived from P and S arrival times from local earthquakes and explosions. To reduce the volume of data and ensure a more uniform source distribution, we compute "composite event" picks for 2597 distributed master events that include pick information for other events within spheres of 2 km radius. The approach reduces random picking error and maximizes the number of S wave picks. To constrain absolute event locations and shallow velocity structure, we also use times from controlled sources, including both refraction shots and quarries. We implement the SIMULPS tomography algorithm to obtain three-dimensional (3-D) V_p and V_p/V_s structure and hypocenter locations of the composite events. Our new velocity model in general agrees with previous studies, resolving low-velocity features at shallow depths in the basins and some high-velocity features in the midcrust. Using our velocity model and 3-D ray tracing, we relocate about 450,000 earthquakes from 1981 to 2005. We observe a weak correlation between seismic velocities and earthquake occurrence, with shallow earthquakes mostly occurring in high P velocity regions and midcrustal earthquakes occurring in low P velocity regions. In addition, most seismicity occurs in regions with relatively low V_p/V_s ratios, although aftershock sequences following large earthquakes are often an exception to this pattern