| 1. |
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| 2. |
- Bozzola, Tiago, et al.
(author)
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Direct Sialic Acid 4-OAc Substitution by Nitrogen, Sulfur and Carbon Nucleophiles with Retention of Stereochemistry
- 2022
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In: RSC Advances. - 2046-2069. ; 12:19, s. 11992-11995
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Journal article (peer-reviewed)abstract
- A direct one-step nucleophilic substitution of the 4-OAc of acetyl protected Neu5Ac is presented. Previously published methods for direct substitution of the 4-OAc are limited to cyclic secondary amines. Here we present conditions that allow for a much wider range of nitrogen nucleophiles as well as thiols and cyanide, to be used. The present investigation significantly broadens the scope of 4-aminations and allows for the introduction of a wide variety of different nucleophiles.
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| 3. |
- Bozzola, Tiago, et al.
(author)
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Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter
- 2022
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In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:23
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Journal article (peer-reviewed)abstract
- In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.
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| 4. |
- Bozzola, Tiago, et al.
(author)
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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
- 2022
-
In: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7, s. 1890-1900
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Journal article (peer-reviewed)abstract
- Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
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| 5. |
- Abrahamsson, Carl-Olof, et al.
(author)
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Xylosylated naphthoic acid-amino acid conjugates for investigation of glycosaminoglycan priming.
- 2008
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In: Carbohydrate Research. - : Elsevier BV. - 1873-426X .- 0008-6215. ; 343:9, s. 1473-1477
-
Journal article (peer-reviewed)abstract
- Three different series of xylosylated naphthoic acid-amino acid conjugates containing one or two amino acid residues were synthesized for the investigation of glycosaminoglycan priming and potential use as anti-tumor drugs. All xylosylated naphthoic acid-conjugates inhibited the growth of normal lung fibroblasts to some extent, whereas the growth of tumor derived T24 carcinoma cells was not affected. There was no correlation between amino acid conjugation, retention time and the antiproliferative activity. Only one compound initiated the priming of glycosaminoglycans. Modification of the naphthalene ring with one or two amino acid residues did not have any effect on proteoglycan biosynthesis or glycosaminoglycan priming in T24 carcinoma cells.
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| 6. |
- Adrian Meredith, Jenny, 1971-
(author)
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Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-1
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- This thesis describes the synthesis of molecules designed for inhibition of two aspartic proteases, viral HIV-1 PR and human BACE-1. It also reports on the structure activity relationships of the targeted enzyme inhibitors. It is estimated that currently 33 million people are infected with HIV, the causative agent of AIDS. The virus targets T-lymphocytes and macrophages of the human immune system. The HIV-1 PR plays an important role in the viral replication, and by inhibiting the enzyme the disease progression can be slowed down or even halted. Herein is reported the design and synthesis of a series of HIV-1 PR inhibitors with novel P2 substituents of which several inhibit the enzyme in the nanomolar range. The aim of the second work was to further develop the inhibitors by the introduction of fluorine. Several attempts were performed to fluorinate different P2-substituents. Alzheimer’s disease (AD) is neurodegenerative, progressive and fatal disorder of the brain. It is associated with accumulation of plaques and tangles that cause impairment and functional decline of brain tissue which result in loss of memory and cognition. The plaques are mainly constituted of amyloid-β peptides that are generated in two steps from the amyloid precursor protein (APP). The cleavage sequence is initiated by the aspartic protease BACE-1, which makes the enzyme a key target in the effort of finding a therapy that aim to slow down the progression of AD. Herein are enclosed the development of two series of potent BACE-1 inhibitors. In the first work a synthetic strategy was developed to truncate a previously reported hydroxyethylene core structure in order to generate more drug-like inhibitors. This generated a series of truncated inhibitors where two amide bonds have been replaced with an ether - or alternatively a secondary amine linkage. A number of these inhibitors show potency against BACE-1. In the second part of the work the aim was investigate the effect of alterations in the P1 position. Five scaffolds with new P1 substituents were designed, synthesized and coupled with two different P2-P3 substituents. This resulted in a series of potent inhibitors that inhibit BACE-1 in the nanomolar range.
