| 1. |
- Lindström, Anton, et al.
(författare)
-
Hierarchical PLS modeling for predicting the binding of a comprehensive set of structurally diverse protein-ligand complexes.
- 2006
-
Ingår i: Journal of Chem Inf Model. - : American Chemical Society (ACS). - 1549-9596. ; 46:3, s. 1154-1167
-
Tidskriftsartikel (refereegranskat)abstract
- A new approach is presented for predicting ligand binding to proteins using hierarchical partial-least-squares regression to latent structures (Hi-PLS). Models were based on information from the 2002 release of the PDBbind database containing (after in-house refinement) high-resolution X-ray crystallography and binding affinity (Kd or Ki) data for 612 protein-ligand complexes. The complexes were characterized by four different descriptor blocks: three-dimensional (3D) structural descriptors of the proteins, protein-ligand interactions according to the Validate scoring function, binding site surface areas, and ligand 2D and 3D descriptors. These descriptor blocks were used in Hi-PLS models, generated using both linear and nonlinear terms, to relate the characterizations to pKd/i. The results show that each of the four descriptor blocks contributed to the model, and the predictions of pKd/i of the internal test set gave a root-mean-square error of prediction (RMSEP) of 1.65. The data were further divided according to the structural classification of the proteins, and Hi-PLS models were constructed for the resulting subclasses. The models for the four subclasses differed considerably in terms of both their ability to predict pKd/i (with RMSEPs ranging from 0.8 to 1.56) and the descriptor block that had the strongest influence. The models were validated with an external test set of 174 complexes from the 2003 release of the PDBbind database. The overall results show that the presented Hi-PLS methodology could facilitate the difficult task of predicting binding affinity.
|
|
| 2. |
- Åberg, Veronica, 1976-, et al.
(författare)
-
Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of A beta-peptide aggregation inhibitors
- 2005
-
Ingår i: Organic and biomolecular chemistry. - London, U.K. : Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 3:15, s. 2817-2823
-
Tidskriftsartikel (refereegranskat)abstract
- A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 degrees C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on A beta-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer A beta(1-40) peptide. The effect was seen even at a 4 : 1 ratio of 2-pyridone and monomeric A beta-peptide.
|
|
| 3. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
-
Enhanement of amyloid fibril binding by ring expansion of thiazolino fused 2-pyridone peptidomimetics
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Thiazolino fused 2-pyridones undergo thiazoline ring opening by reaction with 2-nitrobenzyl bromide through thi- oether attack, and base promoted fragmentation of the resulting sulfonium ions. Subsequent deprotonation of the benzylic carbon and intramolecular 1,4-addition leads to ring closure, generating dihydrothiazine fused 2-pyridones by net ring expansion of the thiazoline ring. Application of the ring expansion procedure to the pyridine and pyrimidine fused thiazolino 2-pyridones provided compounds with enhanced fibril binding activity.
|
|
| 4. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
-
Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-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 in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
|
|
| 5. |
- Adolfsson, Dan E., 1989-
(författare)
-
Synthesis of Ring-fused Peptidomimetics : Interacting with Amyloid Fibrils
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson's and Alzheimer's disease are the two most common neurological disorders in humans. Both conditions involve progressive death of neurons in the central nervous system, decline in bodily functions and eventually (and invariably), death. So far, no cure exists and the available treatments can only ease symptoms. Despite substantial investments in research, the biomolecular processes are still far from fully understood. However, both diseases are associated with formation of fibrillar protein aggregates called amyloid deposits. Whereas Alzheimer’s disease involves aggregation of the Tau and Amyloid β proteins, α-Synuclein fibrilization plays a key role in Parkinson's disease. Although they are chemically distinct, the deposits consist of protein fibres with similar morphology and fold. Small molecules, such as the thiazoline fused 2-pyridones herein presented, can interfere with the formation of amyloid fibres, or bind to them. Besides having potential for diagnostication and treatment, such small molecules constitute valuable tool compounds in future research, to unravel the mechanisms of amyloid formation and pathology. The first step towards successful treatment, diagnostication and prevention of Alzheimer's and Parkinson's disease is understanding the causes and underlying mechanisms better. This thesis narrates the synthesis and development of novel chemical structures: multi ring fused peptidomimetics with the ability to bind mature amyloid fibrils, consisting of α-Synuclein or Amyloid β. The first project (articles I, III and VI) describes method development for the extension of bicyclic