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Lindgren, Anders E. G.
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Publications (10 of 18) Show all publications
Nye, T. M., Tükenmez, H., Singh, P., Flores-Mireles, A. L., Obernuefemann, C. L. .., Pinkner, J. S., . . . Hultgren, S. J. (2022). Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics. Proceedings of the National Academy of Sciences of the United States of America, 119(43), Article ID e2210912119.
Open this publication in new window or tab >>Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
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2022 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2210912119Article in journal (Refereed) Published
Abstract [en]

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

Place, publisher, year, edition, pages
PNAS, 2022
Keywords
antibiotic resistance, antibiotic synergy, multidrug-resistant pathogens, VRE
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-201191 (URN)10.1073/pnas.2210912119 (DOI)36252016 (PubMedID)2-s2.0-85141283133 (Scopus ID)
Funder
NIH (National Institutes of Health), 1U19AI157797-01NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), R01DK128805NIH (National Institutes of Health), RO1DK51406NIH (National Institutes of Health), T32AI007172Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755
Available from: 2023-01-05 Created: 2023-01-05 Last updated: 2023-08-25Bibliographically approved
Reithuber, E., Wixe, T., Ludwig, K. C., Muller, A., Uvell, H., Grein, F., . . . Mellroth, P. (2021). THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates. Proceedings of the National Academy of Sciences of the United States of America, 118(47), Article ID e2108244118.
Open this publication in new window or tab >>THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 47, article id e2108244118Article in journal (Refereed) Published
Abstract [en]

Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate-containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II-binding antibiotics, makes THCz promising scaffolds for development of cell wall-targeting antimicrobials.

Place, publisher, year, edition, pages
National Academy of Sciences of the United States of America, 2021
Keywords
Streptococcus pneumoniae, antibiotic resistance, antimicrobials, cell wall biosynthesis, tetrahydrocarbazole
National Category
Microbiology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-191611 (URN)10.1073/pnas.2108244118 (DOI)000723039000018 ()34785593 (PubMedID)2-s2.0-85121274127 (Scopus ID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilKnut and Alice Wallenberg FoundationRegion StockholmGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2022-01-20 Created: 2022-01-20 Last updated: 2022-01-20Bibliographically approved
Adolfsson, D. E., Tyagi, M., Singh, P., Deuschmann, A., Ådén, J., Gharibyan, A., . . . Almqvist, F. (2020). Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils. Journal of Organic Chemistry, 85(21), 14174-14189
Open this publication in new window or tab >>Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
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2020 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 21, p. 14174-14189Article in journal (Other academic) Published
Abstract [en]

A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
Keywords
Nanofibers, Column chromatography, Peptides and proteins, Mixtures, Alkyls
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-174531 (URN)10.1021/acs.joc.0c01699 (DOI)000589941700068 ()2-s2.0-85095859796 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), R01AI134847-01A1
Note

Previously included in thesis in manuscript form.

Available from: 2020-08-26 Created: 2020-08-26 Last updated: 2023-03-24Bibliographically approved
Reithuber, E., Nannapaneni, P., Rzhepishevska, O. I., Lindgren, A. E. G., Ilchenko, O., Normark, S., . . . Mellroth, P. (2020). The Bactericidal Fatty Acid Mimetic 2CCA-1 Selectively Targets Pneumococcal Extracellular Polyunsaturated Fatty Acid Metabolism. mBio, 11(6), Article ID e03027-20.
Open this publication in new window or tab >>The Bactericidal Fatty Acid Mimetic 2CCA-1 Selectively Targets Pneumococcal Extracellular Polyunsaturated Fatty Acid Metabolism
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2020 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 11, no 6, article id e03027-20Article in journal (Refereed) Published
Abstract [en]