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| 7. |
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| 8. |
- Aili, Ulrika, et al.
(author)
-
Antiproliferative effects of peracetylated naphthoxylosides.
- 2009
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In: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X. ; 19, s. 1763-1766
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Journal article (peer-reviewed)abstract
- The antiproliferative activity, and the capability of priming of glycosaminoglycan chains, of two series of peracetylated mono- and bis-xylosylated dihydroxynaphthalenes have been investigated for normal HFL-1 cells, as well as transformed T24 cells, and compared to the unprotected analogs. Our data show increased antiproliferative activity upon peracetylation, but a loss of selectivity towards T24 cells.
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| 9. |
- Aili, Ulrika, et al.
(author)
-
Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.
- 2010
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In: Cancer Research. - 1538-7445. ; 70:9, s. 3771-3779
-
Journal article (peer-reviewed)abstract
- Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.
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| 10. |
- Alpe, Marianne, 1971-
(author)
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Synthesis of oligosaccharides related to the capsular polysaccharides of Streptococcus pneumoniae serotype 9 and of Cryptococcus neoformans
- 2003
-
Doctoral thesis (other academic/artistic)abstract
- In the present investigation, synthesis of oligosaccharides corresponding to structural elements present in the capsular polysaccharides of Streptococcus pneumoniae and Cryptococcus neoformans has been achieved. The first two sections describe the synthesis of spacer-equipped oligosaccharides corresponding to structures from the CPS of Streptococcus pneumoniae serotypes 9N, 9A and 9L, the production of which involved synthetic challenges such as the construction of β-ManNAc and α-GlcA linkages. The former challenge was met by employing azide displacement of a 2-O-triflate substituent on a β-glucoside, whereas the latter task was accomplished utilizing thioethyl glucuronic acid donors in the presence of various promoters. The pentasaccharide product obtained correspond to the complete repeating unit of the CPS of serotype 9A.The last two sections of this thesis describe the construction of thioglycoside di- and trisaccharide building blocks containing α-Man, β-Xyl, β-GlcA and 6-O-acetyl motifs, as well as subsequent assembly of these building blocks into oligosaccharides corresponding to the repeating units of the capsular polysaccharide of the yeast Cryptococcus neoformans. The GlcA moiety was introduced via trichloroacetimidate coupling involving the peracetylated glucuronic acid methyl ester donor, after which the subsequent necessary benzylation was performed with the di- and trisaccharides. All of the target oligosaccharides were synthesized as amino-spacer glycosides in order to make conjugation to a carrier protein possible.
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| 11. |
- Andersson, Stig, et al.
(author)
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Gymnasiekemi 2
- 2013. - 6
-
Book (other academic/artistic)
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| 12. |
- Aplander, Karolina, et al.
(author)
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Molecular wipes : application to epidemic keratoconjuctivitis
- 2011
-
In: Journal of Medicinal Chemistry. - Easton, Pa. : American Chemical Society. - 0022-2623 .- 1520-4804. ; 54:19, s. 6670-6675
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Journal article (peer-reviewed)abstract
- Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 mu M) and Ad infectivity (IC(50) = 0.7 mu M). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.
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| 13. |
- Belfrage, Anna Karin, 1977-
(author)
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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors : Targeting Different Genotypes and Drug-Resistant Variants
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.
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| 14. |
- Berglund, Per, et al.
(author)
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Linking Education and Research : A Roadmap for Higher Education Institutions at the Dawn of the Knowledge Society
- 2019
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In: Linking education and research. - Basel, Switzerland : MDPI. ; , s. 11-33
-
Book chapter (other academic/artistic)abstract
- In an era characterized by a move towards a “knowledge society”, universities are central in fostering “knowledgeability”, that is the reflexive understanding of knowledge in knowledge societies. The objective of “knowledgeability” can be met through creating a stronger link between education and research. Furthermore, overall student performance, for example in critical thinking and problem solving, can be improved if research-related activities are incorporated into the curriculum.The aim of this paper is to use international examples to discuss the research- education nexus from four different perspectives, namely context, policy, implementation and quality, with case studies from higher education institutions in Singapore and Sweden.We suggest that different integrative technologies can be used to enhance the links, but it will be essential to consider the inputs of training, service and support in using new technology. Interestingly, the act of evaluating the link between education and research will increase awareness of this linkage by stakeholders involved in both education and research. In turn the link can be strengthened, contributing to increased quality in both education and research.
