| 1. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Cyclopenta[ b]indole Derivative Inhibits Aurora B in Primary Cells
- 2020
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:51, s. 33455-33460
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Tidskriftsartikel (refereegranskat)abstract
- The Aurora family of kinases is closely involved in regulating cell division. Inhibition of Aurora A and B with small molecules is currently being investigated in clinical trials for the treatment of different cancers. It has also been evaluated as a treatment option against different autoimmune diseases in preclinical studies. Here, we present a cyclopenta[b]indole derivative capable of inhibiting Aurora B selectively in kinase assays. To evaluate the Aurora B inhibition capacity of the compound, we used a kinase IC50 assay as well as a suppression assay of proliferating primary cells. In addition, we examined if the cells had gained a phenotype characteristic for Aurora B inhibition after treatment with the compound. We found that the compound selectively inhibited Aurora B (IC50 = 1.4 μM) over Aurora A (IC50 > 30 μM). Moreover, the compound inhibited proliferating PBMCs with an IC50 = 4.2 μM, and the cells displayed reduced phosphorylation of histone H3 as well as tetraploidy, consistent with Aurora B inhibition.
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| 2. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Exploring a cascade Heck-Suzuki reaction based route to kinase inhibitors using design of experiments
- 2015
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:11, s. 3382-3392
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Tidskriftsartikel (refereegranskat)abstract
- Design of Experiments (DoE) has been used to optimize a diversity oriented palladium catalyzed cascade Heck-Suzuki reaction for the construction of 3-alkenyl substituted cyclopenta[b]indole compounds. The obtained DoE model revealed a reaction highly dependent on the ligand. Guided by the model, an optimal ligand was chosen that selectively delivered the desired products in high yields. The conditions were applicable with a variety of boronic acids and were used to synthesize a library of 3-alkenyl derivatized compounds. Focusing on inhibition of kinases relevant for combating melanoma, the library was used in an initial structure-activity survey. In line with the observed kinase inhibition, cellular studies revealed one of the more promising derivatives to inhibit cell proliferation via an apoptotic mechanism.
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| 3. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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On the photostability of scytonemin, analogues thereof and their monomeric counterparts
- 2015
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Ingår i: Photochemical and Photobiological Sciences. - : Springer Science and Business Media LLC. - 1474-9092 .- 1474-905X. ; 14:12, s. 2179-2186
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Tidskriftsartikel (refereegranskat)abstract
- As a part of their sun-protective strategy, cyanobacteria produce the natural UV-screener scytonemin. Its accumulation in the extracellular sheaths allows the bacteria to thrive in inhospitable locations highly exposed to solar radiation. Scytonemin is often referred to as photostable and has been reported to be non-fluorescent. Taken together, these properties indicate inherently fast non-radiative relaxation processes. Despite these interesting traits, the photophysics of scytonemin is as yet almost completely unexplored. In this study, we have compared the steady-state photophysics of scytonemin itself and four derivatives thereof. Furthermore, the in vitro photostability of scytonemin was studied in different solvents using a solar simulation system. Scytonemin and the investigated derivatives demonstrated a more rapid photoinduced decay in comparison with two commercial UV-screening agents. The photostability could be modulated by varying the solvent, with the protic solvent ethanol providing the most stabilizing environment.
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| 4. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin
- 2011
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Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 13:16, s. 4458-4461
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Tidskriftsartikel (refereegranskat)abstract
- The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations In Its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated In a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin.
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| 5. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors
- 2020
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:5, s. 2966-2975
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Tidskriftsartikel (refereegranskat)abstract
- Selective direct ruthenium-catalyzed semihydrogenation of diaryl alkynes to the corresponding E-alkenes has been achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands, and affords the desired products in > 99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem semihydrogenation-alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives.