thiazolino 2-pyrdiones by fusion with aromatic nitrogen heterocycles, which enables the desired amyloid binding properties. Derivatisations of the newly generated central scaffold, and variation of the multiple attached substituents, were subsequently performed in efforts to improve binding strength and solubility, and gain selectivity towards certain fibrils. One of the most promising amyloid fibril binders was evaluated in a human cell line and in mice, and found to be protective against accelerator induced neurotoxicity. One pyrimidine fused compound moreover indicated potent inhibition of Amyloid b aggregation. The second project (articles II, IV and V) focuses on development of methods to modify the thiazoline ring. Ring opening induced by electrophiles generates N-alkenyl 2-pyridones but decreases amyloid binding potency. Introduction of a cyclobutane moiety fused with the thiazoline ring is better tolerated, and adds a terminal alkene moiety that can be exploited in future chemical modifications. Expansion of the five membered thiazoline ring to a six membered dihydrothiazine ring, equipped with a nitrophenyl substituent, provides compounds with enhanced fibril binding capacity, which further inhibits Amyloid β fibril formation in vitro. Taken together, the synthetic methodologies allow construction and late stage modification of complex fused heterocycles, with several points of variation. Thus, the developed methods may be of future value in our laboratories and elsewhere.
|
|
| 6. |
- Aliashkevich, Alena, 1990-
(författare)
-
Molecular mechanisms and biological consequences of the production of non-canonical D-amino acids in bacteria
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most bacteria possess a vital net-like macromolecule – peptidoglycan (PG). PG encases bacteria around the cytoplasmic membrane to withstand the high internal turgor pressure and thereby protect the cell from bursting. In addition, PG is a major morphological determinant of bacteria being both required and sufficient to maintain cell shape. During cell growth PG hydrolysis and synthesis are tightly controlled to keep proper cell shape and integrity at all times. Given the essentiality of PG for bacterial growth and survival, the synthesis of this polymer is a major target of many natural and synthetic antibiotics (e.g. penicillins, glycopeptides).For a long time, PG composition was considered to be conserved and static, however it’s now being recognized as a dynamic and plastic macromolecule. The structure and chemistry of PG is influenced by a myriad of environmental cues that include interkingdom/interspecies interactions. Recently, it was found that a wide set of non-canonical D-amino acids (D-amino acids different from D-Ala and D-Glu, NCDAAs) are produced and released to the extracellular milieu by diverse bacteria. In Vibrio cholerae these NCDAAs are produced by broad-spectrum racemase enzyme (BsrV) and negatively regulate PG synthesis through their incorporation into PG. We have shown that in addition to D-Met and D-Leu, which were reported previously, V. cholerae also releases high amounts of D-Arg, which inhibits a broader range of phylogenetically diverse bacteria. Thus, NCDAAs affect not only the producer, but might target other species within the same environmental niche. However, in contrast to D-Met, D-Arg targets cell wall independent pathways. We have shown that non-proteinogenic amino acids also can be racemized by Bsr. A plant amino acid L-canavanine (L-CAN) is converted into D-CAN by a broad-spectrum amino acid racemase (BSAR) of the soil bacterium Pseudomonas putida and subsequently released to the environment. D-CAN gets highly incorporated into the PG of Rhizobiales (such as Agrobacterium tumefaciens, Sinorhizobium meliloti) thereby affecting the overall PG structure, bacterial morphogenesis and growth fitness. We found that detrimental effect of D-CAN in A. tumefaciens can be suppressed by a single amino acid substitution in the cell division PG transpeptidase penicillin-binding protein 3a (PBP3a). Rhizobiales are a polar-growing species that encode multiple LD-transpeptidases (LDTs), enzymes that normally perform PG crosslinking, but that can also incorporate NCDAAs into termini of the PG peptides. As these species incorporate high amounts of D-CAN in their PG, we hypothesized that LDTs might represent the main path used by NCDAAs to edit A. tumefaciens’ PG and cause their detrimental effects. Therefore, we decided to further explore the significance of LDT proteins for growth and morphogenesis in A. tumefaciens. While in the Gram-negative model organism E. coli LDT proteins are non-essential under standard laboratory conditions, we found that A. tumefaciens needs at least one LDT for growth out of the 14 putative LDTs encoded in its genome. Moreover, clustering the LDT proteins based on their sequence similarity revealed that A. tumefaciens has 7 LDTs that are exclusively present among Rhizobiales. Interestingly, the loss of this group of LDTs (but not the rest) leads to reduced growth, lower PG crosslinkage and rounded cell phenotype, which suggests that this group of Rhizobiales- specific LDTs have a major role in maintaining LD-crosslinking homeostasis, which in turn is important for cell elongation and proper shape maintenance in A. tumefaciens.