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| 15. |
- Brisbois, Ronald G., et al.
(author)
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Iodine monochloride
- 2013
-
In: Encyclopedia of Reagents for Organic Synthesis (e-EROS). - 9780471936237 - 9780470842898 ; , s. 65-88
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Book chapter (peer-reviewed)
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| 16. |
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| 17. |
- Chen, Yen Hsi, et al.
(author)
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The GAGOme : a cell-based library of displayed glycosaminoglycans
- 2018
-
In: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 15:11, s. 881-888
-
Journal article (peer-reviewed)abstract
- Glycosaminoglycans (GAGs) are essential polysaccharides in normal physiology and disease. However, understanding of the contribution of specific GAG structures to specific biological functions is limited, largely because of the great structural heterogeneity among GAGs themselves, as well as technical limitations in the structural characterization and chemical synthesis of GAGs. Here we describe a cell-based method to produce and display distinct GAGs with a broad repertoire of modifications, a library we refer to as the GAGOme. By using precise gene editing, we engineered a large panel of Chinese hamster ovary cells with knockout or knock-in of the genes encoding most of the enzymes involved in GAG biosynthesis, to generate a library of isogenic cell lines that differentially display distinct GAG features. We show that this library can be used for cell-based binding assays, recombinant expression of proteoglycans with distinct GAG structures, and production of distinct GAG chains on metabolic primers that may be used for the assembly of GAG glycan microarrays.
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| 18. |
- Cheng, Fang, et al.
(author)
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Potentiation of naphthoxyloside cytotoxicity on human tumor cells by difluoromethylornithine and spermine-NONOate.
- 2009
-
In: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 273, s. 148-154
-
Journal article (peer-reviewed)abstract
- Here we demonstrate a synergistic and tumor selective cytotoxic effect by combined treatment with naphthoxylosides, polyamine synthesis inhibitor, and polyamine based nitric oxide (NO) donor, using in vitro human tumor models. We have earlier reported that heparan sulfate priming naphthoxyloside, 2-(6-hydroxynaphthyl)-O-beta-d-xylopyranoside, which inhibits growth of human tumor cells in vitro and in vivo models, undergoes NO dependent cleavage and accumulates in the nuclei of tumor cells. Polyamine depletion using alpha-difluoromethylornithine (DFMO) increases both the number of NO sensitive sites in heparan sulfate and uptake of the polyamine based NO donor, spermineNONOate, thereby enhancing formation of growth-inhibitory NO induced heparan sulfate products with specific cytotoxic effect on tumor cells. We also show that peracetylation of xylosides doubles the antiproliferative effect towards human cancer cells by making these compounds more permeable to the cells.
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| 19. |
- Ellervik, Ulf, et al.
(author)
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2-Bromoethyl glycosides for synthesis of glycoconjugates on solid support
- 2005
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In: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 61:9, s. 2421-2429
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Journal article (peer-reviewed)abstract
- 2-Bromoethyl glycosides can easily and in high yields be transformed into sulfones by treatment with a suitable thiol followed by oxidation with mCPBA. The observation that the so formed sulfones were cleaved by treatment with NaOMe/MeOH was used to design a new safety catch linker for synthesis of glycoconjugates on solid support. (C) 2005 Elsevier Ltd. All rights reserved.
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| 20. |
- Ellervik, Ulf, et al.