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| 6. |
- Ekebergh, Andreas, 1984
(författare)
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Strategies and Methods for Synthesizing Scytonemin Analogues
- 2012
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Natural product synthesis is an exciting field of organic chemistry, directed toward constructing naturally occurring compounds, which often are both chemically complex and biologically intriguing. Scytonemin is a unique, dimeric natural product found in cyanobacteria. It is the active compound of the cyanobacterial photoprotective mechanism and is biosynthesized when the bacteria are exposed to solar radiation. Scytonemin has furthermore been proposed to have an ancient history, stretching back to the early photosynthetic life. The natural product is composed of two identical 3-benzylidene cyclopenta[b]indole-2-one moieties connected to each other at position one. Nostodione A, the little brother of scytonemin, is another natural product found in cyanobacteria. It also contains the 3-benzylidene cyclopenta[b]indole-2-one skeleton, but is not symmetrically substituted in C-1. Instead it appears as a 1,2-dione. Nostodione A has been proposed to be a biosynthetic precursor to scytonemin. Both scytonemin and nostodione A have shown anti-proliferative properties.In this project, flexible synthetic routes leading to the core skeleton of scytonemin and nostodione A have been developed. The syntheses are based on different ring closing strategies for the annulation of indoles. The commercially available indole-3-acetic acid was used to prepare a number of 3-alkynyl indoles, which thereafter were used to investigate gold- and palladium-catalyzed ring-closing reactions. Using gold in catalytic amounts gave the symmetrical, and undesired, carbazole skeleton exclusively. However, palladium catalysis could successfully be used to construct a number of derivatives containing the 3-benzylidene cyclopenta[b]indole-2-one skeleton. In paper I, we utilized the developed route for the first total synthesis of scytonemin. The dimeric structure was obtained by coupling two monomeric structures oxidatively in a biomimetic approach. In paper II, we presented the first total synthesis of nostodione A. Here, the C-1 position was functionalized by a DDQ mediated oxidation under aqueous conditions.
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| 7. |
- Ekebergh, Andreas, 1984
(författare)
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The cyanobacterial pigments scytonemin and nostodione A - Synthesis, photophysicochemical behavior and biological studies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The natural UV-screener scytonemin is found in a plethora of cyanobacterial species. Its UV-protective ability allows the bacteria to thrive in inhospitable locations exposed to intense solar radiation. Scytonemin has a dimeric structure consisting of two 1-1' linked 3-(4-hydroxybenzylidene)cyclopenta[b]indole-2-one moieties. The cyanobacterial pigment nostodione A consists of the same skeleton, but is not symmetrically appended at C-1. Instead it appears as a 1,2-dione. Both natural products have displayed attractive bioactivity, e.g. inhibition of cancer cell mitosis and in vitro reduction of kinase activity. In this study, flexible synthetic strategies leading to the 3-alkenyl-cyclopenta[b]indole-2-one skeleton have been investigated, with focus on different ring-closing methods for the annulation of indoles. In particular, statistical experimental design has been utilized to successfully optimize a cascade Heck-Suzuki reaction. Here, the cyclopentanone is fused onto the indole with the concurrent assembly of the exocyclic alkenyl moiety. The route has been employed to construct a number of 3-alkenyl-cyclopenta[b]indole-2-one containing compounds with various substituents around the exocyclic double bond. Both the total synthesis of scytonemin and of nostodione A could be completed from suitable 3-alkenyl-cyclopenta[b]indole-2-one fragments, the former via an oxidative enolate coupling of two monomers and the latter via a selective oxidation. A number of relevant derivatives were synthesized via the developed synthetic route and used to investigate the photophysicochemical properties of scytonemin. Scytonemin demonstrated a low photo-stability in organic solvents, contradictory to its reported behavior in vivo. In cyanobacterial colonies, scytonemin is located in the extra cellular polysaccharide matrix, which likely has a stabilizing effect on scytonemin.Lastly, elaboration of the 3-alkenyl-cyclopenta[b]indole-2-one skeleton into kinase inhibitors relevant for combating melanoma was pursued. The kinase inhibiting properties of 17 substances, including scytonemin and nostodione A, were studied. Activity against the clinically proven melanoma target BRAF V600E was found and the most promising compound also displayed favorable properties in cell studies.
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| 8. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Total Synthesis of Nostodione A, a Cyanobacterial Metabolite
- 2012
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Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 14:24, s. 6274-6277
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Tidskriftsartikel (refereegranskat)abstract
- The first total synthesis of the mitotic spindle poison nostodione A is described. The inherent oxidative sensitivity of indoles is utilized for a late introduction of a second carbonyl to the cyclopent[b]indole-2-one system. The tricyclic system is prepared from indole-3-acetic acid and O-silylated 4-ethynylphenol, using a stereoselective intramolecular reductive Heck cyclization as the key transformation.