Streptococcus pneumoniae, a major cause of pneumonia, sepsis, and meningitis worldwide, has the nasopharynges of small children as its main ecological niche. Depletion of pneumococci from this niche would reduce the disease burden and could be achieved using small molecules with narrow-spectrum antibacterial activity. We identified the alkylated dicyclohexyl carboxylic acid 2CCA-1 as a potent inducer of autolysin-mediated lysis of S. pneumoniae, while having low activity against Staphylococcus aureus. 2CCA-1-resistant strains were found to have inactivating mutations in fakB3, known to be required for uptake of host polyunsaturated fatty acids, as well as through inactivation of the transcriptional regulator gene fabT, vital for endogenous, de novo fatty acid synthesis regulation. Structure activity relationship exploration revealed that, besides the central dicyclohexyl group, the fatty acid-like structural features of 2CCA-1 were essential for its activity. The lysis-inducing activity of 2CCA-1 was considerably more potent than that of free fatty acids and required growing bacteria, suggesting that 2CCA-1 needs to be metabolized to exert its antimicrobial activity. Total lipid analysis of 2CCA-1 treated bacteria identified unique masses that were modeled to 2CCA-1 containing lysophosphatidic and phosphatidic acid in wild-type but not in fakB3 mutant bacteria. This suggests that 2CCA-1 is metabolized as a fatty acid via FakB3 and utilized as a phospholipid building block, leading to accumulation of toxic phospholipid species. Analysis of FabT-mediated fakB3 expression elucidates how the pneumococcus could ensure membrane homeostasis and concurrent economic use of host-derived fatty acids.IMPORTANCE Fatty acid biosynthesis is an attractive antibiotic target, as it affects the supply of membrane phospholipid building blocks. In Streptococcus pneumoniae, it is not sufficient to target only the endogenous fatty acid synthesis machinery, as uptake of host fatty acids may bypass this inhibition. Here, we describe a small-molecule compound, 2CCA-1, with potent bactericidal activity that upon interactions with the fatty acid binding protein FakB3, which is present in a limited number of Gram-positive species, becomes metabolized and incorporated as a toxic phospholipid species. Resistance to 2CCA-1 developed specifically in fakB3 and the regulatory gene fabT. These mutants reveal a regulatory connection between the extracellular polyunsaturated fatty acid metabolism and endogenous fatty acid synthesis in S. pneumoniae, which could ensure balance between efficient scavenging of host polyunsaturated fatty acids and membrane homeostasis. The data might be useful in the identification of narrow-spectrum treatment strategies to selectively target members of the Lactobacillales such as S. pneumoniae.

Place, publisher, year, edition, pages
American Society for Microbiology, 2020
National Category
Biochemistry and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-179892 (URN)10.1128/mBio.03027-20 (DOI)000613615800005 ()33323510 (PubMedID)2-s2.0-85098532621 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish Foundation for Strategic Research Region Stockholm
Available from: 2021-02-12 Created: 2021-02-12 Last updated: 2021-02-23Bibliographically approved
Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Open this publication in new window or tab >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America, 2019
Keywords
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)2-s2.0-85066100071 (Scopus ID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2023-08-25Bibliographically approved
Kulén, M., Núñez-Otero, C., Cairns, A. G., Silver, J., Lindgren, A. E. G., Andersson, E. K., . . . Almqvist, F. (2019). Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors. MedChemComm, 10(11), 1966-1987
Open this publication in new window or tab >>Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 11, p. 1966-1987Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2019
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-166479 (URN)10.1039/c9md00405j (DOI)000498725400013 ()2-s2.0-85075072755 (Scopus ID)
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe FoundationsSwedish Foundation for Strategic Research
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2023-08-25Bibliographically approved
Ekblad, T., Verheugd, P., Lindgren, A. E., Nyman, T., Elofsson, M. & Schüler, H. (2018). Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol. SLAS DISCOVERY, 23(4), 353-362
Open this publication in new window or tab >>Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol
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2018 (English)In: SLAS DISCOVERY, ISSN 2472-5552, Vol. 23, no 4, p. 353-362Article in journal (Refereed) Published
Abstract [en]

