A novel evolutionary approach for the discovery of small bioactive molecules

Current approaches for the discovery of bioactive molecules tend to treat all molecules in large collections with the same significance regardless of their ultimate biological activity. Furthermore, these approaches exploit a limited palette of reliable well-working reactions, that have been optimised for the preparation of individual compounds. This thesis describes the development of a new discovery approach –Activity-Directed Synthesis. The approach aims to merge the discovery of small bioactive molecules with the emergence of a synthetic route. In this regard Activity-Directed Synthesis may be analogous with the evolution of biosynthetic pathways as is observed in Nature. For the implementation of Activity-Directed Synthesis, a well-studied chemical toolbox – metal carbenoid chemistry – that has been underutilised in bioactive molecule discovery was used. The approach was demonstrated in the discovery of novel chemotypes of small bioactive molecules that agonise the Androgen Receptor. Both intra- and intermolecular reactions were exploited in sequential rounds of carbenoid reactions which had many alternative outcomes. Three iterative rounds of screening crude reaction mixtures and design of subsequent reaction arrays enabled the rapid discovery of reactions that yielded bioactive products. Hence small-molecule modulators of the Androgen Receptor, based on scaffolds with no previously annotated activity were discovered. A total of 272 microreactions was performed in the case of intramolecular reactions and a total of 326 microreactions was performed in the case of intermolecular reactions. In the case of the intramolecular chemistry, it was demonstrated retrospectively that the approach enabled the parallel optimisation of both the structure of bioactive molecules and the routes for their synthesis. In the case of the intermolecular chemistry, it was demonstrated that non-exhaustive reaction arrays could still lead to the discovery of sub-micromolar modulators of the Androgen Receptor, greatly improving the efficiency of Activity-Directed Synthesis

Eco-biostratigraphic advances in late quaternary geochronology and palaeoclimate : the marginal Gulf of Mexico analogue

This study combines high-resolution planktonic foraminiferal eco-biostratigraphy and palaeoclimatic data from the high-sedimentation-rate core JPC-26 from the northwestern margin of the Gulf of Mexico (GoM). The eco-biozones recognized (GOMPFE1-12) being correlated with published Mg/Ca-based sea surface temperatures. This updated palaeoclimatic and stratigraphic reference record facilitates correlations with the Greenland ice core events and their climatic relationships, and also provides a solid stratigraphic framework for correlations with other palaeoclimatic and palaeoceanographic records in the circum-GOM/Caribbean region. This multidisciplinary approach underlines the utility of supporting conventional dating methodologies with different constraints, and further reveals a powerful tool for reliably correlating marine records between comparable deep-sea marginal settings and coeval sequences of this region

Activity‐directed synthesis: A flexible approach for lead generation

Activity‐directed synthesis (ADS) is a structure‐blind, functional‐driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed

A MSFD complementary approach for the assessment of pressures, knowledge and data gaps in Southern European Seas : the PERSEUS experience

PERSEUS project aims to identify the most relevant pressures exerted on the ecosystems of the Southern European Seas (SES), highlighting knowledge and data gaps that endanger the achievement of SES Good Environmental Status (GES) as mandated by the Marine Strategy Framework Directive (MSFD). A complementary approach has been adopted, by a meta-analysis of existing literature on pressure/impact/knowledge gaps summarized in tables related to the MSFD descriptors, discriminating open waters from coastal areas. A comparative assessment of the Initial Assessments (IAs) for five SES countries has been also independently performed. The comparison between meta-analysis results and IAs shows similarities for coastal areas only. Major knowledge gaps have been detected for the biodiversity, marine food web, marine litter and underwater noise descriptors. The meta-analysis also allowed the identification of additional research themes targeting research topics that are requested to the achievement of GES. 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.peer-reviewe

A Comparative Study on the Condensation Heat Transfer of R-513A as an Alternative to R-134a

This paper presents the two-phase condensation heat transfer and pressure drop characteristics of R-513A as an alternative refrigerant to R-134a in a 9.52-mm OD horizontal microfin copper tube. The test facility had a straight, horizontal test section with an active length of 2.0 m and was cooled by cold water circulated in a surrounding annular space. The annular-side heat transfer coefficients were obtained using the Wilson plot method. The average heat transfer coefficient and pressure drop data are presented at the condensation temperature of 35 °C in the range of 100–440 kg·m−2·s−1 mass flux. The test data of R-513A are compared with those of R-134a, R-1234yf, and R-1234ze(E). The average condensation heat transfer coefficients of the R-513A and R-1234ze(E) refrigerants were similar to R-134a at the lower mass flux (100~150 kg·m−2·s−1), while they were up to 10% higher than R-134a as the mass flux increased. The pressure drop of R-513A was similar to R-1234yf and 10% lower than that of R-134a at the higher mass flux. The R-1234ze(E) pressure drops were 20 % higher compared to those of R-134a at the higher mass flux

Cumulative complexity meta-metrics as an efficiency measure and predictor of PMI during synthetic route design

