| 1. |
- Blunden, Jessica, et al.
(författare)
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State of the Climate in 2012
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Tidskriftsartikel (refereegranskat)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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| 2. |
- Blunden, Jessica, et al.
(författare)
-
State of the climate in 2013
- 2014
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Ingår i: Bulletin of the American Meteorological Society. - 0003-0007. ; 95
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Tidskriftsartikel (refereegranskat)abstract
- © 2014, American Meteorological Society. All rights reserved. In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earth’s surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series.
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| 3. |
- Wang, Haidong, et al.
(författare)
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Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013
- 2014
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 384:9947, s. 957-979
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
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| 4. |
- Franke, Andre, et al.
(författare)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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| 5. |
- Gising, Johan, et al.
(författare)
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Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:6, s. 2894-2898
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.
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| 6. |
- Nordqvist, Anneli, et al.
(författare)
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Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2012
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 620-626
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Tidskriftsartikel (refereegranskat)abstract
- Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.
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| 7. |
- Ofer, O., et al.
(författare)
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Absolute value and temperature dependence of the magnetic penetration depth in Ba(Co 0.074Fe 0.926) 2As 2
- 2012
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 85:6, s. 060506-
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Tidskriftsartikel (refereegranskat)abstract
- The absolute value and temperature dependence of the in-plane magnetic penetration depth lambda have been measured on a single crystal of Ba(Co0.074Fe0.926)(2)As-2 using low-energy muon-spin rotation and microwave cavity perturbation. The magnetic field profiles in the Meissner state are consistent with a local London model beyond a depth of 15 nm. We determine the gap symmetry through measurements of the temperature dependence of the superfluid density which follows a two-gap s-wave model over the entire temperature range below T-c. While the intermediate to high temperature data is well fit by an energy gap model in the BCS-like (weak-coupling) limit, a second smaller gap becomes apparent at low temperatures.
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| 8. |
- Rydfjord, Jonas, et al.
(författare)
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Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids : Development and Mechanistic Investigation
- 2013
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:41, s. 13803-13810
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Tidskriftsartikel (refereegranskat)abstract
- A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).
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| 9. |
- Beranek, Luke P., et al.
(författare)
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Detrital zircon Hf isotopic compositions indicate a northern Caledonian connection for the Alexander terrane
- 2013
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Ingår i: Lithosphere. - 1941-8264 .- 1947-4253. ; 5:2, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Various plate reconstructions predict that the Alexander terrane, a Neoproterozoic-Jurassic crustal fragment now located in the North American Cordillera, evolved in proximity to the northern Appalachian-Caledonian convergent margin during assembly of supercontinent Laurussia. To test stratigraphic connections with Laurussia that are implied by these plate reconstructions, we measured the Hf isotopic compositions of 176 detrital zircons from two relevant sedimentary sequences of the Alexander terrane. An older, Upper Silurian-Lower Devonian terrestrial to shallow-marine molasse sequence yields 405-490 Ma detrital zircons with negative epsilon(Hf(t)) values and Mesoproterozoic to Paleoproterozoic Hf model ages. In combination with paleomagnetic and biogeographic constraints, these Hf data argue for the molasse strata to be now-displaced equivalents of the Old Red Sandstone and primarily sourced from crustally contaminated granitoids in the Greenland, Svalbard, or British Caledonides. Late Silurian-Early Devonian orogenesis in the Alexander terrane is therefore likely related to the Scandian-Salinic phase of Appalachian-Caledonian mountain building. Younger, Middle Devonian sequences of the Alexander terrane are endowed in 390-490 Ma detrital zircons with positive epsilon(Hf(t)) values and Neoproterozoic Hf model ages. These isotopic signatures are consistent with the erosion of local basement rocks during the opening of the Slide Mountain-Angayucham backarc rift and tectonic separation of the Alexander terrane from northern Laurussia.
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| 10. |
- De Rosa, Maria, et al.
