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Towards small molecule inhibitors of mono-ADP-ribosyltransferases
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 95, 546-551 p.Article 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.

Place, publisher, year, edition, pages
2015. Vol. 95, 546-551 p.
Keyword [en]
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: urn:nbn:se:umu:diva-106136DOI: 10.1016/j.ejmech.2015.03.067ISI: 000354139900046PubMedID: 25847771OAI: oai:DiVA.org:umu-106136DiVA: diva2:841501
Funder
Swedish Research Council, 2012-5247Swedish Foundation for Strategic Research , RBc08-0014
Available from: 2015-07-13 Created: 2015-07-09 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products
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. 115 p.
Keyword
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: 2015-09-11Bibliographically approved

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Lindgren, Anders E. G.Andersson, C. DavidCaraballo, RemiSpjut, SaraLinusson, AnnaElofsson, Mikael
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