| 1. |
- Al-Smadi, Derar, 1983-, et al.
(författare)
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Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di-, and Tri-Hydroxypentanones
- 2019
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 84:11, s. 6982-6991
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Tidskriftsartikel (refereegranskat)abstract
- Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes or metal-organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl or phenyl glyoxal promoted by SmI2 resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn products (de = 60−99 %), with moderate enantiomeric excesses (ee = 43−56%), but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2-promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenylsubstituted 2,3-dihydroxybutanones, at yields between 40−60%. Finally, the biocatalytic approach resulted in enantiopure syn (3R,4S) 1,3,4-trihydroxypentan-2-ones.
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| 2. |
- Al-Smadi, Derar, 1983-, et al.
(författare)
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Synthesis of substrates for aldolase-catalyzed reactions : A comparison of methods for the synthesis of substituted phenylacetaldehydes
- 2018
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Ingår i: Synlett. - : Georg Thieme Verlag KG. - 0936-5214 .- 1437-2096. ; 29:9, s. 1187-1190
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Tidskriftsartikel (refereegranskat)abstract
- Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic add (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.
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| 3. |
- Andersson, Charlotta, et al.
(författare)
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Phase-contrast MRI volume flow - a comparison of breath held and navigator based acquisitions
- 2016
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Ingår i: BMC Medical Imaging. - : BioMed Central. - 1471-2342. ; 16:26
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Tidskriftsartikel (refereegranskat)abstract
- Background: Magnetic Resonance Imaging (MRI) 2D phase-contrast flow measurement has been regarded as the gold standard in blood flow measurements and can be performed with free breathing or breath held techniques. We hypothesized that the accuracy of flow measurements obtained with segmented phase-contrast during breath holding, and in particular higher number of k-space segments, would be non-inferior compared to navigator phase-contrast. Volumes obtained from anatomic segmentation of cine MRI and Doppler echocardiography were used for additional reference. Methods: Forty patients, five women and 35 men, mean age 65 years (range 53-80), were randomly selected and consented to the study. All underwent EKG-gated cardiac MRI including breath hold cine, navigator based free-breathing phase-contrast MRI and breath hold phase-contrast MRI using k-space segmentation factors 3 and 5, as well as transthoracic echocardiography within 2 days. Results: In navigator based free-breathing phase-contrast flow, mean stroke volume and cardiac output were 79.7 +/- 17.1 ml and 5071 +/- 1192 ml/min, respectively. The duration of the acquisition was 50 +/- 6 s. With k-space segmentation factor 3, the corresponding values were 77.7 ml +/- 17.5 ml and 4979 +/- 1211 ml/min (p = 0.15 vs navigator). The duration of the breath hold was 17 +/- 2 s. K-space segmentation factor 5 gave mean stroke volume 77.9 +/- 16.4 ml, cardiac output 5142 +/- 1197 ml/min (p = 0.33 vs navigator), and breath hold time 11 +/- 1 s. Anatomical segmentation of cine gave mean stroke volume and cardiac output 91.2 +/- 20.8 ml and 5963 +/- 1452 ml/min, respectively. Echocardiography was reliable in 20 of the 40 patients. The mean diameter of the left ventricular outflow tract was 20.7 +/- 1.5 mm, stroke volume 78.3 ml +/- 15.2 ml and cardiac output 5164 +/- 1249 ml/min. Conclusions: In forty consecutive patients with coronary heart disease, breath holding and segmented k-space sampling techniques for phase-contrast flow produced stroke volumes and cardiac outputs similar to those obtained with free-breathing navigator based phase-contrast MRI, using less time. The values obtained agreed fairly well with Doppler echocardiography while there was a larger difference when compared with anatomical volume determinations using SSFP (steady state free precession) cine MRI.
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| 4. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
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| 5. |
- Andersson, Vincent, et al.
(författare)
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Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:14, s. 6658-6670
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Tidskriftsartikel (refereegranskat)abstract
- The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.
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| 6. |
- Ankner, Tobias, et al.
(författare)
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Mild Oxidative Cleavage of 9-BBN-Protected Amino Acid Derivatives
- 2015
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :17, s. 3767-3770
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Tidskriftsartikel (refereegranskat)abstract
- Protection of the amino acid moiety using 9-BBN is an effective method to enable side chain manipulations in synthesis of complex amino acids. We investigated the standard, mild method for deprotection of the 9-BBN group in methanolic chloroform, and found that it relies on a slow oxidation mediated by molecular oxygen. Building on this insight, we have developed a method that allows for a fast and selective deprotection using simple peroxy acid reagents. After Fmoc protection, products were isolated in >90% yield for a series of amino acid derivatives, including a galactosylated derivative of hydroxylysine.
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| 7. |
- Bergman, Hilde-Marlene, et al.
(författare)
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Metabolite aberrations in early diabetes detected in rat kidney using mass spectrometry imaging
- 2019
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 411:13, s. 2809-2816
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease is a serious complication of diabetes that can ultimately lead to end-stage renal disease. The pathogenesis of diabetic kidney disease is complex, and fundamental research is still required to provide a better understanding of the driving forces behind it. We report regional metabolic aberrations from an untargeted mass spectrometry imaging study of kidney tissue using an insulinopenic rat model of diabetes. Diabetes was induced by intravenous injection of streptozotocin, and kidneys were harvested 2weeks thereafter. Imaging was performed using nanospray desorption electrospray ionization connected to a high-mass-resolving mass spectrometer. No histopathological changes were observed in the kidney sections; however, mass spectrometry imaging revealed a significant increase in several 18-carbon unsaturated non-esterified fatty acid species and monoacylglycerols. Notably, these 18-carbon acyl chains were also constituents of several increased diacylglycerol species. In addition, a number of short- and long-chain acylcarnitines were found to be accumulated while several amino acids were depleted. This study presents unique regional metabolic data indicating a dysregulated energy metabolism in renal mitochondria as an early response to streptozotocin-induced type I diabetes.
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| 8. |
- Caron, Giulia, et al.
(författare)
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Intramolecular hydrogen bonding : An opportunity for improved design in medicinal chemistry
- 2019
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Ingår i: Medicinal research reviews (Print). - : Wiley. - 0198-6325 .- 1098-1128. ; 39:5, s. 1707-1729
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Forskningsöversikt (refereegranskat)abstract
- Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion-Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB-associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.
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| 9. |
- Doak, Bradley C., et al.
(författare)
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Cyclophilin Succumbs to a Macrocyclic Chameleon
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 61:21, s. 9469-9472
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Tidskriftsartikel (refereegranskat)abstract
- Targets that have large and groove-shaped binding sites, such as cyclophilin, are difficult to drug with small molecules. Macrocycles of natural product origin can be ideal starting points for such targets as illustrated by the transformation of sanglifehrin A into an orally bioavailable potential candidate drug. Optimization benefits from development of convergent, modular synthetic routes in combination with structure and property based methods for lead optimization.
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| 10. |
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