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  • 1.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry, UiT The Arctic University of Norway, Tromsø, Norway.
    Cervin, Gunnar
    Trepos, Rozenn
    Labriere, Christophe
    Hellio, Claire
    Pavia, Henrik
    Svenson, Johan
    Design and Biological Evaluation of Antifouling Dihydrostilbene Oxime Hybrids2018Ingår i: Marine Biotechnology, ISSN 1436-2228, E-ISSN 1436-2236, Vol. 20, nr 2, s. 257-267Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    By combining the recently reported repelling natural dihydrostilbene scaffold with an oxime moiety found in many marine antifoulants, a library of nine antifouling hybrid compounds was developed and biologically evaluated. The prepared compounds were shown to display a low antifouling effect against marine bacteria but a high potency against the attachment and growth of microalgae down to MIC values of 0.01 μg/mL for the most potent hybrid. The mode of action can be characterized as repelling via a reversible non-toxic biostatic mechanism. Barnacle cyprid larval settlement was also inhibited at low μg/mL concentrations with low levels or no toxicity observed. Several of the prepared compounds performed better than many reported antifouling marine natural products. While several of the prepared compounds are highly active as antifoulants, no apparent synergy is observed by incorporating the oxime functionality into the dihydrostilbene scaffold. This observation is discussed in light of recently reported literature data on related marine natural antifoulants and antifouling hybrids as a potentially general strategy for generation of improved antifoulants.

  • 2.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chammaa, Samy
    Kindahl, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids2017Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, nr 11, s. 2797-2800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Incorporation of the fluorogenic l-(7-hydroxycoumarin-4-yl)ethylglycine into proteins is a valuable biological tool. Coumarins are typically accessed via the Pechmann reaction, which requires acidic conditions and lacks substrate flexibility. A Pd-mediated coupling is described between o-methoxyboronic acids and a glutamic acid derived (Z)-vinyl triflate, forming latent coumarins. Global deprotection with BBr3 forms the coumarin scaffold in a single step. This mild and scalable route yielded five analogues, including a probe suitable for use at lower pH.

  • 3.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hubert, Madlen
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Zhou, Xin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Albers, Michael Franz
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Photoactivated Colibactin Probes Induce Cellular DNA Damage2019Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, nr 5, s. 1417-1421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks(+) bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks(+) like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.

  • 4.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sepcic, Kristina
    Turk, Tom
    Frangez, Robert
    Svenson, Johan
    Natural cholinesterase inhibitors from marine organisms2019Ingår i: Natural product reports (Print), ISSN 0265-0568, E-ISSN 1460-4752, Vol. 36, nr 8, s. 1053-1092Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Inhibition of cholinesterases is a common approach for the management of several disease states. Most notably, cholinesterase inhibitors are used to alleviate the symptoms of neurological disorders like dementia and Alzheimer's disease and treat myasthenia gravis and glaucoma. Historically, most drugs of natural origin have been isolated from terrestrial sources and inhibitors of cholinesterases are no exception. However, the last 50 years have seen a rise in the quantity of marine natural products with close to 25 000 reported in the scientific literature. A number of marine natural products with potent cholinesterase inhibitory properties have also been reported; isolated from a variety of marine sources from algae to ascidians. Representing a diverse range of structural classes, these compounds provide inspirational leads that could aid the development of therapeutics. The current paper aims to, for the first time, comprehensively summarize the literature pertaining to cholinesterase inhibitors derived from marine sources, including the first papers published in 1974 up to 2018. The review does not report bioactive extracts, only isolated compounds, and a specific focus lies on compounds with reported doseresponse data. In vivo and mechanistic data is included for compounds where this is reported. In total 185 marine cholinesterase inhibitors and selected analogs have been identified and reported and some of the compounds display inhibitory activities comparable or superior to cholinesterase inhibitors in clinical use.

  • 5.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. UiT Arctic Univ Norway, Dept Chem, N-9037 Tromsö, Norway.
    Trepos, Rozenn
    Cervin, Gunnar
    Brathen, Kari Anne
    Lindgard, Bente
    Reiersen, Rigmor
    Cahil, Patrick
    Pavia, Henrik
    Hellio, Claire
    Svenson, Johan
    Prevention of Marine Biofouling Using the Natural Allelopathic Compound Batatasin-Ill and Synthetic Analogues2017Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, nr 7, s. 2001-2011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current study reports the first comprehensive evaluation of a class of allelopathic terrestrial natural products as antifoulants in a marine setting. To investigate the antifouling potential of the natural dihydrostilbene scaffold, a library of 22 synthetic dihydrostilbenes with varying substitution patterns, many of which occur naturally in terrestrial plants, were prepared and assessed for their antifouling capacity. The compounds were evaluated in an extensive screen against 16 fouling marine organisms. The dihydrostilbene scaffold was shown to possess powerful general antifouling effects against both marine microfoulers and macrofoulers with inhibitory activities at low concentrations. The species of microalgae examined displayed a particular sensitivity toward the evaluated compounds at low ng/mL concentrations. It was shown that several of the natural and synthetic compounds exerted their repelling activities via nontoxic and reversible mechanisms. The activities of the most active compounds such as 3,5-dimethoxybibenzyl (5), 3,4-dimethoxybibenzyl (9), and 3-hyolroxy-3',4,5'-trirnethoxybibenzyl (20) were comparable to the commercial antifouling booster biocide. Sea-nine, which was employed as a positive control. The investigation of terrestrial allelopathic natural products to counter marine fouling represents a novel strategy for the design of "green" antifouling technologies, and these compounds offer a potential alternative to traditional biocidal antifoulants.