(författare)
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Syntheses of new tuberculosis inhibitors promoted by microwave irradiation
- 2014
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 119:2, s. 181-191
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Forskningsöversikt (refereegranskat)abstract
- Tuberculosis (TB) represents a major public health problem. The growing number of (extensively) multi-drug resistance cases indicates that there is an urgent need for discovery of new anti-TB entities, addressed towards new and specific targets, and continuous development of fast and efficient synthetic strategies to access them easily. Microwave-assisted chemistry is well suited for small-scale laboratory synthetic work, allowing full control of reaction conditions, such as temperature, pressure, and time. Microwave-assisted high-speed organic synthesis is especially useful in the lead optimization phase of drug discovery. To illustrate the advantages of modern microwave heating technology, we herein describe applications and approaches that have been useful for the synthesis of new drug-like anti-TB compounds.
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| 11. |
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| 12. |
- Finn, Robert D., et al.
(författare)
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The Pfam protein families database
- 2010
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 38, s. d211-d222
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Tidskriftsartikel (refereegranskat)abstract
- Pfam is a widely used database of protein families and domains. This article describes a set of major updates that we have implemented in the latest release (version 24.0). The most important change is that we now use HMMER3, the latest version of the popular profile hidden Markov model package. This software is similar to 100 times faster than HMMER2 and is more sensitive due to the routine use of the forward algorithm. The move to HMMER3 has necessitated numerous changes to Pfam that are described in detail. Pfam release 24.0 contains 11 912 families, of which a large number have been significantly updated during the past two years. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/).
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| 13. |
- Gising, Johan, et al.
(författare)
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Microwave-assisted synthesis of anti-tuberculosis, HIV and hepatitis C agents
- 2014
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Ingår i: Microwaves in Drug Discovery and Development. - Unitec House, 2 Albert Place, London N3 1QB, UK : Future Medicine. - 9781910419298 - 9781910419311 ; , s. 34-54
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Bokkapitel (refereegranskat)abstract
- Microwave heating technology is ideally suited to small-scale discovery chemistry applications, as it allows for full reaction control, rapid (super)heating, short reaction times, high safety and rapid feedback. These unique properties offer unparalleled opportunities for medicinal chemists to speed up the lead optimization process in early drug discovery. To illustrate these advantages, we herein describe a number of recent applications of dedicated microwave instrumentation in the synthesis of small molecules targeting three of the most prevalent infectious diseases: tuberculosis, HIV/AIDS and hepatitis C.
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| 14. |
- Gising, Johan, et al.
(författare)
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Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C
- 2012
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 10:14, s. 2713-2729
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Tidskriftsartikel (refereegranskat)abstract
- The unique properties of microwave in situ heating offer unparalleled opportunities for medicinal chemists to speed up lead optimisation processes in early drug discovery. The technology is ideal for small-scale discovery chemistry because it allows full reaction control, short reaction times, high safety and rapid feedback. To illustrate these advantages, we herein describe applications and approaches in the synthesis of small molecules to combat four of the most prevalent infectious diseases; tuberculosis, HIV/AIDS, malaria and hepatitis C, using dedicated microwave instrumentation.
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| 15. |
- Gliganic, Luke A., et al.
(författare)
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Late-Holocene climatic variability indicated by three natural archives in arid southern Australia
- 2014
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 24:1, s. 104-117
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Tidskriftsartikel (refereegranskat)abstract
- Three terrestrial climate proxies are used to investigate the evolution of Holocene palaeoenvironments in southern central Australia, all of which present a coherent record of palaeohydrology. Single-grain optically stimulated luminescence from sediments supplemented by C-14 from charcoal and lacustrine shells was obtained to date shoreline deposits (Lake Callabonna) and the adjacent Mt Chambers Creek alluvial fan. Our findings are complemented by a U/Th-based record of speleothem growth in the Mt Chambers Creek catchment, which we interpret to reflect increased precipitation. Together, these archives shed light on the timing of, and possible sources of water for, Holocene pluvial intervals. We identified several phases of elevated lake levels dated at similar to 5.8-5.2, 4.5, 3.5-2.7 and 1 kyr, most of which correspond to fluvial activity resulting from increased precipitation in the adjacent ranges. The enhanced hydrology during phases of the late Holocene likely increased the reliability of resources for regional human populations during a time of reduced winter rainfall. When considered within the framework of the current understanding of Holocene palaeoclimate in central Australia, our data suggest that the pattern of landscape response was broadly synchronous with larger scale climatic variability and punctuated by pluvial periods greater than today.
