A new lignan glycoside and other constituents from Cephalaria ambrosioides

A new lignan glycoside, 1,5-dihydroxy-2-(4"-beta-D-glucopyranosyloxy-3"-methoxyphenyl)-6-(4'-hydroxy-3'-methoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, named ambrosidine ([structure: see text]), along with seven known compounds (four iridoids and three hydroxycinnamic esters) were isolated from the roots of Cephalaria ambrosioides. The structures of these compounds were determined by use of NMR and MS techniques and by chemical transformations. The cytotoxic activity of the novel compound [structure: see text] was evaluated against five human solid tumour cell lines.     

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

Oligonucleotides modified by a 2′-deoxy-2′-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ‘‘switched off-state’’. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-β-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a β-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19–47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to β-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T_0.5 ca 7 h) to hydrazone-based structures.     

Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.     

Pentaerythrityltetramine scaffolds for solid-phase combinatorial chemistry

Straightforward synthesis for two pentaerythrityltetramine precursors, 2,2-bis(azidomethyl)propane-1,3-diamine (1) and 2-[N-(allyloxycarbonyl)aminomethyl]-2-azidomethylpropane-1,3-diamine (2), has been described. Both propane-1,3-diamines have been attached by reductive amination to a solid-supported backbone amide linker derived from 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid. The presence of the two methoxy substituents on the linker is essential to avoid cross-linking between two linkers. The remaining free primary amino group of the propane-1,3-diamine moiety may then be selectively acylated with an appropriately protected amino acid using conventional N,N-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBt) activation without any interference by the secondary amino function. The latter group may be subsequently acylated by an anhydride method. Sequential reduction of the azido group and removal of the allyloxycarbonyl protection from 2 allow further coupling of two different amino acids, and hence, this handle may be utilized in construction of branched structures containing four different amino acids or peptides. Solid-supported 1 may, in turn, be used for the synthesis of similar constructs containing two identical branches. It is worth noting that no acid-labile protecting groups are required in this approach, and hence, this dimension may be saved for the cleavage of the linker. The applicability of the scaffolds to library synthesis has been demonstrated by preparation of 11 pentaerythrityl-branched tetra- and octapeptides.     

13C isotope effects on 1H chemical shifts: NMR spectral analysis of 13C‐labelled D‐glucose and some 13C‐labelled amino acids

The one‐ and two‐bond ¹³C isotope shifts, typically ?1.5 to ?2.5 ppb and ?0.7 ppb respectively, in non‐cyclic aliphatic systems and up to ?4.4 ppb and ?1.0 ppb in glucose cause effects that need to be taken into account in the adaptive NMR spectral library‐based quantification of the isotopomer mixtures. In this work, NMR spectral analyses of some ¹³C‐labelled amino acids, D ‐glucose and other small compounds were performed in order to obtain rules for prediction of the ¹³C isotope effects on ¹H chemical shifts. It is proposed that using the additivity rules, the isotope effects can be predicted with a sufficient accuracy for amino acid isotopomer applications. For glucose the effects were found strongly non‐additive. The complete spectral analysis of fully ¹³C‐labelled D ‐glucose made it also possible to assign the exocyclic proton signals of the glucose. Copyright © 2009 John Wiley & Sons, Ltd.     

UV Sensitivity of Vegetative and Reproductive Tissues of Two Antarctic Brown Algae is Related to Differential Allocation of Phenolic Substances

UV sensitivity of the vegetative and reproductive tissues of two Antarctic brown macroalgae was compared. Photosynthesis as well as the content and localization of phenolic substances were determined. Responses to UV radiation were quantified as chlorophyll fluorescence (F_v/F_m). Ascoseira mirabilis showed high UV tolerance, while in Cystosphaera jacquinotii F_v/F_m decreased by 15–21%, the receptacles being more tolerant than the vegetative blades. The phlorotannin contents showed an opposite pattern: the soluble fraction dominated in C. jacquinotii while in A. mirabilis the insoluble fraction was more abundant. Soluble phlorotannins were higher in the reproductive than in vegetative tissues in both species. Images of tissue cross‐sections under violet‐blue light excitation confirmed a high allocation of phenolic compounds (as blue autofluorescence) in C. jacquinotii, both in reproductive and vegetative blades. The allocation and proportions of the soluble and insoluble phlorotannins could be related with the observed UV tolerance of the vegetative and reproductive tissues.     

