Publications by authors named "Fredrik Almqvist"

140 Publications

Effects of individual differences, society, and culture on youth-rated problems and strengths in 38 societies.

J Child Psychol Psychiatry 2022 Feb 15. Epub 2022 Feb 15.

National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Clinicians increasingly serve youths from societal/cultural backgrounds different from their own. This raises questions about how to interpret what such youths report. Rescorla et al. (2019, European Child & Adolescent Psychiatry, 28, 1107) found that much more variance in 72,493 parents' ratings of their offspring's mental health problems was accounted for by individual differences than by societal or cultural differences. Although parents' reports are essential for clinical assessment of their offspring, they reflect parents' perceptions of the offspring. Consequently, clinical assessment also requires self-reports from the offspring themselves. To test effects of individual differences, society, and culture on youths' self-ratings of their problems and strengths, we analyzed Youth Self-Report (YSR) scores for 39,849 11-17 year olds in 38 societies.

Methods: Indigenous researchers obtained YSR self-ratings from population samples of youths in 38 societies representing 10 culture cluster identified in the Global Leadership and Organizational Behavioral Effectiveness study. Hierarchical linear modeling of scores on 17 problem scales and one strengths scale estimated the percent of variance accounted for by individual differences (including measurement error), society, and culture cluster. ANOVAs tested age and gender effects.

Results: Averaged across the 17 problem scales, individual differences accounted for 92.5% of variance, societal differences 6.0%, and cultural differences 1.5%. For strengths, individual differences accounted for 83.4% of variance, societal differences 10.1%, and cultural differences 6.5%. Age and gender had very small effects.

Conclusions: Like parents' ratings, youths' self-ratings of problems were affected much more by individual differences than societal/cultural differences. Most variance in self-rated strengths also reflected individual differences, but societal/cultural effects were larger than for problems, suggesting greater influence of social desirability. The clinical significance of individual differences in youths' self-reports should thus not be minimized by societal/cultural differences, which-while important-can be taken into account with appropriate norms, as can gender and age differences.
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http://dx.doi.org/10.1111/jcpp.13569DOI Listing
February 2022

The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models.

Biomolecules 2021 11 12;11(11). Epub 2021 Nov 12.

Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland Galway, H91 W5P7 Galway, Ireland.

Animal models of Parkinson's disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.
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http://dx.doi.org/10.3390/biom11111685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615715PMC
November 2021

THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates.

Proc Natl Acad Sci U S A 2021 11;118(47)

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet 171 77 Stockholm, Sweden.

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.
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http://dx.doi.org/10.1073/pnas.2108244118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617507PMC
November 2021

Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones.

J Org Chem 2021 12 12;86(23):16582-16592. Epub 2021 Nov 12.

Department of Chemistry, Umeå University, 90187 Umeå, Sweden.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via -alkylation and generates -alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.
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http://dx.doi.org/10.1021/acs.joc.1c01875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650012PMC
December 2021

KSO-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones.

Org Biomol Chem 2021 11 18;19(44):9758-9772. Epub 2021 Nov 18.

Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones KSO-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.
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http://dx.doi.org/10.1039/d1ob01580jDOI Listing
November 2021

Selected applications of Meldrum's acid - a tutorial.

Org Biomol Chem 2021 06;19(23):5014-5027

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.

Due to its unique structure and the vast array of substituents that can be attached to its core, Meldrum's acid is a molecule with exceptional chemical properties. In water, it has a remarkably low pKa value of about 4.9. Its C5 position is readily involved in electrophilic substitution reactions whereas the C4 and C6 positions are easily attacked by nucleophiles. At elevated temperatures Meldrum's acid undergoes distinctive decomposition pathways, which can be used in cycloaddition and acylation reactions. In this Tutorial Review, the authors intend to introduce the principles of the synthetic chemistry of Meldrum's acid and provide the essential knowledge for the design and preparation of compounds with desired properties. As there are many reviews focusing on a specific detail of Meldrum's acid chemistry, we would like to give a broader picture of this diverse molecule for undergraduate and graduate students as well as experienced lab leaders. For achieving this goal, some recent advances in using Meldrum's acid derivatives in synthetic scenarios are presented with the hope to further stimulate and promote research leading to additional innovative applications of this synthetically highly relevant molecule.
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http://dx.doi.org/10.1039/d1ob00395jDOI Listing
June 2021

A 2-pyridone amide inhibitor of transcriptional activity in .

Antimicrob Agents Chemother 2021 Feb 16. Epub 2021 Feb 16.

