| 1. |
- Caldeweyher, Eike, et al.
(författare)
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Hybrid Machine Learning Approach to Predict the Site Selectivity of Iridium-Catalyzed Arene Borylation
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 145:31, s. 17367-17376
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Tidskriftsartikel (refereegranskat)abstract
- The borylation of aryl and heteroaryl C–H bonds is valuable for the site-selective functionalization of C–H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the C–H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp2)–H bonds during pharmaceutical development.
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| 2. |
- Andappan, Murugaiah M. S., et al.
(författare)
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From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:5, s. 2265-2278
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Tidskriftsartikel (refereegranskat)abstract
- A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
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| 3. |
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| 4. |
- Belfrage, Anna Karin, 1977-, et al.
(författare)
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Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
- 2015
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :5, s. 978-986
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Tidskriftsartikel (refereegranskat)abstract
- The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.
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| 5. |
- Borhade, Sanjay R, et al.
(författare)
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Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides
- 2014
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 3:6, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.
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| 6. |
- Bradshaw, Clare, et al.
(författare)
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Physical Disturbance by Bottom Trawling Suspends Particulate Matter and Alters Biogeochemical Processes on and Near the Seafloor
- 2021
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Bottom trawling is known to affect benthic faunal communities but its effects on sediment suspension and seabed biogeochemistry are less well described. In addition, few studies have been carried out in the Baltic Sea, despite decades of trawling in this unique brackish environment and the frequent occurrence of trawling in areas where hypoxia and low and variable salinity already act as ecosystem stressors. We measured the physical and biogeochemical impacts of an otter trawl on a muddy Baltic seabed. Multibeam bathymetry revealed a 36 m-wide trawl track, comprising parallel furrows and sediment piles caused by the trawl doors and shallower grooves from the groundgear, that displaced 1,000 m3 (500 t) sediment and suspended 9.5 t sediment per km of track. The trawl doors had less effect than the rest of the gear in terms of total sediment mass but per m2 the doors had 5× the displacement and 2× the suspension effect, due to their greater penetration and hydrodynamic drag. The suspended sediment spread >1 km away over the following 3–4 days, creating a 5–10 m thick layer of turbid bottom water. Turbidity reached 4.3 NTU (7 mgDW L–1), 550 m from the track, 20 h post-trawling. Particulate Al, Ti, Fe, P, and Mn were correlated with the spatio-temporal pattern of suspension. There was a pulse of dissolved N, P, and Mn to a height of 10 m above the seabed within a few hundred meters of the track, 2 h post-trawling. Dissolved methane concentrations were elevated in the water for at least 20 h. Sediment biogeochemistry in the door track was still perturbed after 48 h, with a decreased oxygen penetration depth and nutrient and oxygen fluxes across the sediment-water interface. These results clearly show the physical effects of bottom trawling, both on seabed topography (on the scale of km and years) and on sediment and particle suspension (on the scale of km and days-weeks). Alterations to biogeochemical processes suggest that, where bottom trawling is frequent, sediment biogeochemistry may not have time to recover between disturbance events and elevated turbidity may persist, even outside the trawled area.
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| 7. |
- Byrne, Liam, et al.
(författare)
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Enantioselective Synthesis of Atropisomeric Biaryls using Biaryl 2,5-Diphenylphospholanes as Ligands for Palladium-Catalysed Suzuki-Miyaura Reactions
- 2021
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Ingår i: Advanced Synthesis and Catalysis. - : John Wiley & Sons. - 1615-4150 .- 1615-4169. ; 363:1, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the development of biaryl 2,5-diphenylphospholanes as a new class of C-2-symmetric, monodentate ligands for asymmetric Suzuki-Miyaura (ASM) reactions. Screening of a series of exemplary phospholanes led to the identification of two ligands that were used to prepare a range of atropisomeric biaryl and heterobiaryl products with good to excellent levels of enantioselectivity (up to 97:3 e.r.) under mild conditions. DFT studies suggest that the formation of a constraining ligand pocket and coordination of one of the biaryl methoxy groups in the optimised ligands to the metal centre is crucial for restricting conformational freedom in the bond-forming step.
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| 8. |
- Claerhout, Stijn, et al.
(författare)
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Synthesis of functionalized furopyrazines as restricted dipeptidomimetics
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 68:14, s. 3019-3029
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Tidskriftsartikel (refereegranskat)abstract
- Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald-Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a beta-turn.
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| 9. |
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| 10. |
- Danielsson, Christian, et al.
(författare)
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Polytherapy with hERG-blocking antiepileptic drugs : Increased risk for embryonic cardiac arrhythmia and teratogenicity
- 2007
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Ingår i: Birth defects research. Clinical and molecular teratology. - : Wiley. - 1542-0752 .- 1542-0760. ; 79:8, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED. METHODS: The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique. RESULTS: All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations. CONCLUSIONS: The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances.
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