C‐3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the costeffective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–tX–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–cX–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –tX– or –cX– and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for d-xylo and d-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–tX–Aaa– or –Aaa–tX–tX–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–cX–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish

Origin of problems related to Staudinger reduction in carbopeptoid syntheses

Abstract We report the solid phase synthesis of –GG-X-GG– type α/β-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc derivative (e.g., Fmoc-RibAFU(ip)-OH) and the azido derivative (e.g., N3-RibAFU(ip)-OH) via Staudinger reaction with nBu3P can be successfully applied. Both X-ray diffraction, 1H- and 31P-NMR, and theoretical (QM) data support and explain why the application of Ph3P as Staudinger reagent is “ineffective” in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (–CONH–) bond. The failure of the polypeptide chain elongation with N3-cX originates from the “coincidence” of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack during the hydrolysis of a quasi penta-coordinated triphenylphosphinimine. Nevertheless, the synthesis of the above α/β-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo- and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts

A közlekedési bűncselekmények

A közlekedési bűncselekményeket azért választottam szakdolgozatom témájául, mert mindennapjainkat áthatja és befolyásolja. Olyan területe az életünknek, amely a legnagyobb veszéllyel jár, ugyanis az emberek életét, egészségét, testi épségét veszélyezteti.Bscigazgatásszervez

Foldamer stability coupled to aggregation propensity of elongated Trp-cage miniproteins

Here we present folding associated aggregation propensity of three Trp-cage foldamers: E0, E5 and E10, models of different size but still comparable molecular properties. ECD, VCD and FT-IR spectroscopy measurements were used to monitor their concentration dependent, heat induced (5°C 65°C) alpha-beta fold transition. The ECD curves of E0 are referring to an ensemble of highly dynamic structures. ECD of both E5 and E10 foldamers show the expected Trp-cage fold, dominated by their -helical properties. No sign of -structures was revealed by ECD at any conditions (5°C<T<65°C, 5<pH<7, c~30 M) for any of these miniproteins. However, at higher concentration (c~1-30mM) both VCD and FT-IR spectral features of E5 as well as E10 resemble to that of a beta-strand (~1615 cm-1), accompanied with free beta-edges, or native beta-sheets (~1630 cm-1). E5 at lower (c~1-3mM), while E10 at higher concentration (c~30mM) witness the alpha to native-beta to beta-sheet folding transitions, monitored by the characteristic C=O vibrational normal mode frequency shift as follows: ~1650 cm-1, ~1630 cm-1m, ~1615 cm-1, respectively. The latter folding path is irreversible. The shortest polypeptide E0 (20 aa) has an unordered or very dynamic fold, while E10 (30 aa) presents the most tightly packed Trp-cage 3D-structure. We have found that both high dynamicity and/or tight molecular core packing are different in nature, but common in efficacy to prevent the polypeptide backbone chain against self-aggregation. However, E5 is intermediate in size (25 aa) and stability, and thus among these three it is the most vulnerable foldamer against aggregation. The present molecular triad, E0, E5 and E10, serve as a good example of larger globular proteins for which, aggregation and amyloid-fiber like nano-particle formations is often associated with Alzheimer’s, Creutzfeldt–Jakob, or Prion diseases

Extracellular Vesicles Derived from Bone Marrow in an Early Stage of Ionizing Radiation Damage Are Able to Induce Bystander Responses in the Bone Marrow

Ionizing radiation (IR)-induced bystander effects contribute to biological responses to radiation, and extracellular vesicles (EVs) play important roles in mediating these effects. In this study we investigated the role of bone marrow (BM)-derived EVs in the bystander transfer of radiation damage. Mice were irradiated with 0.1Gy, 0.25Gy and 2Gy, EVs were extracted from the BM supernatant 24 h or 3 months after irradiation and injected into bystander mice. Acute effects on directly irradiated or EV-treated mice were investigated after 4 and 24 h, while late effects were investigated 3 months after treatment. The acute effects of EVs on the hematopoietic stem and progenitor cell pools were similar to direct irradiation effects and persisted for up to 3 months, with the hematopoietic stem cells showing the strongest bystander responses. EVs isolated 3 months after irradiation elicited no bystander responses. The level of seven microRNAs (miR-33a-3p, miR-140-3p, miR-152-3p, miR-199a-5p, miR-200c-5p, miR-375-3p and miR-669o-5p) was altered in the EVs isolated 24 hour but not 3 months after irradiation. They regulated pathways highly relevant for the cellular response to IR, indicating their role in EV-mediated bystander responses. In conclusion, we showed that only EVs from an early stage of radiation damage could transmit IR-induced bystander effects