Impact of UV radiation on the early development of the giant kelp (Macrocystis pyrifera) gametophytes

The mechanisms and dose-response of UV action on the early development of Macrocystis pyrifera (L.) C. Agardh gametophytes were investigated. Post-release, zoospores undergo germination, germ tube elongation, DNA synthesis, nuclear division and translocation, which were followed for 41 h under laboratory conditions. The spores were exposed to UV radiation before germination (3 h post-release) or before nuclear division (20 h post-release). Biologically effective UV-B doses (BEDDNA300 nm) higher than those used in the experiments are needed for a 50% inhibition in germination (BED50 > 1600 J m-2). Nuclear division/translocation was more sensitive to UV radiation. When the spores were cultured in the dark, UV exposure at both 3 and 20 h post-release resulted in a dose-responsive inhibition of nuclear division/translocation (BED50 64 and 86 J m-2). Culturing in the light indicated recovery in the spores that were irradiated at 3 h post-release (BED50 356 J m-2), whereas no light-dependent recovery occurred within 41 h of culture when irradiated at 20 h post-release (BED50 80 J m-2). The results present a possible mechanism of UV inhibition in early life stages of the giant kelp, suggesting that environmentally relevant UV-B levels can perturb or delay the development and recruitment of the gametophytes by inhibiting nuclear events.     

A compact olfactometer for IMS measurements and testing human perception

Production of easily controllable and measurable odor stimuli is needed when studying human olfaction, olfaction-related physiology and psychological reactions to odors. Controlled odor producing instruments are called olfactometers. For testing and calibrating new olfactometers or sensor arrays, a reliable input signal has to be produced to verify their accurate functionality. A common input signal in various olfactometers has been the use of volatile organic compounds (VOCs) in gaseous form. We present a compact olfactometer able to produce controlled continuous odor stimuli from three individual channels. For measuring the output gas flow, we used a ChemPro 100i (Environics, Finland) device that is based on aspiration ion mobility spectrometry (aIMS). IMS is a robust and sensitive method for measuring VOCs and is used especially in detecting toxic industrial chemicals and chemical warfare agents, but the technology is also suitable for other olfactory-related applications. The olfactometer was used to produce synthetic jasmine scent using three main odor components from jasmine oil and all the components were diluted using propylene glycol. The dilutions were supplied to the system using programmable syringe pumps, which guided the dilutions to individual evaporation units. We conducted experiments to verify the functionality of our olfactometer. Analysis of the ChemPro100i data showed that olfactometer can use different odor components to produce continuous, stable output flows with controlled concentrations.     

A modular approach to catalyst hydrophobicity for an asymmetric aldol reaction in a biphasic aqueous environment

Catalyst 5, an ion pair consisting of a hydrophilic cation and a lipophilic anion, fulfils the solubility requirements needed to couple efficiency (enantioselectivities and anti-diastereoselectivities up to > or = 99%) and catalyst recyclability in asymmetric aldol reactions under aqueous biphasic conditions.     

A Five‐year Study of Solar Ultraviolet Radiation in Southern Chile (39° S): Potential Impact on Physiology of Coastal Marine Algae?

This study reports 5 years of (1998-2003) data on continuous solar-irradiation measurements from a scanning spectroradiometer (SUV-100) in Valdivia, Chile (39 degrees S), accompanied by evaluation of the impact of ultraviolet radiation (UVR) on marine macroalgae of this site. UVR conditions showed a strong seasonal variation, which was less pronounced toward longer wavelengths. Daily maximum dose rates (clear days) averaged in winter-summer: UV-B(290-315 nm) 0.30-2.1, UV-B(290-320 nm) 0.70-3.7, UV-A(315-400 nm) 20.6-62.1, UV-A(320-400 nm) 20.2-60.5 W m(-2), and photosynthetically active radiation (PAR) 969-2423 micromol m(-2) s(-1). The corresponding daily doses (all the days) ranged: UV-B(290-315 nm) 2.6-40.7, UV-B(290-320 nm) 6.7-78.5, UV-A(315-400 nm) 228-1539, UV-A(320-400 nm) 224-1501, and PAR 2008-13308 kJ m(-2) d(-1). Taking into consideration action spectra of a biological interest, the risk of UV exposure could be up to 37 times higher in summer than in winter. The photosynthetic activity (as maximum quantum yield of chlorophyll fluorescence, F(v)/F(m)) of the brown alga Lessonia nigrescens from the infralittoral zone was markedly more sensitive to UVR than of the green alga Enteromorpha intestinalis from the upper midlittoral, and the UV-B wave band increased markedly photoinhibition. In L. nigrescens, maximal photoinhibition (40%) took place at weighted (the action spectrum for photoinhibition of photosynthesis) UVR doses of 800 kJ m(-2), irrespective of the season (corresponding midsummer daily dose in Valdivia is 480 kJ m(-2)). In winter, when this alga was at its most sensitive, the weighted UV dose causing 35-40% photoinhibition was around 200 kJ m(-2). In E. intestinalis, weighted doses of 800 kJ m(-2) resulted in low photoinhibition (<10 %) and no clear seasonal patterns could be inferred. These results confirm that midday summer levels of UV-B and their daily doses in southern Chile are high enough to produce stress to intertidal macroalgae.