(author)
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2-(Trimethylsilyl)ethyl Glycosides. Transformation into the Corresponding. 1-O-Acyl Sugars
- 1993
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In: Acta Chemica Scandinavica. - : Danish Chemical Society. - 0904-213X. ; 47:8, s. 826-828
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Journal article (peer-reviewed)abstract
- (Trimethylsilyl)ethyl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside and (trimethylsilyl)ethyl 2,3,6-tri-O-acetyl-4-O-(2,3,6-tri-O-acetyl-4-O-[2-acetamido-4,6-di-O-ace tyl-2- deoxy-3-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-beta-D- galactopyranosyl]-beta-D-galactopyranosyl)-beta-D-glucopyranoside have been transformed in high yield into the corresponding 1-O-beta-acyl saccharides by treatment with various carboxylic anhydrides in the presence of boron trifluoride-diethyl ether in toluene. The carboxylic anhydrides (4-pentenoic, 2-cyclopentenylacetic, 2,4-dimethoxy-benzoic, and 2-methoxybenzoic anhydride) were synthesized from the corresponding carboxylic acids by treatment with N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride.
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| 21. |
- Ellervik, Ulf
(author)
-
9-Anthraldehyde acetals as protecting groups.
- 2003
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In: Tetrahedron Letters. - 0040-4039. ; 44:11, s. 2279-2281
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Journal article (peer-reviewed)abstract
- Anthraldehyde acetals can be introduced regioselectively to carbohydrates in high yields. Advantages over conventional acetal protecting groups are increased crystallinity and strong absorbance and fluorescence which facilitate purification and reaction monitoring. The anthraldehyde acetals can be deprotected selectively in the presence of benzylidene acetals and can be cleaved regioselectively to yield 6-O-(9-anthracenyl)methyl ethers.
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| 22. |
- Ellervik, Ulf, et al.
(author)
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A high yielding chemical synthesis of sialyl Lewis x tetrasaccharide and Lewis x trisaccharide; examples of regio- and stereodifferentiated glycosylations
- 1998
-
In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:25, s. 9314-9322
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Journal article (peer-reviewed)abstract
- Virtually complete regioselective galactosylation of the diol acceptor p-methoxyphenyl 6-O-benzyl-2-deoxy-2-tetrachlorophthalimido-β-D- glucopyranoside (8) with the donor phenyl 2,3,4-tri-O-acetyl-6-O-benzyl-1- thio-β-D-galactopyranoside (11) gave the lactosamine derivative 14, which was fucosylated with the donor 15 to give the Le(x) trisaccharide glycoside 2 after deprotection. Regioselective sialylation of the partially protected Le(x) trisaccharide triol 24 with the sialyl donor 25 gave, after deprotection, the SLe(x) tetrasaccharide glycoside 1. The overall yields of 2 and 1 from the monosaccharide starting materials 8, 11, 15, and 25 were 56% and 29%, respectively. In contrast to the virtually complete regio- and stereoselective galactosylation of 8, fucosylation with the benzyl-protected donor 15 gave the corresponding 1→3- and 1→4-linked disaccharides in a ratio of 3.6:1 (highly stereo- but not regioselective glycosylation), whereas fucosylation with acetyl-protected donor 18 gave a 2.2:1 β/α-mixture of 4- O-linked disaccharides (highly regio- but not stereoselective glycosylation).
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| 23. |
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| 24. |
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| 25. |
- Ellervik, Ulf, et al.
(author)
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Anomeric Effect in Furanosides. Experimental Evidence from Conformationally Restricted Compounds
- 1994
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 116, s. 2340-2347
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Journal article (peer-reviewed)abstract
- A series of conformationally restricted 0-, C-, S-, and N-“furanosides” have been synthesized, where the number 3 and 4 carbons are part of a norbornane ring system. All the carbons of the tetrahydrofuran ring are kept in one plane by the rigid norbornane skeleton, permitting only the ring oxygen to move above or below the tetrahydrofuran ring plane. This causes the substituents on carbon 2 to occupy a pseudoaxial or a pseudoequatorial position. The “norbornane-furanosides” were investigated by NMR, X-ray crystallography, and molecular mechanics calculations. The O-and S-furanosides preferred the conformation with a pseudoaxial anomeric substituent, whereas its C-furanosidic counterpart preferred the conformation with a pseudoequatorial substituent. These findings constitute the first demonstration of a “by definition” anomeric effect in furanosides. © 1994, American Chemical Society. All rights reserved.
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