| 1. |
- Meinander, K., et al.
(författare)
-
Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity
- 2013
-
Ingår i: Medchemcomm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:3, s. 549-553
-
Tidskriftsartikel (refereegranskat)abstract
- Pseudopeptides based on the kallikrein-related peptidase 3 (KLK3) activating bicyclic peptide “C-4” comprising hydrocarbon-based disulphide bridge mimetics have been synthesized. After investigating different synthetic approaches, the pseudopeptides were successfully cyclized from two L-allylglycine side chains via an alkene ring-closing metathesis reaction during the peptide synthesis. The alkene-linker was formed in a 1 : 1 E/Z isomer ratio. The resulting pseudopeptides were almost as potent as the parent peptide, increasing the activity of KLK3 over four-fold at 200 μg ml−1 (130–140 μM) concentrations.
|
|
| 2. |
- Dahlén, Kristian, 1973, et al.
(författare)
-
Synthesis of 2,3,6,8-tetrasubstituted chromone scaffolds.
- 2006
-
Ingår i: The Journal of organic chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 71:18, s. 6863-6871
-
Tidskriftsartikel (refereegranskat)abstract
- A useful and efficient synthetic strategy to 2,3,6,8-tetrasubstituted chromone derivatives has been developed. 2-Aryl/styryl-8-bromo-6-chloro-3-hydroxychromone derivatives were synthesized and used as scaffolds by introducing a variety of substituents in the 3-, 6-, and 8-positions using palladium-mediated reactions. Excellent regioselectivity in all positions could be obtained by performing reactions in the 8-position first, in which Stille, Heck, Suzuki, and Sonogashira reactions gave good to excellent yields of product (63-98%). Stille and Heck reactions in the 6-position also gave the desired products in good yields (64-86%). The hydroxy group in the 3-position was activated as a triflate and used in productive Stille reactions (63-94%). This hydroxyl group was also used in O-alkylation reactions with different functionalized alkyl bromides (57-88%). The flavonoids, which are based on the chromone structure, and other related ring systems, have several interesting biological activities. The chromones are also interesting structural scaffolds, and they have for example been designed to be used as mimetics of short peptides. The versatile applicability of chromone derivatives and especially their potential use in drug discovery implicates the importance of access to efficient synthetic routes to such compounds.
|
|
| 3. |
- Dyrager, Christine, 1975, et al.
(författare)
-
Inhibitors and promoters of tubulin polymerization : Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents
- 2011
-
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 19:8, s. 2659-2665
-
Tidskriftsartikel (refereegranskat)abstract
- A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC50 values in the 5-280 mu M range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of beta-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.
|
|
| 4. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
-
Chroman-4-one and chromone based somatostatin beta-turn mimetics
- 2016
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 114, s. 59-64
-
Tidskriftsartikel (refereegranskat)abstract
- A scaffold approach has been used to develop somatostatin beta-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' beta-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K-i-values in the low mu M range when evaluated for their affinity for the sst2 and sst4 receptors. (C) 2016 Elsevier Masson SAS. All rights reserved.
|
|
| 5. |
- Leemann, Simon, et al.
(författare)
-
Status of the MAX IV Storage Rings
- 2010
-
Ingår i: Proceedings of IPAC’10. - 9789290833529 ; , s. 2618-2620
-
Konferensbidrag (refereegranskat)abstract
- In 2009 the MAX IV facility was granted funding by Swedish authorities. Construction of the facility will begin this summer and user operation is expected by 2015. MAX IV will consist of a 3.4 GeV linac as a driver for a short-pulse radiation facility (with planned upgrade to a seeded/cascaded FEL) as well as an injector for two storage rings at different energies serving user communities in separate spectral ranges. Thanks to a novel compact multibend-achromat design, the 3 GeV ring will deliver a 500 mA electron beam with a horizontal emittance below 0.3 nmrad to x-ray insertion devices located in 19 dispersion-free 5 m straight sections. When the 3 GeV ring goes into operation in 2015 it is expected to become the highest electron-brightness storage ring light source world-wide. The 1.5 GeV ring will serve as a replacement for both present-day MAX II and MAX III storage rings. Its below 6 nm rad horizontal emittance electron beam will be delivered to IR and UV insertion devices in twelve 3.5 m straight sections. We report on design progress for the two new storage rings of the MAX IV facility.
|
|
| 6. |
- Seifert, Tina, 1985, et al.
(författare)
-
Chroman-4-one- and Chromone-based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells
- 2014
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:23, s. 9870-9888
-
Tidskriftsartikel (refereegranskat)abstract
- Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Nε-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
|
|
| 7. |
- Wallén, Erik A A, et al.
(författare)
-
Synthesis of 3-aminomethyl-2-aryl- 8-bromo-6-chlorochromones.
- 2007
-
Ingår i: Organic letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 9:3, s. 389-91
-
Tidskriftsartikel (refereegranskat)abstract
- [reaction: see text] An efficient synthetic route to Cbz-protected 3-aminomethyl-2-aryl-8-bromo-6-chlorochromones has been developed. 3-Aryl-1-(3-bromo-5-chloro-2-hydroxyphenyl)-2-propen-1-one or 2-aryl-8-bromo-6-chlorochroman-4-one could be reacted under Mannich conditions yielding 2-aryl-8-bromo-6-chloro-3-methylenechroman-4-one, which was further converted to the target compound via an aza-Michael reaction followed by an SeO(2) oxidation. This procedure represents a new method to introduce a primary aminomethyl group at the 3-position of a 2-arylchromone scaffold. The Cbz-protected 3-aminomethyl-2-aryl-8-bromo-6-chlorochromones can, e.g., be used in the synthesis of chromone-based beta-turn peptidomimetics.
|
|
| 8. |
- Eriksson, Mikael, et al.
