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Bäck, Marcus
Publications (10 of 14) Show all publications
Snipstad, S., Hak, S., Baghirov, H., Sulheim, E., Mørch, Ý., Lélu, S., . . . Åslund, A. K. O. (2017). Labeling nanoparticles: Dye leakage and altered cellular uptake. Cytometry Part A, 91(8), 760-766
Open this publication in new window or tab >>Labeling nanoparticles: Dye leakage and altered cellular uptake
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2017 (English)In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 91, no 8, p. 760-766Article in journal (Refereed) Published
Abstract [en]

In vitro and in vivo behavior of nanoparticles (NPs) is often studied by tracing the NPs with fluorescent dyes. This requires stable incorporation of dyes within the NPs, as dye leakage may give a wrong interpretation of NP biodistribution, cellular uptake, and intracellular distribution. Furthermore, NP labeling with trace amounts of dye should not alter NP properties such as interactions with cells or tissues. To allow for versatile NP studies with a variety of fluorescence-based assays, labeling of NPs with different dyes is desirable. Hence, when new dyes are introduced, simple and fast screening methods to assess labeling stability and NP-cell interactions are needed. For this purpose, we have used a previously described generic flow cytometry assay; incubation of cells with NPs at 4 and 37C. Cell-NP interaction is confirmed by cellular fluorescence after 37C incubation, and NP-dye retention is confirmed when no cellular fluorescence is detected at 4C. Three different NP-platforms labeled with six different dyes were screened, and a great variability in dye retention was observed. Surprisingly, incorporation of trace amounts of certain dyes was found to reduce or even inhibit NP uptake. This work highlights the importance of thoroughly evaluating every dye-NP combination before pursuing NP-based applications. © 2016 International Society for Advancement of Cytometry.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
cellular uptake; flow cytometry; leakage; liposomes; nanoemulsions; polymeric nanoparticles
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-146318 (URN)10.1002/cyto.a.22853 (DOI)000408333700004 ()27077940 (PubMedID)2-s2.0-84963800614 (Scopus ID)
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2018-04-19Bibliographically approved
Nordeman, P., Johansson, L. B. G., Bäck, M., Estrada, S., Hall, H., Sjölander, D., . . . Antoni, G. (2016). 11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates. ACS Medicinal Chemistry Letters, 7(4), 368-373
Open this publication in new window or tab >>11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates
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2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed) Published
Abstract [en]

Three oligothiophenes were evaluated as PET tracers for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver and spleen. To verify the specificity of the oligothiophenes towards amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, in vivo rat and monkey PET-CT studies showed very low uptake in the brain, pancreas and heart of the healthy animals indicating low non-specific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Chemical Sciences Cell Biology
Identifiers
urn:nbn:se:liu:diva-122273 (URN)10.1021/acsmedchemlett.5b00309 (DOI)000374436700007 ()
Note

Funding agencies:  Swedish Research Council; Swedish Foundation for Strategic Research; LiU-Neuro; Ehrling-Persson Foundation; Goran-Gustafsson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

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Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2018-04-25Bibliographically approved
Magnusson, K., Appelqvist, H., Cieślar-Pobuda, A., Bäck, M., Kågedal, B., Jonasson, J., . . . Nilsson, P. R. (2015). An imidazole functionalized pentameric thiophene displays different staining patterns in normal and malignant cells. Frontiers in Chemistry, 3, Article ID 58.
Open this publication in new window or tab >>An imidazole functionalized pentameric thiophene displays different staining patterns in normal and malignant cells
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2015 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 3, article id 58Article in journal (Refereed) Published
Abstract [en]

Molecular tools for fluorescent imaging of cells and their components are vital for understanding the function and activity of cells. Here, we report an imidazole functionalized pentameric oligothiophene, p-HTIm, that can be utilized for fluorescent imaging of cells. p-HTIm fluorescence in normal cells appeared in a peripheral punctate pattern partially co-localized with lysosomes, whereas a one-sided perinuclear Golgi associated localization of the dye was observed in malignant cells. The uptake of p-HTIm was temperature dependent and the intracellular target was reached within 1 h after staining. The ability of p-HTIm to stain cells was reduced when the imidazole side chain was chemically altered, verifying that specific imidazole side-chain functionalities are necessary for achieving the observed cellular staining. Our findings confirm that properly functionalized oligothiophenes can be utilized as fluorescent tools for vital staining of cells and that the selectivity towards distinct intracellular targets are highly dependent on the side-chain functionalities along the conjugated thiophene backbone.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2015
Keywords
Oligothiophenes, fluorescence, cells, imaging, imidazole
National Category
Clinical Medicine Chemical Sciences Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-121813 (URN)10.3389/fchem.2015.00058 (DOI)000373364600001 ()
Note

Vid tiden för disputation förelåg publikationen som manuskript

Funding agencies:  Swedish Foundation for Strategic Research; GeCONil [POIG.02.03.01-24-099/13]; ERC from the European Research Council

Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2017-12-01Bibliographically approved
Cieslar-Pobuda, A., Bäck, M., Magnusson, K., Vilas Jain, M., Rafat, M., Ghavami, S., . . . Los, M. J. (2014). Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives. Cytometry Part A, 85A(7), 628-635
Open this publication in new window or tab >>Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives
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2014 (English)In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 85A, no 7, p. 628-635Article in journal (Refereed) Published
Abstract [en]