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| 9. |
- Janjetovic, Mario, et al.
(författare)
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Catalytic Iodination of the Aliphatic C-F Bond by YbI3(THF)(3): Mechanistic Insight and Synthetic Utility
- 2016
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Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 18:12, s. 2804-2807
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Tidskriftsartikel (refereegranskat)abstract
- A facile iodination protocol, of unactivated alkyl fluorides: using catalytic amounts of YbI3(THF)(3) in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is presented. H-1 NMR spectroscopy demonstrates a two-step :catalytic cycle where TMSI regenerates active YbI3(THF)(3). Finally, the catalytic reaction is extended a one-pot procdure to demonstrate a potential application of the method Overall, the findings present a distinct strategy for C-F bond transformations in the presence of catalytic YbI3(THF)(3).
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| 10. |
- Karlsson, Isabella, 1980, et al.
(författare)
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Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen
- 2014
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:7, s. 1294-1303
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Tidskriftsartikel (refereegranskat)abstract
- Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-L-Trp ethyl ester and L-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
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| 11. |
- Larsen, Dennis, et al.
(författare)
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Exceptionally rapid oxime and hydrazone formation promoted by catalytic amine buffers with low toxicity
- 2018
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Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6539 .- 2041-6520. ; 9:23, s. 5252-5259
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Tidskriftsartikel (refereegranskat)abstract
- Hydrazone and oxime bond formation between α-nucleophiles (e.g. hydrazines, alkoxy-amines) and carbonyl compounds (aldehydes and ketones) is convenient and is widely applied in multiple fields of research. While the reactants are simple, a substantial drawback is the relatively slow reaction at neutral pH. Here we describe a novel molecular strategy for accelerating these reactions, using bifunctional buffer compounds that not only control pH but also catalyze the reaction. The buffers can be employed at pH 5-9 (5-50 mM) and accelerate reactions by several orders of magnitude, yielding second-order rate constants of >10 M-1s-1. Effective bifunctional amines include 2-(aminomethyl)imidazoles and N,N-dimethylethylenediamine. Unlike previous diaminobenzene catalysts, the new buffer amines are found to have low toxicity to human cells, and can be used to promote reactions in cellular applications.
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| 12. |
- Sundin, Elin, 1992, et al.
(författare)
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Singlet Fission and Electron Injection from the Triplet Excited State in Diphenylisobenzofuran-Semiconductor Assemblies: Effects of Solvent Polarity and Driving Force
- 2020
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Ingår i: Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 124:38 Josef Michl Festschrift, s. 20794-20805
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Tidskriftsartikel (refereegranskat)abstract
- Singlet fission has emerged as a promising way to overcome the Shockley-Queisser limit in solar energy conversion devices, and a few studies have claimed proof-of-principle results using dye-sensitized photoelectrodes. However, a detailed understanding of what factors govern the fate of the excited state on mesoporous surfaces is still lacking. Here, we have studied how the excitation progresses into singlet fission, electron injection, or formation of molecular charge separated states in diphenylisobenzofuran derivatives with flexible carbon linkers attached to nanocrystalline mesoporous ZrO2, TiO2, and SnO2 thin films. We show that singlet fission occurs for the molecule attached to ZrO2 films when the assembly is immersed in nonpolar solvents, and that singlet fission is hampered by the formation of a molecular charge separated state in more polar solvents. On TiO2 surfaces, direct electron injection from the singlet excited state outcompetes the singlet fission. Instead, triplet formation occurs via charge recombination from the conduction band of TiO2 in nonpolar solvents. When the molecule is attached to SnO2 films, singlet fission partly outcompetes electron injection from the singlet excited state and the two processes occur in parallel. Subsequent to singlet fission on SnO2, triplet injection into the conduction band of SnO2 is observed. The results presented here provide a detailed picture of the singlet fission dynamics in molecules attached to mesoporous semiconductor surfaces, demonstrating that both the semiconductor substrate as well as the environment around the molecules have a large impact, which can be useful in the design of future devices.
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