(författare)
-
Some small-emittance light-source lattices with multi-bend achromats
- 2008
-
Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 587:2-3, s. 221-226
-
Tidskriftsartikel (refereegranskat)abstract
- Two examples of low-emittance light-source lattices are discussed. Both use similar building blocks consisting of 7-bend achromats. The small emittances generated by these lattices are further reduced by the introduction of insertion devices (IDs), resulting in beam emittance values ranging from 0.2 to 0.9 nm rad, depending on the number of achromats chosen. The two examples discussed here are rings with 12 and 20 achromats. The performances of any intermediate number of achromats can easily be estimated. A higher number of achromats of this type seems to result in an uncomfortably small dynamic aperture. The Touschek losses and Intra Beam Scattering (IBS) effect are calculated together with some means to reduce their impact. To calculate this impact, certain technical solutions are assumed, which are described. Other technical solutions could naturally be chosen. The impact of emittance on brilliance is also discussed and the brilliance curves for the two cases are presented and compared with the zero-emittance case ("ultimate source"). (C) 2008 Elsevier B.V. All rights reserved.
|
|
| 9. |
- Lyytinen, Gustaf, et al.
(författare)
-
Electronic cigarette vaping with nicotine causes increased thrombogenicity and impaired microvascular function in healthy volunteers : a randomised clinical trial
- 2023
-
Ingår i: Cardiovascular Toxicology. - : Springer Nature. - 1530-7905 .- 1559-0259. ; 23:7-8, s. 255-264
-
Tidskriftsartikel (refereegranskat)abstract
- Electronic cigarette (EC) vaping is increasingly popular, despite growing evidence of adverse health effects. To further evaluate the impact of EC use on vascular health, we investigated the effects of brief EC inhalation on flow-dependent thrombus formation and microcirculation in healthy volunteers. The study was performed with a randomised double-blind crossover design. Twenty-two healthy subjects aged between 18 and 45 years with occasional tobacco use were recruited. Subjects inhaled 30 puffs of EC aerosol with and without nicotine on two occasions separated by a wash-out period of at least 1 week. Blood samples were collected at baseline and at 15 and 60 min following exposure and analysed with the Total-Thrombus-formation analysis system evaluating fibrin-rich thrombus formation and platelet thrombus formation in whole blood under flow. Microvascular function was assessed at baseline and 30 min after exposure by laser speckle contrast imaging and iontophoresis of acetylcholine and sodium nitroprusside (SNP) to evaluate the endothelium-dependent and independent pathways of vasodilation. Compared with nicotine free EC aerosol, exposure to EC aerosol with nicotine significantly increased platelet thrombus formation and fibrin-rich thrombus formation at 15 min (p = 0.017 and p = 0.037, respectively) with normalisation after 60 min. Peak SNP-mediated microvascular perfusion, i.e. endothelium-independent vasodilation, was reduced following EC vaping with nicotine compared with baseline (p = 0.006). Thirty puffs of EC aerosol with nicotine increased platelet and fibrin-dependent thrombus formation and reduced microvascular dilatation capacity. No compelling effects of EC vaping without nicotine were observed, indicating nicotine as the main effector.Trial registration: ClinicalTrials.gov Identifier: NCT04175457 URL: https://clinicaltrials.gov/ct2/show/NCT04175457.
|
|
| 10. |
- Lyytinen, Gustaf, et al.
(författare)
-
Use of heated tobacco products (IQOS) causes an acute increase in arterial stiffness and platelet thrombus formation
- 2024
-
Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 390
-
Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Heated tobacco products (HTPs) are novel alternative tobacco products being promoted as an alternative to cigarettes. To evaluate the impact of HTP use on vascular function, we investigated the effects of a brief HTP usage on arterial stiffness and platelet thrombus formation in healthy volunteers.Methods: In a randomised crossover study, twenty-four healthy young adults with occasional tobacco use smoked the HTP IQOS 3 Multi (Phillip Morris Int.) and “no-exposure” was used as a control, with a wash-out period of at least one week in-between. Arterial stiffness was assessed through pulse wave velocity and pulse wave analysis. Blood samples, collected at baseline and 5 min following exposure, were analysed with the Total-Thrombus-formation analysis system evaluating platelet and fibrin-rich thrombus formation tendency.Results: HTP exposure caused immediate heightened pulse wave velocity (+0.365 m/s, 95% CI: +0.188 to 0.543; p = 0.004) and enhanced augmentation index corrected to heart rate (+6.22%, 95% CI: +2.33 to 10.11; p = 0.003) compared to the no-exposure occasion. Similarly, blood pressure and heart rate transiently increased immediately following HTP inhalation. Platelet thrombus formation significantly increased following HTP exposure (area under the curve +59.5, 95% CI: +25.6 to 93.4; p < 0.001) compared to no-exposure. No effect was seen on fibrin-rich thrombus formation following HTP-exposure.Conclusions: Brief HTP use in healthy young adults had immediate adverse effects on vascular function resulting in increased arterial stiffness and platelet thrombus formation, known risk factors for the development of atherosclerosis. Further research is needed to address long term health impacts.
|
|