Fluorescent compounds capable of staining cells selectively without affecting their viability are gaining importance in biology and medicine. Recently, a new family of optical dyes, denoted luminescent conjugated oligothiophenes (LCOs), has emerged as an interesting class of highly emissive molecules for studying various biological phenomena. Properly functionalized LCOs have been utilized for selective identification of disease-associated protein aggregates and for selective detection of distinct cells. Herein, we present data on differential staining of various cell types, including cancer cells. The differential staining observed with newly developed pentameric LCOs is attributed to distinct side chain functionalities along the thiophene backbone. Employing flow cytometry and fluorescence microscopy we examined a library of LCOs for stainability of a variety of cell lines. Among tested dyes we found promising candidates that showed strong or moderate capability to stain cells to different extent, depending on target cells. Hence, LCOs with diverse imidazole motifs along the thiophene backbone were identified as an interesting class of agents for staining of cancer cells, whereas LCOs with other amino acid side chains along the backbone showed a complete lack of staining for the cells included in the study. Furthermore, for p-HTMI,a LCO functionalized with methylated imidazole moieties, the staining was dependent on the p53 status of the cells, indicating that the molecular target for the dye is a cellular component regulated by p53. We foresee that functionalized LCOs will serve as a new class of optical ligands for fluorescent classification of cells and expand the toolbox of reagents for fluorescent live imaging of different cells.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keywords
cancer stem cells; luminescent conjugated oligothiophenes; fluorescent probes
National Category
Clinical Medicine Chemical Sciences Medical Biotechnology Computer and Information Sciences
Identifiers
urn:nbn:se:liu:diva-109171 (URN)10.1002/cyto.a.22437 (DOI)000338007700010 ()24500794 (PubMedID)
Available from: 2014-08-12 Created: 2014-08-11 Last updated: 2018-01-11Bibliographically approved
Simon, R., Shirani, H., Åslund, K. O., Bäck, M., Haroutunian, V., Gandy, S. & Nilsson, P. R. (2014). Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts. Chemistry - A European Journal, 20(39), 12537-12543
Open this publication in new window or tab >>Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
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2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 39, p. 12537-12543Article in journal (Refereed) Published
Abstract [en]

A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2014
Keywords
fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-111655 (URN)10.1002/chem.201402890 (DOI)000342626200026 ()25111601 (PubMedID)
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2017-12-05Bibliographically approved
Simon, R., Bäck, M., Shirani, H., Lindgren, M. & Nilsson, P. R. (2014). pH-dependent optical transitions in anionic pentameric oligothiophenes.
Open this publication in new window or tab >>pH-dependent optical transitions in anionic pentameric oligothiophenes
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Understanding the photo-physical processes in fluorescent probes are essential as such dyes are widely utilized in molecular biology. Here we report the pH-dependent optical transitions of a library of anionic pentameric luminescent conjugated oligothiophenes (LCOs) that have been used for fluorescent identification of protein aggregates, the pathological hallmark of many devastating diseases. Absorption-, excitation- and emission spectra were recorded for all LCOs in different buffers with a pH range from 3.5 to 7. p-FTAA, a LCO having a central core consisting of a trimeric thiophene  building block with head-to-head acetic acid functionalization as well as terminal carboxyl groups extending the pentameric thiophene backbone, displayed pH/dependent optical characteristics correlating to a non-planar to planar transition of the conjugated backbone as well as aggregation between adjacent thiophene chain upon protonation of the  acetic acid side chains. In contrast, chemically related analogues to p-FTAA lacking the  terminal carboxyl groups extending the pentameric thiophene backbone or the conformational ability to undergo a non/planar to planar transition of the  conjugated backbone, displayed different optical characteristics compared to p-FTAA. Overall these studies highlighted that minor chemical alteration of LCOs can result in major difference in the optical characteristics obtained from the dyes and the results might aid in designing novel LCOs that have  superior optical performance as amyloid ligands.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-111656 (URN)
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2014-10-28Bibliographically approved
Sandgren, V., Bäck, M., Kvarnström, I. & Dahlgren, A. (2013). Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents. Open Medicinal Chemistry Journal, 7, 1-15
Open this publication in new window or tab >>Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
2013 (English)In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, p. 1-15Article in journal (Refereed) Published
Abstract [en]

Novel BACE-1 inhibitors with a hydroxyethylene central core have been  developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e., 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.

Place, publisher, year, edition, pages
Bussum, Netherlands: Bentham Open, 2013
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76171 (URN)10.2174/1874104501307010001 (DOI)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
Bäck, M. (2009). Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.

Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.

Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. p. 74
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1253
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17850 (URN)978-91-7393-642-2 (ISBN)
Public defence
2009-05-15, Hörsal Planck, Campus Valla, Linköpings universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2014-01-09Bibliographically approved
Bäck, M., Nyhlén, J., Kvarnström, I., Appelgren, S., Borkakoti, N., Jansson, K., . . . Samuelsson, B. (2008). Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.. Bioorganic & medicinal chemistry, 16(21), 9471-9486
Open this publication in new window or tab >>Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
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2008 (English)In: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, no 21, p. 9471-9486Article in journal (Refereed) Published
Abstract [en]

Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

Keywords
Alzheimer’s disease, BACE-1 inhibitors, P1 modifications, Peptidomimetics
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17848 (URN)10.1016/j.bmc.2008.09.041 (DOI)18842420 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2009-04-22Bibliographically approved
Bäck, M., Johansson, P.-O., Wångsell, F., Thorstensson, F., Kvarnström, I., Ayesa, S., . . . Samuelsson, B. (2007). Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.. Bioorganic & Medicinal Chemistry, 15(22), 7184-7202
Open this publication in new window or tab >>Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 7184-7202Article in journal (Refereed) Published
Abstract [en]

Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17846 (URN)10.1016/j.bmc.2007.07.027 (DOI)17845856 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2017-12-13Bibliographically approved
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