  • 6.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry, UiT The Arctic University of Norway, Breivika, N-9037, Tromsø, Norway.
    Trepos, Rozenn
    Cervin, Gunnar
    Larsen, Lesley
    Larsen, David S.
    Pavia, Henrik
    Hellio, Claire
    Cahill, Patrick
    Svenson, Johan
    Probing the Structure-Activity Relationship of the Natural Antifouling Agent Polygodial against both Micro- and Macrofoulers by Semisynthetic Modification2017Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, nr 2, s. 515-525Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current study represents the first comprehensive investigation into the general antifouling activities of the natural drimane sesquiterpene polygodial. Previous studies have highlighted a high antifouling effect toward macrofoulers, such as ascidians, tubeworms, and mussels, but no reports about the general antifouling effect of polygodial have been communicated before. To probe the structural and chemical basis for antifouling activity, a library of 11 polygodial analogues was prepared by semisynthesis. The library was designed to yield derivatives with ranging polarities and the ability to engage in both covalent and noncovalent interactions, while still remaining within the drimane sesquiterpene scaffold. The prepared compounds were screened against 14 relevant marine micro- and macrofouling species. Several of the polygodial analogues displayed inhibitory activities at sub-microgram/mL concentrations. These antifouling effects were most pronounced against the macrofouling ascidian Ciona savignyi and the barnacle Balanus improvisus, with inhibitory activities observed for selected compounds comparable or superior to several commercial antifouling products. The inhibitory activity against the microfouling bacteria and microalgae was reversible and significantly less pronounced than for the macrofoulers. This study illustrates that the macro- and microfoulers are targeted by the compounds via different mechanisms.

  • 7.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. a Department of Chemistry, UiT The Arctic University of Norway, Tromsø, Norway.
    Zuzek, Monika C.
    Frangez, Robert
    Andersen, Jeanette H.
    Hansen, Espen
    Olsen, Elisabeth K.
    Cergolj, Marija
    Sepcic, Kristina
    Hansen, Kine O.
    Svenson, Johan
    Synthetic analogs of stryphnusin isolated from the marine sponge Stryphnus fortis inhibit acetylcholinesterase with no effect on muscle function or neuromuscular transmission2016Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, nr 47, s. 11220-11229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The marine secondary metabolite stryphnusin (1) was isolated from the boreal sponge Stryphnus fortis, collected off the Norwegian coast. Given its resemblance to other natural acetylcholinesterase antagonists, it was evaluated against electric eel acetylcholinesterase and displayed inhibitory activity. A library of twelve synthetic phenethylamine analogs, 2a-7a and 2b-7b, containing tertiary and quaternary amines respectively were synthesized to investigate the individual structural contributions to the activity. Compound 7b was the strongest competitive inhibitor of both acetylcholinesterase and butyrylcholinesterase with IC50 values of 57 and 20 mu M, respectively. This inhibitory activity is one order of magnitude higher than the positive control physostigmine, and is comparable with several other marine acetylcholinesterase inhibitors. The physiological effect of compound 7b on muscle function and neuromuscular transmission was studied and revealed a selective mode of action at the investigated concentration. This data is of importance as the interference of therapeutic acetylcholinesterase inhibitors with neuromuscular transmission can be problematic and lead to unwanted side effects. The current findings also provide additional insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

  • 8. Olsen, Elisabeth K.
    et al.
    Hansen, Espen
    Moodie, Lindon W. K.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Isaksson, Johan
    Sepcic, Kristina
    Cergolj, Marija
    Svenson, Johan
    Andersen, Jeanette H.
    Marine AChE inhibitors isolated from Geodia barretti: natural compounds and their synthetic analogs2016Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, nr 5, s. 1629-1640Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (K-i) of 29 and 19 mu M respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

  • 9. Rodrigues, Leticia
    et al.
    Schneider, Fabian
    Zhang, Xiaohan
    Larsson, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Moodie, Lindon W. K.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dietz, Hendrik
    Papadakis, Christine M.
    Winter, Gerhard
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Hubert, Madlen
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Cellular uptake of self-assembled phytantriol-based hexosomes is independent of major endocytic machineries2019Ingår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 553, s. 820-833Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite increasing interests in non-lamellar liquid crystalline dispersions, such as hexosomes, for drug delivery, little is known about their interactions with cells and mechanism of cell entry. Here we examine the cellular uptake of hexosomes based on phytantriol and mannide monooleate by HeLa cells using live cell microscopy in comparison to conventional liposomes. To investigate the importance of specific endocytosis pathways upon particle internalization, we silenced regulatory proteins of major endocytosis pathways using short interfering RNA. While endocytosis plays a significant role in liposome internalization, hexosomes are not taken up via endocytosis but through a mechanism that is dependent on cell membrane tension. Biophysical studies using biomembrane models highlighted that hexosomes have a high affinity for membranes and an ability to disrupt lipid layers. Our data suggest that direct biomechanical interactions of hexosomes with membrane lipids play a crucial role and that the unique morphology of hexosomes is vital for their membrane activity. Based on these results, we propose a mechanism, where hexosomes destabilize the bilayer, allowing them to "phase through" the membrane. Understanding parameters that influence the uptake of hexosomes is critical to establish them as carrier systems that can potentially deliver therapeutics efficiently to intracellular sites of action.

  • 10.
    Shukla, Lakshmi
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Moodie, Lindon W. K.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kindahl, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis and Spectroscopic Properties of Fluorinated Coumarin Lysine Derivatives2018Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, nr 8, s. 4792-4799Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The site-selective incorporation of fluorescent amino acids into proteins has emerged as a valuable alternative to expressible protein reporters. For successful application, a robust and scalable, yet flexible, route to non-natural amino acids is required. This work describes an improved synthesis of coumarin-conjugated lysine derivatives where fluorinated variants are accessed. These analogues can be utilized at low pH and should find application probing biological processes that operate under acidic conditions.

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