Functioning as a surrogate for step count, a cumulative complexity meta-metric, calculated along the longest linear sequence of a synthetic route, is demonstrated to be a useful predictor of process mass intensity (PMI). In contrast, common theoretical measures of efficiency such as ideality and convergence, in this case, were found to be of limited use. A workflow and model are presented which allow prediction of PMI from for small molecules (0.9) when applied to a test dataset and a small number of literature examples. Requiring no empirical investigation, this method provides estimates of achievable, long-term PMI for synthetic routes and can be applied at the design phase. The overall procedure has been developed to be amenable to future automation, allowing rapid application across large numbers of synthetic routes

Late Glacial Marine Transgression and Ecosystem Response in the Landlocked Elefsis Bay (Northern Saronikos Gulf, Greece)

Coastal landscapes are sensitive to changes due to the interplay between surface and submarine geological processes, climate variability, and relative sea level fluctuations. The sedimentary archives of such marginal areas record in detail the complex evolution of the paleoenvironment and the diachronic biota response. The Elefsis Bay is nowadays a landlocked shallow marine basin with restricted communication to the open Saronikos Gulf. A multi-proxy investigation of a high-resolution sediment core recovered from the deepest part of the basin offered a unique opportunity to record the paleoenvironmental and aquatic ecosystem response to climate and glacioeustatic sea level changes since the Late Glacial marine transgression. The retrieved sedimentary deposits, subjected to thorough palynological (pollen, non-pollen palynomorphs, dinoflagellates), micropaleontological (benthic foraminifera, calcareous nannoplankton, ostracods), and mollusc analyses, indicates isolation of the Elefsis Bay from the Saronikos Gulf and the occurrence of a shallow freshwater paleolake since at least 13,500 cal BP, while after 11,350 cal BP the transition towards lagoon conditions is evidenced. The marine transgression in the Elefsis Bay is dated at 7500 cal BP, marking the establishment of the modern marine realm

ROSACE: A Proposed European Design for the Copernicus Ocean Colour System Vicarious Calibration Infrastructure

International audienceThe European Copernicus programme ensures long-term delivery of high-quality, global satellite ocean colour radiometry (OCR) observations from its Sentinel-3 (S3) satellite series carrying the ocean and land colour instrument (OLCI). In particular, the S3/OLCI provides marine water leaving reflectance and derived products to the Copernicus marine environment monitoring service, CMEMS, for which data quality is of paramount importance. This is why OCR system vicarious calibration (OC-SVC), which allows uncertainties of these products to stay within required specifications, is crucial. The European organisation for the exploitation of meteorological satellites (EUMETSAT) operates the S3/OLCI marine ground segment, and envisions having an SVC infrastructure deployed and operated for the long-term. This paper describes a design for such an SVC infrastructure, named radiometry for ocean colour satellites calibration and community engagement (ROSACE), which has been submitted to Copernicus by a consortium made of three European research institutions, a National Metrology Institute, and two small-to medium-sized enterprises (SMEs). ROSACE proposes a 2-site infrastructure deployed in the Eastern and Western Mediterranean Seas, capable of delivering up to about 80 high quality matchups per year for OC-SVC of the S3/OLCI missions

Santorini volcano as a potential Martian analogue: the Balos Cove Basalts

Summarization: The interpretation of geologic processes on Mars from sparse meteorite, remote sensing and rover data is influenced by knowledge gained from well-characterized terrestrial analogues. This calls for detailed study of candidate terrestrial analogues and comparison of their observable features to those encountered on the surface of Mars. We evaluated the mineralogical, geochemical, and physical properties of the Balos cove basalts (BCB) from the island of Santorini and compared them to Martian meteorites, Mars rover surface measurements, and other verified Martian analogues obtained from the International Space Analogue Rockstore (ISAR). Twenty rock samples were collected from the Balos cove area based on their freshness, integrity, and basaltic appearance in the field. Optical microscopy of BCB revealed a pilotaxitic to trachytic texture, with olivine and clinopyroxene phenocrysts in a fine groundmass of olivine, clinopyroxene, plagioclase, magnetite, and devitrified glass. All major minerals show normal zoning, including calcic plagioclase (An 78–85 at the core and An 60–76 at the rim), augite (En 36-48 Wo 41-44 Fs 11–21 ), and olivine (Fo 74–88 ). The dominant bands in the infrared-attenuated total reflectance (IR-ATR) spectra from BCB can be assigned to olivine (~875 cm −1 ), calcic plagioclase (~1130 cm −1 ), and augite (~970 cm −1 ). The whole-rock chemical compositions and mineralogy of the BCB are similar to published analyses of typical olivine-phyric shergottites and basalts and basaltic materials analyzed in Gusev and Gale craters on Mars. BCB porosity is in the range of 7–15% and is similar to the porosities of the ISAR samples. Although no terrestrial rock is ever a perfect match to Martian compositions, the differences in mineralogy and geochemistry between BCB and some classes of Martian samples are relatively subtle and the basalts of Santorini are as close a match as other accepted Mars basalt analogues. The Santorini site offers excellent field logistics that, together with the petrology of the outcrop, makes it a valuable locality for testing and calibration deployments, field training, and other activities related to current and future Mars exploration.Παρουσιάστηκε στο: Icaru