Macrodomains recognize intracellular adenosine diphosphate (ADP)-ribosylation resulting in either removal of the modification or a protein interaction event. Research into compounds that modulate macrodomain functions could make important contributions. We investigated the interactions of all seven individual macrodomains of the human poly(ADP-ribose) polymerase (PARP) family members PARP9, PARP14, and PARP15 with five mono-ADP-ribosylated (automodified) ADP-ribosyltransferase domains using an AlphaScreen assay. Several mono-ADP-ribosylation-dependent interactions were identified, and they were found to be in the micromolar affinity range using surface plasmon resonance (SPR). We then focused on the interaction between PARP14 macrodomain-2 and the mono-ADP-ribosylated PARP10 catalytic domain, and probed a similar to 1500-compound diverse library for inhibitors of this interaction using AlphaScreen. Initial hit compounds were verified by concentration-response experiments using AlphaScreen and SPR, and they were tested against PARP14 macrodomain-2 and -3. Two initial hit compounds and one chemical analog each were further characterized using SPR and microscale thermophoresis. In conclusion, our results reveal novel macrodomain interactions and establish protocols for identification of inhibitors of such interactions.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
ADP-ribosylation, macrodomain inhibitor, PARP, protein-protein interaction, AlphaScreen
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-147337 (URN)10.1177/2472555217750870 (DOI)000429940100005 ()29316839 (PubMedID)2-s2.0-85044350008 (Scopus ID)
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2023-03-24Bibliographically approved
Lindgren, A. E. G., Oberg, C. T., Hillgren, J. M. & Elofsson, M. (2016). Total Synthesis of the Resveratrol Oligomers (+/-)-Ampelopsin B and (+/-)-E-Viniferin. European Journal of Organic Chemistry (3), 426-429
Open this publication in new window or tab >>Total Synthesis of the Resveratrol Oligomers (+/-)-Ampelopsin B and (+/-)-E-Viniferin
2016 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 3, p. 426-429Article in journal (Refereed) Published
Abstract [en]

The total synthesis of the resveratrol dimers (+/-)-ampelopsin B and (+/-)-E-viniferin is reported. Highlights of the approach include the use of cyclopropylmethyl groups to protect aromatic alcohols. This group allows an acid promoted three-step, one-pot deprotection-epimerization-cyclization of an advanced intermediate to give (+/-)-ampelopsin B. An important advantage with our strategy is the possibility of synthesizing analogs to these natural products to further study the chemistry and biology of resveratrol oligomers.

Keywords
Protecting groups, Cyclopropylmethyl, Polyphenols, Total synthesis, Natural products
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-116747 (URN)10.1002/ejoc.201501486 (DOI)000368815700002 ()2-s2.0-84957844325 (Scopus ID)
Available from: 2016-02-19 Created: 2016-02-11 Last updated: 2023-03-24Bibliographically approved
Lindgren, A. (2015). Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diphtheria Toxin-like ADP-Ribosyltransferases

The Human ADP-ribosyl transferases (ARTDs) are a group of poorly studied enzymes which are believed to be involved in e.g. DNA repair, protein degradation, transcription regulation and cell death. Medicinal chemistry programmes aimed at developing selective inhibitors of these ARTDs were initiated. A suitable starting compound for one of these enzymes, ARTD3, was found by screening a library of NAD-mimics using a thermal shift assay. A virtual screening protocol was instead developed in order to find novel inhibitors of ARTD7, 8, and 10. The hit compounds were then further developed into selective inhibitors of the corresponding ARTDs by systematically varying different structural features using a combination of synthetic organic chemistry, computational chemistry and structural biology. Compounds were initially characterized using differential scanning fluorimetry which was later replaced with an enzymatic assay to obtain IC50 values. Biotinylated analogs were also synthesized in an attempt to develop an AlphaScreen assay. A selective ARTD3 inhibitor was ultimately identified and found to delay DNA repair in cells after γ-irradiation. These compounds are potentially valuable tools for elucidating the biological role of the poorly characterized ARTD-family of proteins.

Total Synthesis of Resveratrol Based Natural Products

The polyphenolic natural product (-)-hopeaphenol was found to inhibit the type III secretion system present in certain gram-negative bacteria. (-)-Hopeaphenol is a tetramer of resveratrol and in order to investigate whether the entire structure was essential for inhibition two resveratrol dimers, ε-viniferin and ampelopsin B, were synthesized using a flexible and divergent synthetic route. Highlights of the synthetic strategy include the use of cyclopropylmethyl protecting groups, allowing an acid mediated three-step-one-pot deprotection-epimerization-cyclization of an advanced intermediate to form ampelopsin B. All previously reported syntheses of these two natural products include a dimerization of resveratrol which severly limits the possibilities to synthesize structural analogs. This new strategy enables the synthesis of a wide variety of analogs to ε-viniferin and ampelopsin B.