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| 16. |
- Helmfors, Linda, 1983-
(författare)
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Understanding the dual nature of lysozyme: part villain – part hero : A Drosophila melanogaster model of lysozyme amyloidosis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloid proteins are a distinct class of proteins that can misfold into β-sheet rich structures that later mature to form the characteristic species known as amyloid fibrils, and accumulate in tissues in the human body. The misfolding event is often caused by mutations (or outer factors such as changes in pH) that destabilize the native protein structure. The mature amyloid fibrils were initially believed to be associated with diseases connected to protein misfolding such as Alzheimer’s disease (AD), Parkinson’s disease, transthyretin amyloidosis and lysozyme amyloidosis. However, now it is known that many different factors are involved in these diseases such as failure in protein clearance, lysosomal dysfunction and formation of intermediate misfolded protein species, which possess cytotoxic properties, preceding the formation of mature fibrils.In this thesis the amyloidogenic protein lysozyme has been examined in vivo by using Drosophila melanogaster (fruit fly) as a model organism. The effects of over-expressing human lysozyme and amyloidogenic variants in Drosophila have been investigated both in the absence and presence of the serum amyloid P component (SAP), a protein known to interact with amyloid species. In addition, the role of lysozyme in AD has been investigated by co-expressing human lysozyme and amyloid β in Drosophila.The lysozyme protein is an enzyme naturally found in bodily fluids such as tears, breast milk and saliva. It is engaged in the body’s defense and acts by hydrolyzing the cell wall of invading bacteria. Certain disease-associated point mutations in the gene encoding lysozyme destabilize the protein and cause it to misfold which results in systemic amyloidosis. To investigate the in vivo misfolding behavior of lysozyme we developed and established a Drosophila model of lysozyme amyloidosis. SAP is commonly found attached to amyloid deposits in the body; however, the role of SAP in amyloid diseases is unknown. To investigate the effect of SAP in lysozyme misfolding, these two proteins were co-expressed in Drosophila.The amyloid β peptide is involved in AD, building up the plaques found in AD patient brains. These plaques trigger neuroinflammation and since lysozyme is upregulated during various inflammation conditions, a possible role of lysozyme in AD was investigated by overexpressing lysozyme in a Drosophila model of AD. Interaction between lysozyme and the amyloid β protein was also studied by biophysical measurements.During my work with this thesis, the dual nature of lysozyme emerged; on the one hand a villain, twisted by mutations, causing the lysozyme amyloidosis disease. On the other hand a hero, delaying the toxicity and maybe the neurological damage caused by the amyloid β peptide.
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| 17. |
- Hill, Timothy A., et al.
(författare)
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Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:10, s. 4094-4102
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (14−38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC50 values of 260 nM to 100 μM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC50 values of 330 ± 70, 450 ± 50, and 260 ± 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC50 values of 10.7 ± 4.5 and 99.5 ± 1.7 μM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.
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| 18. |
- Kara, Emily L., et al.
(författare)
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Time-scale dependence in numerical simulations : Assessment of physical, chemical, and biological predictions in a stratified lake at temporal scales of hours to months
- 2012
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Ingår i: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 35, s. 104-121
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the predictive ability of a one-dimensional coupled hydrodynamic-biogeochemical model across multiple temporal scales using wavelet analysis and traditional goodness-of-fit metrics. High-frequency in situ automated sensor data and long-term manual observational data from Lake Mendota, Wisconsin, USA, were used to parameterize, calibrate, and evaluate model predictions. We focused specifically on short-term predictions of temperature, dissolved oxygen, and phytoplankton biomass over one season. Traditional goodness-of-fit metrics indicated more accurate prediction of physics than chemical or biological variables in the time domain. This was confirmed by wavelet analysis in both the time and frequency domains. For temperature, predicted and observed global wavelet spectra were closely related, while observed dissolved oxygen and chlorophyll fluorescence spectral characteristics were not reproduced by the model for key time scales, indicating that processes not modeled may be important drivers of the observed signal. Although the magnitude and timing of physical and biological changes were simulated adequately at the seasonal time scale through calibration, time scale-specific dynamics, for example short-term cycles, were difficult to reproduce, and were relatively insensitive to the effects of varying parameters. The use of wavelet analysis is novel to aquatic ecosystem modeling, is complementary to traditional goodness-of-fit metrics, and allows for assessment of variability at specific temporal scales. In this way, the effect of processes operating at distinct temporal scales can be isolated and better understood, both in situ and in silico. Wavelet transforms are particularly well suited for assessment of temporal and spatial heterogeneity when coupled to high-frequency data from automated in situ or remote sensing platforms.
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| 19. |
- MacGregor, Kylie A, et al.
(författare)
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Development of quinone analogues as dynamin GTPase inhibitors
- 2014
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 85, s. 191-206
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Tidskriftsartikel (refereegranskat)abstract
- Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.
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| 20. |
- Mane, Rajendra S, et al.
(författare)
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Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
- 2013
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Ingår i: Tetrahedron Letters. - : Elsevier BV. - 0040-4039 .- 1359-8562. ; 54:50, s. 6912-6915
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Tidskriftsartikel (refereegranskat)abstract
- A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.
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| 21. |
- McGeachie, Andrew B, et al.
(författare)
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Pyrimidyn Compounds : Dual-Action Small Molecule Pyrimidine-Based Dynamin Inhibitors
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 8:7, s. 1507-1518
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Tidskriftsartikel (refereegranskat)abstract
- Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based "Pyrimidyn" compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin's role in endocytosis.
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| 22. |
- Motwani, Hitesh V., et al.
(författare)
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Aspartic protease inhibitors containing tertiary alcohol transition-state mimics
- 2014
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 90, s. 462-490
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Forskningsöversikt (refereegranskat)abstract
- Aspartic proteases (APs) are a class of enzymes engaged in the proteolytic digestion of peptide substrates. APs play important roles in physiological and infectious pathways, making them plausible drug targets. For instance in the treatment of HIV infections, access to an efficient combination of protease and reverse transcriptase inhibitors have changed a terminal illness to a chronic but manageable disease. However, the benefits have been limited due to the emergence of drug resistant viral strains, poor pharmacokinetic properties of peptidomimetic inhibitors and adverse effects associated with the treatment. In the 1980s, D. Rich and co-workers proposed a novel strategy for the development of AP inhibitors by replacing the secondary hydroxyl group with a tertiary alcohol as part of the transition state (TS) mimicking moiety. This strategy has been extensively explored over the last decade with a common belief that masking of the polar group, e.g. by intramolecular hydrogen bonding, has the potential to enhance transcellular transport. This is the first review presenting the advances of AP inhibitors comprising a tertiary hydroxyl group. The inhibitors have been classified into different tert-hydroxy TS mimics and their design strategies, synthesis, biological activities, structure-activity-relationships and X-ray structures are discussed.
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| 23. |
- Mowbray, Sherry L, et al.
(författare)
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Inhibition of Glutamine Synthetase : A Potential Drug Target in Mycobacterium tuberculosis
- 2014
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 19:9, s. 13161-13176
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Forskningsöversikt (refereegranskat)abstract
- Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.
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| 24. |
- Nordeman, Patrik, et al.
(författare)
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11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
- 2014
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 41:6, s. 536-543
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.
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| 25. |
- Nordeman, Patrik, et al.
(författare)
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Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System : Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
- 2012
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:24, s. 11393-11398
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Tidskriftsartikel (refereegranskat)abstract
- A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.
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| 26. |
- Nordeman, Patrik
(författare)
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Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.
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| 27. |
- Odell, Adam F, et al.
(författare)
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A Novel p53 Mutant Found in Iatrogenic Urothelial Cancers Is Dysfunctional and Can Be Rescued by a Second-site Global Suppressor Mutation
- 2013
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:23, s. 16704-16714
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to herbal remedies containing the carcinogen aristolochic acid (AA) has been widespread in some regions of the world. Rare A→T TP53 mutations were recently discovered in AA-associated urothelial cancers. The near absence of these mutations among all other sequenced human tumors suggests that they could be biologically silent. There are no cell banks with established lines derived from human tumors with which to explore the influence of the novel mutants on p53 function and cellular behavior. To investigate their impact, we generated isogenic mutant clones by integrase-mediated cassette exchange at the p53 locus of platform (null) murine embryonic fibroblasts and kidney epithelial cells. Common tumor mutants (R248W, R273C) were compared with the AA-associated mutants N131Y, R249W, and Q104L. Assays of cell proliferation, migration, growth in soft agar, apoptosis, senescence, and gene expression revealed contrasting outcomes on cellular behavior following introduction of N131Y or Q104L. The N131Y mutant demonstrated a phenotype akin to common tumor mutants, whereas Q104L clone behavior resembled that of cells with wild-type p53. Wild-type p53 responses were restored in double-mutant cells harboring N131Y and N239Y, a second-site rescue mutation, suggesting that pharmaceutical reactivation of p53 function in tumors expressing N131Y could have therapeutic benefit. N131Y is likely to contribute directly to tumor phenotype and is a promising candidate biomarker of AA exposure and disease. Rare mutations thus do not necessarily point to sites where amino acid exchanges are phenotypically neutral. Encounter with mutagenic insults targeting cryptic sites can reveal specific signature hotspots.
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| 28. |
- Odell, Luke R., et al.
(författare)
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Continuous Flow Palladium(II) : Catalyzed Oxidative Heck Reactions with Arylboronic Acids
- 2010
-
Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :12, s. 2270-2274
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Tidskriftsartikel (refereegranskat)abstract
- Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.
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| 29. |
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| 30. |
- Odell, Luke R., et al.
(författare)
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Molybdenum Hexacarbonyl Mediated CO Gas-Free Carbonylative Reactions
- 2012
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Ingår i: Synlett. - : Georg Thieme Verlag KG. - 0936-5214 .- 1437-2096. ; :5, s. 685-698
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Tidskriftsartikel (refereegranskat)abstract
- This Account summarizes predominately our own experiences in developing microwave-heated palladium-catalyzed Mo(CO)6-mediated gas-free carbonylative reactions, although contributions from other groups, including non-palladium-catalyzed examples, have also been covered. Presented reactions include amino-, amido-, and alkoxycarbonylations as well as carbonylative cyclizations and carbonylative cross-couplings, using Mo(CO)6 as a solid source of CO. The methodology was developed mainly for rapid small-scale applications, avoiding the problematic use of gaseous CO in a standard laboratory. In most cases, the reported Mo(CO)6-mediated carbonylations were conducted in sealed vessels and with reaction times of less than 1 hour. The Account also highlights relevant applications in medicinal and high-speed chemistry.
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| 31. |
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| 32. |
- Odell, Luke R, et al.
(författare)
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The Pthaladyns : GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening
- 2010
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:14, s. 5267-5280
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Tidskriftsartikel (refereegranskat)abstract
- We report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a 170 μM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the “pthaladyns”) with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.58 ± 0.06 μM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II (5−10 fold). Only pthaladyn-23 (dynamin I IC50 17.4 ± 5.8 μM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC50 of 12.9 ± 5.9 μM. This compound was also competitive with respect to Mg2+·GTP. Thus the pthaladyns are the first GTP competitive inhibitors of dynamin I and II GTPase and may be effective new tools for the study of neuronal endocytosis.
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| 33. |
- Rendell, Luke, et al.
(författare)
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Why copy others? Insights from the social learning tournament
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 328:5975, s. 208-213
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Tidskriftsartikel (refereegranskat)abstract
- Social learning (learning through observation or interaction with other individuals) is widespread in nature and is central to the remarkable success of humanity, yet it remains unclear why copying is profitable and how to copy most effectively. To address these questions, we organized a computer tournament in which entrants submitted strategies specifying how to use social learning and its asocial alternative (for example, trial-and-error learning) to acquire adaptive behavior in a complex environment. Most current theory predicts the emergence of mixed strategies that rely on some combination of the two types of learning. In the tournament, however, strategies that relied heavily on social learning were found to be remarkably successful, even when asocial information was no more costly than social information. Social learning proved advantageous because individuals frequently demonstrated the highest-payoff behavior in their repertoire, inadvertently filtering information for copiers. The winning strategy (discountmachine) relied nearly exclusively on social learning and weighted information according to the time since acquisition.
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| 34. |
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| 35. |
- Sawant, Rajiv T., et al.
(författare)
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Organocatalytic asymmetric cross-aldol reaction of 2-chloroethoxy acetaldehyde : diversity-oriented synthesis of chiral substituted 1,4-dioxanes and morpholines
- 2013
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Ingår i: Tetrahedron. - : Elsevier BV. - 0957-4166 .- 1362-511X. ; 24:2-3, s. 134-141
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report a facile organocatalytic asymmetric direct cross-aldol reaction of 2-chloroethoxy acetaldehyde with aromatic aldehydes using (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol as an organocatalyst to afford anti-2-(2-chloroethoxy)-1-arylpropane-1,3-diols with excellent enantioselectivities (95-98%) and moderate diastereoselectivities (3.5-7:1). The 1,3-diols, obtained after the aldehyde reduction, represent highly functional intermediates that allow for further diversification into both chiral 1,4-dioxanes and morpholines, compounds that frequently display interesting biological activities.
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| 36. |
- Sköld, Christian, et al.
(författare)
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Transmetallation Versus β-Hydride Elimination : The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
- 2012
-
Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 18:15, s. 4714-4722
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Tidskriftsartikel (refereegranskat)abstract
- The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.
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| 37. |
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| 38. |
- Sävmarker, Jonas, 1979-, et al.
(författare)
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Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
- 2012
-
Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 14:9, s. 2394-2397
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Tidskriftsartikel (refereegranskat)abstract
- A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.
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| 39. |
- Trejos, Alejandro, et al.
(författare)
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Alkenes with Metal-Directing Groups as Reaction Components
- 2013
-
Ingår i: <em>Science of Synthesis:</em> <em>Cross-Coupling and Heck-Type Reactions, Volume 3, Metal-Catalyzed Heck-Type Reactions and C-C Cross Coupling via C–H Activation</em>. - Stuttgart : Georg Thieme Verlag KG. - 9783131734112 ; , s. 345-390
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Bokkapitel (refereegranskat)
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| 40. |
- Trejos, Alejandro, et al.
(författare)
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Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
- 2012
-
Ingår i: ChemistryOpen. - : Wiley-VCH Verlagsgesellschaft. - 2191-1363. ; 1:1, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.
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| 41. |
- Veron, Jean-Baptiste, et al.
(författare)
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Synthesis and evaluation of isoleucine derived angiotensin II AT(2) receptor ligands
- 2014
-
Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 24:2, s. 476-479
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Tidskriftsartikel (refereegranskat)abstract
- Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT(2)R ligand, were designed, synthesized and evaluated for their affinity to the AT(2)R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, K-i = 8.5 mu M) was over 12-times more potent than the lead compound 2.
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| 42. |
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| 43. |
- Wilder-Smith, Annelies, et al.
(författare)
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DengueTools : innovative tools and strategies for the surveillance and control of dengue
- 2012
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Ingår i: Global Health Action. - Järfälla : CoAction Publishing. - 1654-9716 .- 1654-9880. ; 5, s. 17273-
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Tidskriftsartikel (refereegranskat)abstract
- Dengue fever is a mosquito-borne viral disease estimated to cause about 230 million infections worldwide every year, of which 25,000 are fatal. Global incidence has risen rapidly in recent decades with some 3.6 billion people, over half of the world's population, now at risk, mainly in urban centres of the tropics and subtropics. Demographic and societal changes, in particular urbanization, globalization, and increased international travel, are major contributors to the rise in incidence and geographic expansion of dengue infections. Major research gaps continue to hamper the control of dengue. The European Commission launched a call under the 7th Framework Programme with the title of 'Comprehensive control of Dengue fever under changing climatic conditions'. Fourteen partners from several countries in Europe, Asia, and South America formed a consortium named 'DengueTools' to respond to the call to achieve better diagnosis, surveillance, prevention, and predictive models and improve our understanding of the spread of dengue to previously uninfected regions (including Europe) in the context of globalization and climate change. The consortium comprises 12 work packages to address a set of research questions in three areas: Research area 1: Develop a comprehensive early warning and surveillance system that has predictive capability for epidemic dengue and benefits from novel tools for laboratory diagnosis and vector monitoring. Research area 2: Develop novel strategies to prevent dengue in children. Research area 3: Understand and predict the risk of global spread of dengue, in particular the risk of introduction and establishment in Europe, within the context of parameters of vectorial capacity, global mobility, and climate change. In this paper, we report on the rationale and specific study objectives of 'DengueTools'. DengueTools is funded under the Health theme of the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 Dengue Tools.
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