Department of Clinical Microbiology, Umeå University, 901 85 Umeå, Sweden

is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to life-long sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target would be beneficial. 2-pyridone amides are potent and specific inhibitors of infectivity. The first generation compound KSK120, inhibits the developmental cycle of resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of and the effect was only observable upon re-infection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to since KSK213 was inactive in the closely related animal pathogen and in The molecular target of KSK213 may thus be different in or non-essential in and Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNAse III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for infections.
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http://dx.doi.org/10.1128/AAC.01826-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092867PMC
February 2021

Mycobacterium tuberculosis Rv3160c is a TetR-like transcriptional repressor that regulates expression of the putative oxygenase Rv3161c.

Sci Rep 2021 01 15;11(1):1523. Epub 2021 Jan 15.

Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a major health threat listed among the top 10 causes of death worldwide. Treatment of multidrug-resistant Mtb requires use of additional second-line drugs that prolong the treatment process and result in higher death rates. Our team previously identified a 2-pyridone molecule (C10) that blocks tolerance to the first-line drug isoniazid at C10 concentrations that do not inhibit bacterial growth. Here, we discovered that the genes rv3160c and rv3161c are highly induced by C10, which led us to investigate them as potential targets. We show that Rv3160c acts as a TetR-like transcriptional repressor binding to a palindromic sequence located in the rv3161c promoter. We also demonstrate that C10 interacts with Rv3160c, inhibiting its binding to DNA. We deleted the rv3161c gene, coding for a putative oxygenase, to investigate its role in drug and stress sensitivity as well as C10 activity. This Δrv3161c strain was more tolerant to isoniazid and lysozyme than wild type Mtb. However, this tolerance could still be blocked by C10, suggesting that C10 functions independently of Rv3161c to influence isoniazid and lysozyme sensitivity.
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http://dx.doi.org/10.1038/s41598-021-81104-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810876PMC
January 2021

The Bactericidal Fatty Acid Mimetic 2CCA-1 Selectively Targets Pneumococcal Extracellular Polyunsaturated Fatty Acid Metabolism.

mBio 2020 12 15;11(6). Epub 2020 Dec 15.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

, 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 , while having low activity against 2CCA-1-resistant strains were found to have inactivating mutations in , known to be required for uptake of host polyunsaturated fatty acids, as well as through inactivation of the transcriptional regulator gene , vital for endogenous, 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 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 expression elucidates how the pneumococcus could ensure membrane homeostasis and concurrent economic use of host-derived fatty acids. Fatty acid biosynthesis is an attractive antibiotic target, as it affects the supply of membrane phospholipid building blocks. In , 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 and the regulatory gene These mutants reveal a regulatory connection between the extracellular polyunsaturated fatty acid metabolism and endogenous fatty acid synthesis in , 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 such as .
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http://dx.doi.org/10.1128/mBio.03027-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773995PMC
December 2020

Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils.

J Org Chem 2020 11 25;85(21):14174-14189. Epub 2020 Oct 25.

Umeå University, Department of Chemistry, 901 87 Umeå, Sweden.

A BF·OEt catalyzed intramolecular Povarov reaction was used to synthesize 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with several -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 . Analogues substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
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http://dx.doi.org/10.1021/acs.joc.0c01699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660745PMC
November 2020

Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based inhibitors.

Medchemcomm 2019 Nov 17;10(11):1966-1987. Epub 2019 Oct 17.

Department of Chemistry , Umeå University , 901 87 Umeå , Sweden . Email:

infections are a global health problem and new approaches to treat 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 infectivity. 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 inhibited infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. 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 , effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.
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http://dx.doi.org/10.1039/c9md00405jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069368PMC
November 2019

Synthesis of Densely Functionalized -Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones.

Org Lett 2019 09 16;21(17):6946-6950. Epub 2019 Aug 16.

Department of Chemistry, Umeå University, 90187 Umeå, Sweden.

We report the synthesis of 6-arylthio-substituted--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.
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http://dx.doi.org/10.1021/acs.orglett.9b02549DOI Listing
September 2019

Chemical disarming of isoniazid resistance in .

Proc Natl Acad Sci U S A 2019 05 6;116(21):10510-10517. Epub 2019 May 6.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110;

() 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 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 , 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 strains harboring mutations in the gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect persistence, we discovered that INH resistance is not absolute and can be reversed.
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http://dx.doi.org/10.1073/pnas.1818009116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535022PMC
May 2019

A role for the auxin precursor anthranilic acid in root gravitropism via regulation of PIN-FORMED protein polarity and relocalisation in Arabidopsis.

New Phytol 2019 08 7;223(3):1420-1432. Epub 2019 Jun 7.