Abstract [sv]

Populärvetenskaplig sammanfattning

Små molekyler för att identifiera proteiners funktion

Vår arvsmassa innehåller cirka 24000 gener som i sin tur innehåller information för hur de tusentals proteiner vi är uppbyggda av ska framställas. Många läkemedel fungerar genom att en molekyl interagerar med ett av dessa proteiner och hämmar dess funktion för att på så sätt framkalla en önskad effekt. Vi vet dock inte vilken funktion många av våra proteiner fyller vilket ofta gör utvecklingen av nya läkemedel svår eller omöjlig. Den första delen av denna avhandling beskriver en grupp proteiner kallade ARTDs och hur små molekyler kan framställas och systematiskt förbättras för att till slut helt kunna slå ut vissa av dessa ARTDs. Genom att sedan studera vilka effekter detta medför kan man ta reda på vilken funktion proteinet fyller. På längre sikt skulle denna kunskap sedan kunna användas för att utveckla nya läkemedel genom att till exempel slå ut de proteiner som orsakar en sjukdom.

Totalsyntes av naturprodukter

Naturprodukter defineras inom kemin som naturligt förekommande molekyler som produceras av levande organismer. De kan hittas i allt från mikroorganismer och växter till djur och kan vara en del av deras ämnesomsättning, en restprodukt eller ha någon annan funktion, känd eller okänd. Människor, och i vissa fall även andra djur, har sedan urminnes tider ovetandes använt dessa molekyler för en mängd olika syften, som gifter, färgämnen eller läkemedel. Penicillin är en av de mest kända, men mer än hälften av de nya läkemedel som godkänts de senaste trettio åren bygger på naturprodukter eller har inspirerats av dessa. De fortsätter således att vara viktiga för utvecklingen av nya läkemedel trots att vi idag har möjligheten att utveckla sådana från grunden.

Att framställa naturprodukter på konstgjord väg kallas totalsyntes och är ofta en mycket svår och tidskrävande process. Vanligtvis rör det sig om mycket stora och komplexa molekyler och det finns sällan ett uppenbart sätt att genomföra totalsyntesen. För att bättre klara av detta måste nya metoder utvecklas. Den andra delen av denna avhandling beskriver nya metoder för att framställa komplexa molekyler kallade polyfenoler. Målet var att dessa metoder skulle vara så pass flexibla att de även kan användas för att framställa nya polyfenoler som aldrig tidigare existerat men som har förbättrade egenskaper.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2015. p. 115
Keywords
organic synthesis, quinazolinone, ARTD, PARP, total synthesis, polyphenols, bensofuranes
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-108010 (URN)978-91-7601-329-8 (ISBN)
Public defence
2015-10-02, KBC-huset, KB3A9 (lilla hörsalen i KBC-huset), Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-11 Created: 2015-09-01 Last updated: 2018-06-07Bibliographically approved
Ekblad, T., Lindgren, A. E. G., Andersson, C. D., Caraballo, R., Thorsell, A.-G., Karlberg, T., . . . Elofsson, M. (2015). Towards small molecule inhibitors of mono-ADP-ribosyltransferases. European Journal of Medicinal Chemistry, 95, 546-551
Open this publication in new window or tab >>Towards small molecule inhibitors of mono-ADP-ribosyltransferases
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2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 95, p. 546-551Article in journal (Refereed) Published
Abstract [en]

Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

Keywords
Mono-ADP-ribosyltransferase, mART, Poly(ADP-ribose) polymerase, Diphtheria toxin-like ADP-ribosyltransferase, ARTD inhibitor, PARP inhibitor
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-106136 (URN)10.1016/j.ejmech.2015.03.067 (DOI)000354139900046 ()25847771 (PubMedID)2-s2.0-84926206190 (Scopus ID)
Funder
Swedish Research Council, 2012-5247Swedish Foundation for Strategic Research , RBc08-0014
Available from: 2015-07-13 Created: 2015-07-09 Last updated: 2023-03-23Bibliographically approved
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