Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support

The synthetic utility and theoretical basis of a photolabile hydroxylamine-linker are presented. The developed protocols enable the efficient synthesis and chemoselective photolytic release of either hydroxamates or carboxamides from solid support. The bidetachable mode of the linker unit is uniquely dependent on the solvent. Hydroxamic acids are obtained by performing photolysis in protic solvents, whereas photolysis in aprotic solvents enables the selective release of carboxamides

Oxidative Modification of Tryptophan-Containing Peptides

We herein present a broadly useful method for the chemoselective modification of a wide range of tryptophan-containing peptides. Exposing a tryptophan-containing peptide to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a selective cyclodehydration between the peptide backbone and the indole side chain of tryptophan to form a fully conjugated indolyl-oxazole moiety. The modified peptides show a characteristic and significant emission maximum at 425 nm, thus making the method a useful strategy for fluorescence labeling

Synthesis and structural characterization of piperazino-modified DNA that favours hybridization towards DNA over RNA

We report the synthesis of two C4′-modified DNA analogues and characterize their structural impact on dsDNA duplexes. The 4′-C-piperazinomethyl modification stabilizes dsDNA by up to 5°C per incorporation. Extension of the modification with a butanoyl-linked pyrene increases the dsDNA stabilization to a maximum of 9°C per incorporation. Using fluorescence, ultraviolet and nuclear magnetic resonance (NMR) spectroscopy, we show that the stabilization is achieved by pyrene intercalation in the dsDNA duplex. The pyrene moiety is not restricted to one intercalation site but rather switches between multiple sites in intermediate exchange on the NMR timescale, resulting in broad lines in NMR spectra. We identified two intercalation sites with NOE data showing that the pyrene prefers to intercalate one base pair away from the modified nucleotide with its linker curled up in the minor groove. Both modifications are tolerated in DNA:RNA hybrids but leave their melting temperatures virtually unaffected. Fluorescence data indicate that the pyrene moiety is residing outside the helix. The available data suggest that the DNA discrimination is due to (i) the positive charge of the piperazino ring having a greater impact in the narrow and deep minor groove of a B-type dsDNA duplex than in the wide and shallow minor groove of an A-type DNA:RNA hybrid and (ii) the B-type dsDNA duplex allowing the pyrene to intercalate and bury its apolar surface

Photolabile Linkers for Solid-Phase Synthesis

Photolabile linkers are the subjects of intense research because they allow the release of the target molecule simply by irradiation. Photochemical release of synthesis products is often facilitated without additional reagents under mild reaction conditions, which may even be environmentally friendly and appealing in the context of greener chemistry. The mild conditions also allow for applications of released material in subsequent biological screening experiments, where contamination with cleavage reagents would be detrimental. This Review pays attention to the increasing number of photolabile linkers developed for solid-phase synthesis and release and covers: (i) o-nitrobenzyloxy linkers, (ii) o-nitrobenzylamino linkers, (iii) α-substituted o-nitrobenzyl linkers, (iv) o-nitroveratryl linkers, (v) phenacyl linkers, (vi) p-alkoxyphenacyl linkers, (vii) benzoin linkers, (viii) pivaloyl linkers, and (ix) other photolabile linkers

Supplementation of docosahexaenoic acid (DHA), vitamin D₃ and uridine in combination with six weeks of cognitive and motor training in prepubescent children: a pilot study

BACKGROUND: Learning and memory have been shown to be influenced by combination of dietary supplements and exercise in animal models, but there is little available evidence from human subjects. The aim of this pilot study was to investigate the effect of combining a motor- and cognitive exercise program with dietary supplementation consisting of 500 mg docosahexaenoic acid (DHA), 10 μg vitamin D3 and 1000 mg uridine (DDU-supplement) in 16 prepubescent children (age 8–11 years). METHODS: We designed a randomized, placebo-controlled, double-blinded study lasting 6 weeks in which DDU-supplement or placebo was ingested daily. During the intervention period, all children trained approximately 30 min 3 days/week using an internet-based cognitive and motor training program (Mitii). Prior to and post the intervention period dietary record, blood sampling, physical exercise tests and motor and cognitive tests were performed. RESULTS: Fourteen of the 16 children completed the intervention and ingested the supplement as required. 6 weeks DDU-supplementation resulted in a significant increase in the blood concentration of vitamin D2+3 and DHA (p = 0.023 and p < 0.001, respectively). Power calculation based on one of the cognitive tasks revealed a proper sample size of 26 children. CONCLUSION: All children showed improved performance in the trained motor- and cognitive tasks, but it was not possible to demonstrate any significant effects on the cognitive tests from the dietary supplementation. However, DDU-supplementation did result in increased blood concentration of DHA and vitamin D2+3.: TRIAL REGISTRATION: Clinical registration ID: NCT02426554 (clinical Trial.gov). January 2015 retrospectively registered

Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa

Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)Published versio

Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa

Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development

Glacial sedimentation, fluxes and erosion rates associated with ice retreat in Petermann Fjord and Nares Strait, north-west Greenland

Petermann Fjord is a deep (>1000 m) fjord that incises the coastline of north-west Greenland and was carved by an expanded Petermann Glacier, one of the six largest outlet glaciers draining the modern Greenland Ice Sheet (GrIS). Between 5 and 70 m of unconsolidated glacigenic material infills in the fjord and adjacent Nares Strait, deposited as the Petermann and Nares Strait ice streams retreated through the area after the Last Glacial Maximum. We have investigated the deglacial deposits using seismic stratigraphic techniques and have correlated our results with high-resolution bathymetric data and core lithofacies. We identify six seismo-acoustic facies in more than 3500 line kilometres of sub-bottom and seismic-reflection profiles throughout the fjord, Hall Basin and Kennedy Channel. Seismo-acoustic facies relate to bedrock or till surfaces (Facies I), subglacial deposition (Facies II), deposition from meltwater plumes and icebergs in quiescent glacimarine conditions (Facies III, IV), deposition at grounded ice margins during stillstands in retreat (grounding-zone wedges; Facies V) and the redeposition of material downslope (Facies IV). These sediment units represent the total volume of glacial sediment delivered to the mapped marine environment during retreat. We calculate a glacial sediment flux for the former Petermann ice stream as 1080–1420 m3 a−1 per metre of ice stream width and an average deglacial erosion rate for the basin of 0.29–0.34 mm a−1. Our deglacial erosion rates are consistent with results from Antarctic Peninsula fjord systems but are several times lower than values for other modern GrIS catchments. This difference is attributed to fact that large volumes of surface water do not access the bed in the Petermann system, and we conclude that glacial erosion is limited to areas overridden by streaming ice in this large outlet glacier setting. Erosion rates are also presented for two phases of ice retreat and confirm that there is significant variation in rates over a glacial–deglacial transition. Our new glacial sediment fluxes and erosion rates show that the Petermann ice stream was approximately as efficient as the palaeo-Jakobshavn Isbræ at eroding, transporting and delivering sediment to its margin during early deglaciation

Mouse Transcobalamin Has Features Resembling both Human Transcobalamin and Haptocorrin

In humans, the cobalamin (Cbl) -binding protein transcobalamin (TC) transports Cbl from the intestine and into all the cells of the body, whereas the glycoprotein haptocorrin (HC), which is present in both blood and exocrine secretions, is able to bind also corrinoids other than Cbl. The aim of this study is to explore the expression of the Cbl-binding protein HC as well as TC in mice. BLAST analysis showed no homologous gene coding for HC in mice. Submaxillary glands and serum displayed one protein capable of binding Cbl. This Cbl-binding protein was purified from 300 submaxillary glands by affinity chromatography. Subsequent sequencing identified the protein as TC. Further characterization in terms of glycosylation status and binding specificity to the Cbl-analogue cobinamide revealed that mouse TC does not bind Concanavalin A sepharose (like human TC), but is capable of binding cobinamide (like human HC). Antibodies raised against mouse TC identified the protein in secretory cells of the submaxillary gland and in the ducts of the mammary gland, i.e. at locations where HC is also found in humans. Analysis of the TC-mRNA level showed a high TC transcript level in these glands and also in the kidney. By precipitation to insolubilised antibodies against mouse TC, we also showed that >97% of the Cbl-binding capacity and >98% of the Cbl were precipitated in serum. This indicates that TC is the only Cbl-binding protein in the mouse circulation. Our data show that TC but not HC is present in the mouse. Mouse TC is observed in tissues where humans express TC and/or HC. Mouse TC has features in common with both human TC and HC. Our results suggest that the Cbl-binding proteins present in the circulation and exocrine glands may vary amongst species