Umeå Plant Science Centre (UPSC), Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences (SLU), 90183, Umeå, Sweden.

distribution of auxin within plant tissues is of great importance for developmental plasticity, including root gravitropic growth. Auxin flow is directed by the subcellular polar distribution and dynamic relocalisation of auxin transporters such as the PIN-FORMED (PIN) efflux carriers, which can be influenced by the main natural plant auxin indole-3-acetic acid (IAA). Anthranilic acid (AA) is an important early precursor of IAA and previously published studies with AA analogues have suggested that AA may also regulate PIN localisation. Using Arabidopsis thaliana as a model species, we studied an AA-deficient mutant displaying agravitropic root growth, treated seedlings with AA and AA analogues and transformed lines to over-produce AA while inhibiting its conversion to downstream IAA precursors. We showed that AA rescues root gravitropic growth in the AA-deficient mutant at concentrations that do not rescue IAA levels. Overproduction of AA affects root gravitropism without affecting IAA levels. Treatments with, or deficiency in, AA result in defects in PIN polarity and gravistimulus-induced PIN relocalisation in root cells. Our results revealed a previously unknown role for AA in the regulation of PIN subcellular localisation and dynamics involved in root gravitropism, which is independent of its better known role in IAA biosynthesis.
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http://dx.doi.org/10.1111/nph.15877DOI Listing
August 2019

Viral mimetic priming enhances α-synuclein-induced degeneration: Implications for Parkinson's disease.

Brain Behav Immun 2019 08 25;80:525-535. Epub 2019 Apr 25.

Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, Ireland. Electronic address:

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.
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http://dx.doi.org/10.1016/j.bbi.2019.04.036DOI Listing
August 2019

Visible-Light-Mediated Synthesis of β-Chloro Ketones from Aryl Cyclopropanes.

Angew Chem Int Ed Engl 2019 06 22;58(25):8577-8580. Epub 2019 May 22.

Department of Organic Chemistry, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.

We report the visible-light-mediated synthesis of β-chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid, and nitric acid. The operationally simple and catalyst-free method uses cheap standard laboratory reagents and displays broad functional-group tolerance. Moreover, scale up of the reaction and late-stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β-chloro ketone in a reaction sequence. We propose a light-driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid to produce small quantities of molecular chlorine. The mechanistic hypothesis is supported by O labelling and UV/Vis experiments, cyclovoltammetry, and several control reactions.
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http://dx.doi.org/10.1002/anie.201902473DOI Listing
June 2019

Pyridine-Fused 2-Pyridones via Povarov and A Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding.

J Org Chem 2019 04 20;84(7):3887-3903. Epub 2019 Mar 20.

Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ) , Leibniz Universität Hannover , Schneiderberg 1b , Hannover 30167 , Germany.

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.
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http://dx.doi.org/10.1021/acs.joc.8b03015DOI Listing
April 2019

Selective auxin agonists induce specific AUX/IAA protein degradation to modulate plant development.

Proc Natl Acad Sci U S A 2019 03 8;116(13):6463-6472. Epub 2019 Mar 8.

Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, SE-901 83 Umeå, Sweden;

Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCF functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.
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http://dx.doi.org/10.1073/pnas.1809037116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442611PMC
March 2019

Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli.

Nat Microbiol 2018 12 1;3(12):1362-1368. Epub 2018 Oct 1.

Department of Molecular Microbiology, Washington University in St Louis, St Louis, MO, USA.

Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases. During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane β-barrel translocation domain, a β-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2). Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.
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http://dx.doi.org/10.1038/s41564-018-0255-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258349PMC
December 2018

Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy.

ACS Chem Neurosci 2018 11 19;9(11):2542-2547. Epub 2018 Jun 19.

Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-171 76 Stockholm , Sweden.

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 C ( t = 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 [C]14 compared to [C]12 (0.8 vs 0.2 SUV, respectively). [C]14 was rapidly eliminated from plasma, with [C]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.
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http://dx.doi.org/10.1021/acschemneuro.8b00236DOI Listing
November 2018

Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes.

J Med Chem 2018 05 27;61(9):4165-4175. Epub 2018 Apr 27.

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 (A), 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-A selective PrfA inhibitors with potent antivirulence properties.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00289DOI Listing
May 2018

Testing Syndromes of Psychopathology in Parent and Youth Ratings Across Societies.

J Clin Child Adolesc Psychol 2019 Jul-Aug;48(4):596-609. Epub 2018 Jan 24.

ab Instituto de Psicologia e Ciências da Educação, Universidade Lusíada Norte (Porto).

