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Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Mikael Elofsson)
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 [en]
organic synthesis, quinazolinone, ARTD, PARP, total synthesis, polyphenols, bensofuranes
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-108010ISBN: 978-91-7601-329-8 (print)OAI: oai:DiVA.org:umu-108010DiVA: diva2:850251
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
List of papers
1. Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
Open this publication in new window or tab >>Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 23, 9556-9568 p.Article in journal (Refereed) Published
Abstract [en]

The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-84774 (URN)10.1021/jm401394u (DOI)000328529700015 ()
Available from: 2014-01-29 Created: 2014-01-20 Last updated: 2017-12-06Bibliographically approved
2. PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
Open this publication in new window or tab >>PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
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2013 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 8, 1698-1703 p.Article in journal (Refereed) Published
Abstract [en]

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-81013 (URN)10.1021/cb4002014 (DOI)000323363000008 ()
Available from: 2013-09-30 Created: 2013-09-30 Last updated: 2017-12-06Bibliographically approved
3. Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
Open this publication in new window or tab >>Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 17, 7706-7718 p.Article in journal (Refereed) Published
Abstract [en]

The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-57906 (URN)10.1021/jm300746d (DOI)22823910 (PubMedID)
Available from: 2012-08-21 Created: 2012-08-21 Last updated: 2017-12-07Bibliographically approved
4. Towards small molecule inhibitors of mono-ADP-ribosyltransferases
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, 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.

Keyword
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)
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

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Lindgren, Anders

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