|
|
| 7. |
- Almqvist, Andreas, et al.
(författare)
-
An Abbott curve based rough surface contact mechanics approach
- 2005
-
Ingår i: Proceedings of the World Tribology Congress III - 2005. - New York : American Society of Mechanical Engineers. ; , s. 397-398
-
Konferensbidrag (refereegranskat)abstract
- In this way all the height information of the surface profile is preserved and not only a few parameters, like Ra, Rq, Rz, Rsk, etc. The aim of this work is to investigate how classes of surfaces based on a single Abbott curve perform in terms of contact mechanical parameters like the real area of contact. The result shows that surfaces taken from a class of random surfaces generated from a specific Abbott curve behaves similar in a contact mechanics simulation. That is, the distribution of for example the real area of contact within such a class is compact, having a small deviation from its mean.This implies that it is possible to simulate classes of surfaces based on Abbott curves and to use the results to predict contact mechanical properties of real surface topographies.
|
|
| 8. |
- Almqvist, Andreas, et al.
(författare)
-
Development of a lubrication simulation model
- 2009
-
Ingår i: Svenska mekanikdagarna. - Stockholm : Svenska nationalkommittén för mekanik. ; , s. 74-
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Almqvist, Andreas, et al.
(författare)
-
On the dry elasto-plastic contact of nominally flat surfaces
- 2007
-
Ingår i: Tribology International. - : Elsevier BV. - 0301-679X .- 1879-2464. ; 40:4, s. 574-579
-
Tidskriftsartikel (refereegranskat)abstract
- A model to be used for numerical simulation of the contact of linear elastic perfectly plastic rough surfaces was developed. Energy dissipation due to plastic deformation is taken into account. Spectral theory and an FFT-techique are used to facilitate the numerical solution process. Results of simulations using four two-dimensional profiles with different topographies in contact with a rigid plane for a number loads are reported. From the results it is clear that the real area of contact (Ar) changes almost linearly with load and is only slightly affected by the difference in topography. A plasticity index is defined as the ratio of plastically deformed area (Ap) and Ar. Plastic deformation occurs even at low loads and there is a significant difference in plasticity index between the surface profiles considered. An investigation on how the spectral content of the surface profile influences the results presented is also performed. This is to ensure that the metrological limitations of the optical profilerused to measure the surfaces do not have a significant influence. It is concluded that the highest frequencies of the measured profile have a negligible influence on the real area of contact.
|
|
| 12. |
|
|
| 13. |
- Almqvist, Fredrik, et al.
(författare)
-
An Improved Procedure for the Synthesis of Bicyclo[2.2.2]octane- 2,6-dione
- 1993
-
Ingår i: Synthetic Communications. - : Informa UK Limited. - 0039-7911 .- 1532-2432. ; 23:11, s. 1499-1505
-
Tidskriftsartikel (refereegranskat)abstract
- Conjugate addition of Meldrum's acid to 2-cyclohexenone followed by direct cyclization in PPA/acetic acid constitutes a shorter, more reproducible and higher yielding route to bicyclo[2.2.2]octane-2,6-dione than previous methods. The crude dione could be used as substrate for the baker's yeast reduction to (IR, 4S, 6S)-bicyclo[2.2.2]octane-6-ol-2-one.
|
|
| 14. |
- Almqvist, Fredrik, et al.