As societies become increasingly diverse, mental health professionals need instruments for assessing emotional, behavioral, and social problems in terms of constructs that are supported within and across societies. Building on decades of research findings, multisample alignment confirmatory factor analyses tested an empirically based 8-syndrome model on parent ratings across 30 societies and youth self-ratings across 19 societies. The Child Behavior Checklist for Ages 6-18 and Youth Self-Report for Ages 11-18 were used to measure syndromes descriptively designated as , and . For both parent ratings (61,703) and self-ratings (= 29,486), results supported aggregation of problem items into 8 first-order syndromes for all societies (configural invariance), plus the invariance of item loadings (metric invariance) across the majority of societies. Supported across many societies in both parent and self-ratings, the 8 syndromes offer a parsimonious phenotypic taxonomy with clearly operationalized assessment criteria. Mental health professionals in many societies can use the 8 syndromes to assess children and youths for clinical, training, and scientific purposes.
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http://dx.doi.org/10.1080/15374416.2017.1405352DOI Listing
May 2020

Inhibition of curli assembly and biofilm formation by the human systemic amyloid precursor transthyretin.

Proc Natl Acad Sci U S A 2017 11 30;114(46):12184-12189. Epub 2017 Oct 30.

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048;

During biofilm formation, and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer's-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.
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http://dx.doi.org/10.1073/pnas.1708805114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699053PMC
November 2017

Thiazolino 2-Pyridone Amide Isosteres As Inhibitors of Chlamydia trachomatis Infectivity.

J Med Chem 2017 11 3;60(22):9393-9399. Epub 2017 Nov 3.

Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC ≤ 20 nM).
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http://dx.doi.org/10.1021/acs.jmedchem.7b00716DOI Listing
November 2017

Effects of small-molecule amyloid modulators on a Drosophila model of Parkinson's disease.

PLoS One 2017 1;12(9):e0184117. Epub 2017 Sep 1.

Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.

Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility. FlyTracker allows for automated analysis of walking and climbing locomotor behavior, as it collects large sequences of data over time in an unbiased manner. We found that the molecules per se have no toxic or kinetic effects on normal flies. Feeding aS-expressing flies with the amyloid-promoting molecule FN075, remarkably, resulted in increased fly mobility at early time points; however, this effect switched to reduced mobility at later time points, and flies had shorter life spans than controls. In contrast, an amyloid inhibitor increased both fly kinetics and life span. In agreement with increased aS amyloid formation, the FN075-fed flies had less soluble aS, and in vitro aS-FN075 interactions stimulated aS amyloid formation. In addition to a new quantitative approach to probe mobility (available in FlyTracker), our results imply that aS regulates brain activity such that initial removal (here, by FN075-triggered assembly of aS) allows for increased fly mobility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184117PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581160PMC
October 2017

Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines.

Org Lett 2016 12 28;18(24):6228-6231. Epub 2016 Nov 28.

Department of Chemistry, Umeå University , 90187 Umeå, Sweden.

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.
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http://dx.doi.org/10.1021/acs.orglett.6b02667DOI Listing
December 2016

Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria.

Proc Natl Acad Sci U S A 2016 12 5;113(51):14733-14738. Epub 2016 Dec 5.

Department of Chemistry, Umeå University, 901 87 Umeå, Sweden;

Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could fulfill this function. Here we report the crystal structures of PrfA in complex with GSH and in complex with GSH and its cognate DNA, the hly operator PrfA box motif. These structures reveal the structural basis for a GSH-mediated allosteric mode of activation of PrfA in the cytosol of the host cell. The crystal structure of PrfA in complex only with DNA confirms that PrfA can adopt a DNA binding-compatible structure without binding the GSH activator molecule. By binding to PrfA in the cytosol of the host cell, GSH induces the correct fold of the HTH motifs, thus priming the PrfA protein for DNA interaction.
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http://dx.doi.org/10.1073/pnas.1614028114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187702PMC
December 2016

Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens.

mBio 2016 Apr 26;7(2):e00221-16. Epub 2016 Apr 26.

Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Unlabelled: Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs.

Importance: Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.
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http://dx.doi.org/10.1128/mBio.00221-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850256PMC
April 2016

Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA.

Cell Chem Biol 2016 Mar;23(3):404-14

Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden; Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden; Molecular Infection Medicine, Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden. Electronic address:

The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes cellular uptake by reducing the expression of virulence genes. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA-binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds at two separate sites on the protein: one within a hydrophobic pocket or tunnel, located between the C- and N-terminal domains of PrfA, and the second in the vicinity of the DNA-binding helix-turn-helix motif. At both sites the compound interacts with residues important for PrfA activation and helix-turn-helix formation. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.
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http://dx.doi.org/10.1016/j.chembiol.2016.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802734PMC
March 2016

Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.

J Med Chem 2016 Mar 22;59(5):2094-108. Epub 2016 Feb 22.

Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤ 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 μM. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01759DOI Listing
March 2016
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