Optimization of pharmacokinetic properties by modification of a carbazole-based cannabinoid receptor subtype 2 (CB2) ligand

Recently, the development of the fluorinated PET tracer [F-18]1a for imaging of CB2 receptors in the central nervous system was reported. [F-18]1a showed high CB2 affinity and selectivity over the CB1 subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N-dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents (23a, 24a), modified hydrogenation state (26a) and enlarged fluoroalkyl substituent (13a, 13b) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a, 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b. Partial hydrogenation of the aromatic carbazole system (26a) was not tolerated by the CB2 receptor. A methylsulfonyl moiety in 6-position (24a) led to considerably reduced CB2 affinity, whereas a 6-methoxy moiety (23a) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of la resulted in fluoroisopropyl derivatives 13 with unchanged high CB2 affinity and CB2: CB1 selectivity. Compared with the fluoroethyl derivative 1a, the carbazole N-atom of the fluoroisopropyl derivative 13a (K-i(CB2) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N-oxides was not observed and N-dealkylation took place to a less amount. (C) 2017 Elsevier Masson SAS. All rights reserved.Medicinal Chemistr

Optimization of the metabolic stability of a fluorinated cannabinoid receptor subtype 2 (CB2) ligand designed for PET studies

The central CB2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [F-18]7a was reported, which shows high CB2 affinity and high selectivity over the CB1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (K-i = 7.9 nM) and the ketone 26a (K-i = 8.6 nM) displayed high CB2 affinity and CB2:CB1 selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD(7.4) value of 5.56 +/- 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification. (C) 2018 Elsevier Masson SAS. All rights reserved.Medicinal Chemistr

Climate change in the Baltic Sea region: a summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge of the effects of global warming on past and future changes in climate of the Baltic Sea region is summarised and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focuses on the atmosphere, land, cryosphere, ocean, sediments, and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in palaeo-, historical, and future regional climate research, we find that the main conclusions from earlier assessments still remain valid. However, new long-term, homogenous observational records, for example, for Scandinavian glacier inventories, sea-level-driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution, and new scenario simulations with improved models, for example, for glaciers, lake ice, and marine food web, have become available. In many cases, uncertainties can now be better estimated than before because more models were included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth system have been studied, and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication, and climate change. New datasets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal timescales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first palaeoclimate simulations regionalised for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA), and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics are dominated by tides, the Baltic Sea is characterised by brackish water, a perennial vertical stratification in the southern subbasins, and a seasonal sea ice cover in the northern subbasins

Climate Change in the Baltic Sea Region: A Summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge about the effects of global warming on past and future changes in climate of the Baltic Sea region is summarized and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focusses on the atmosphere, land, cryosphere, ocean, sediments and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in paleo-, historical and future regional climate research, we find that the main conclusions from earlier assessments remain still valid. However, new long-term, homogenous observational records, e.g. for Scandinavian glacier inventories, sea-level driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution and new scenario simulations with improved models, e.g. for glaciers, lake ice and marine food web, have become available. In many cases, uncertainties can now be better estimated than before, because more models can be included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth System have been studied and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication and climate change. New data sets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal time scales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first paleoclimate simulations regionalized for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA) and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics is dominated by tides, the Baltic Sea is characterized by brackish water, a perennial vertical stratification in the southern sub-basins and a seasonal sea ice cover in the northern sub-basins</p

Late-Stage Aromatic C–H Oxygenation

Synthetic methods for oxidative aromatic C–O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C–O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites of pharmaceuticals, and may be used directly to install a C–F bond to block metabolic hotspots. A charge-transfer interaction between the reagent bis(methanesulfonyl) peroxide and the substrate arenes may be relevant for the chemoselective functionalization of arenes over other functional groups

Condensed-Phase, Halogen-Bonded CF₃I and C₂F₅I Adducts for Perfluoroalkylation Reactions

A family of practical, liquid trifluoromethylation and pentafluoroethylation reagents is described. We show how halogen bonding can be used to obtain easily handled liquid reagents from gaseous CF3I and CF3CF2I. The synthetic utility of the new reagents is exemplified by a novel direct arene trifluoromethylation reaction as well as adaptations of other perfluoroalkylation reactions

Understanding past and future sea surface temperature trends in the Baltic Sea

The Baltic Sea is one of the fastest-warming semi-enclosed seas in the world over the last decades, yielding critical consequences on physical and biogeochemical conditions and on marine ecosystems. Although long-term trends in sea surface temperature (SST) have long been attributed to trends in air temperature, there are however, strong seasonal and sub-basin scale heterogeneities of similar magnitude than the average trend which are not fully explained. Here, using reconstructed atmospheric forcing fields for the period 1850–2008, oceanic climate simulations were performed and analyzed to identify areas of homogenous SST trends using spatial clustering. Our results show that the Baltic Sea can be divided into five different areas of homogeneous SST trends: the Bothnian Bay, the Bothnian Sea, the eastern and western Baltic proper, and the southwestern Baltic Sea. A classification tree and sensitivity experiments were carried out to analyze the main drivers behind the trends. While ice cover explains the seasonal north/south warming contrast, the changes in surface winds and air-sea temperature anomalies (along with changes in upwelling frequencies and heat fluxes) explain the SST trends differences between the sub-basins of the southern part of the Baltic Sea. To investigate future warming trends climate simulations were performed for the period 1976–2099 using two RCP scenarios. It was found that the seasonal north/south gradient of SST trends should be reduced in the future due to the vanishing of sea ice, while changes in the frequency of upwelling and heat fluxes explained the lower future east/west gradient of SST trend in fall. Finally, an ensemble of 48 climate change simulations has revealed that for a given RCP scenario the atmospheric forcing is the main source of uncertainty. Our results are useful to better understand the historical and future changes of SST in the Baltic Sea, but also in terms of marine ecosystem and public management, and could thus be used for planning sustainable coastal development

Aryl Sulfonium Salts for Site‐Selective Late‐stage Trifluoromethylation

Incorporation of the CF3 group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox‐catalyzed cross‐coupling of aryl thianthrenium salts with a copper‐based trifluoromethyl reagent, which enables a site‐selective late‐stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives