| 1. |
- Lagerlund, Olof, et al.
(författare)
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Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
- 2009
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 65:36, s. 7646-7652
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Tidskriftsartikel (refereegranskat)abstract
- Palladium-catalyzed aminocarbonylations of alkenyl chlorides, bromides, and triflates were investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded moderate to good yields producing a wide variety of acrylamides after 20 minutes of microwave irradiation. In addition, the aminocarbonylation reaction was, for the first time, expanded to include alkenyl phosphates as starting materials.
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| 2. |
- Lagerlund, Olof
(författare)
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Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed. A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS. A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized. The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.
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| 3. |
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| 4. |
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| 5. |
- 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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| 6. |
- Odell, Luke R., et al.
(författare)
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Functionalized 3-amino-imidazo[1,2-a]pyridines : A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:16, s. 4790-4793
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Tidskriftsartikel (refereegranskat)abstract
- 3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.
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| 7. |
- Salvigsen, Otto, et al.
(författare)
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Glacial history and shoreline displacement on Erdmannflya and Bohemanflya, Spitsbergen, Svalbard
- 1990
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Ingår i: Polar Research. - 0800-0395 .- 1751-8369. ; 8:2, s. 261-273
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Tidskriftsartikel (refereegranskat)abstract
- Traces of former glaciation were studied on Erdmannflya and Bohemanflya. Both peninsulas were probably completely covered by glaciers during the Late Weichselian and the final deglaciation took place around 10,000 C-14 years BP. Esmarkbreen readvanced shortly after 9,500 BP, probably a local and shortlasting event. Raised beaches occur to about 60 m above sea level, and date back to about 10,000 BP. Initial land emergence was rapid, about 3m/100 years. It seems to have been followed by a marine transgression between 8,500 and 7,500 BP, which resulted in a large and distinct beach bridge and marine abrasion cliffs about 10-12 m above present sea level. Mytilus edulis lived in the area between at least 9,000 and 5,000 BP. Five thousand years ago relative sea level probably stood 3-4 m higher than today. Relative sea level has remained close to present during the last centuries. Different positions of glacier fronts in this century have also been mapped.
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