(författare)
-
Neighboring Group Participation in a Regio- and Stereoselective Chlorination of a Bicyclo[2.2.2]octanone
- 1996
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 61:20, s. 6947-6951
-
Tidskriftsartikel (refereegranskat)abstract
- The zinc chloride-mediated acetylation of the optically active silyl enol ether 2a gave the beta-diketone 3a (48%) together with the regio- and stereoselectively chlorinated compound 4 (27%). The yield of 4 increased to 70% by starting from the O-acetyl derivative 2c. The chlorination most likely occurs via neighboring group participation by the endo acetoxy group.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Almqvist, Fredrik, et al.
(författare)
-
Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
-
Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 2:21, s. 3085-3090
-
Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
|
|
| 19. |
- Almqvist, Fredrik, et al.
(författare)
-
Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
-
Ingår i: Organic and Biomolecular Chemistry. - 1477-0539. ; 2:21, s. 3085-3090
-
Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
|
|
| 20. |
- Almqvist, Fredrik, et al.
(författare)
-
Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
-
Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 2:21, s. 3085-90
-
Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
|
|
| 21. |
- Almqvist, Fredrik, et al.
(författare)
-
Synthesis of Optically Active endo, endo Bicyclo[2.2.2]octane-2,5- diol, Bicyclo[2.2.2]octan-2,5-dione and Related Compounds
- 1996
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 61:11, s. 3794-3798
-
Tidskriftsartikel (refereegranskat)abstract
- Optically active C-2-symmetric (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol ((+)-12; 98% ee) and several selectivity protected optically active intermediates useful for synthetic transformations were synthesized via a 1,2-carbonyl transposition route starting from the easily available optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one ((-)-2). The synthetic route also allowed the preparation of optically active (1S,4S)-bicyclo[2.2.2]octane-2,5-dione ((+)-14; 98% ee).
|
|
| 22. |
- Andersson, Emma K., et al.
(författare)
-
Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
- 2013
-
Ingår i: Chemistry and Biology. - : Elsevier. - 1074-5521 .- 1879-1301. ; 20:10, s. 1245-1254
-
Tidskriftsartikel (refereegranskat)abstract
- Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."
|
|
| 23. |
- Andersson, Hans, et al.
(författare)
-
Complete regioselective addition of grignard reagents to pyrazine N-oxides, toward an efficient enantioselective synthesis of substituted piperazines.
- 2010
-
Ingår i: Organic letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 12:2, s. 284-6
-
Tidskriftsartikel (refereegranskat)abstract
- A conceptually new one-pot strategy for the synthesis of protected substituted piperazines via the addition of Grignard reagents to pyrazine N-oxides is presented. This strategy is high yielding (33-91% over three steps), step-efficient, and fast. The synthesized N,N-diprotected piperazines are convenient to handle and allow for orthogonal deprotection at either nitrogen for selective transformations. In addition, this is a synthetic route to enantiomerically enriched piperazines by using a combination of phenyl magnesium chloride and (-)-sparteine, which resulted in enantiomeric excesses up to 83%.
|
|
| 24. |
- Andersson, Hans, et al.
(författare)
-
Efficient, mild and completely regioselective synthesis of substituted pyridines
- 2010
-
Ingår i: Chemical Communications. - : RSC Publishing. - 1359-7345 .- 1364-548X. ; 46:19, s. 3384-3386
-
Tidskriftsartikel (refereegranskat)abstract
- Addition of Grignard reagents to pyridine N-oxides in THF at low temperature (-78 to -20 °C) and treatment with TFAA provides an efficient general procedure for synthesis of substituted pyridines. The method is compatible with a range of functional groups such as esters, halogens and nitriles.
|
|
| 25. |
- Andersson, Hans, 1978-
(författare)
-
Reaction Between Grignard reagents and Heterocyclic N-oxides : Synthesis of Substituted Pyridines, Piperidines and Piperazines
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides. The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed. In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound. In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.
|
|
