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Cairns, Andrew G.
Publications (6 of 6) Show all publications
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)
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: 2019-06-10Bibliographically approved
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-06-13Bibliographically approved
Singh, P., Cairns, A. G., Adolfsson, D. E., Ådén, J., Sauer, U. H. & Almqvist, F. (2019). Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones. Organic Letters
Open this publication in new window or tab >>Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones
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2019 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052Article in journal (Refereed) Epub ahead of print
Abstract [en]

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Inorganic Chemistry Polymer Chemistry
Identifiers
urn:nbn:se:umu:diva-162826 (URN)10.1021/acs.orglett.9b02549 (DOI)31419146 (PubMedID)
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2019-09-03
Cairns, A. G., Vazquez-Romero, A., Mahdi-Moein, M., Ådén, J., Elmore, C. S., Takano, A., . . . Schou, M. (2018). Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy [Letter to the editor]. ACS Chemical Neuroscience, 9(11), 2542-2547
Open this publication in new window or tab >>Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
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2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 11, p. 2542-2547Article in journal, Letter (Refereed) Published
Abstract [en]

Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Alpha-synuclein, carbon-11, PET
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-151139 (URN)10.1021/acschemneuro.8b00236 (DOI)000451496200005 ()29901990 (PubMedID)
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-12-19Bibliographically approved
Kulén, M., Lindgren, M., Hansen, S., Cairns, A. G., Grundström, C., Begum, A., . . . Almqvist, F. (2018). Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes. Journal of Medicinal Chemistry, 61(9), 4165-4175
Open this publication in new window or tab >>Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4165-4175Article in journal (Refereed) Published
Abstract [en]

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-148830 (URN)10.1021/acs.jmedchem.8b00289 (DOI)000432204800027 ()29667825 (PubMedID)2-s2.0-85046422455 (Scopus ID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-28Bibliographically approved
Barange, D. K., Johnson, M. T., Cairns, A. G., Olsson, R. & Almqvist, F. (2016). Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines. Organic Letters, 18(24), 6228-6231
Open this publication in new window or tab >>Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines
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2016 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 24, p. 6228-6231Article in journal (Refereed) Published
Abstract [en]

Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-130226 (URN)10.1021/acs.orglett.6b02667 (DOI)000390180300004 ()
Available from: 2017-01-16 Created: 2017-01-14 Last updated: 2018-06-09Bibliographically approved
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