The present study reveals an unexpected anomaly observed in the acid-catalyzed hydrolysis of the 5,6-O-isopropylidene group in 3-O-protected D-gluco- and D-allofuranose derivatives. Although the removal of the 5,6-O-isopropylidene protecting group is typically rapid and quantitative under acidic conditions, an unexpected inhibition of this reaction is observed for the two C3-epimers, 3-O-imidazole sulfonyl moiety. X-ray data show a two-faced imidazole ring orientation in the crystal, while solution state NOE data reveal a critical interaction type between the isopropylidene and the imidazole rings. Advanced conformational searches coupled with ab initio molecular modeling illuminate and explain the NMR and kinetic data and lay the groundwork for the most plausible mechanism of this unprecedented inhibition. These results provide valuable insights into the cross-coupling of carbohydrate O-protecting groups and shed light on how specific ring orientations and steric effects can trigger the inhibition of an otherwise easily feasible reaction, such as an acid-catalyzed hydrolysis.

Rapid and accurate characterization of carbohydrate ring conformers in oligosaccharides, glycoproteins, foldamers, and other sugar‐containing molecules remains a challenge. Here, a state‐of‐the‐art, fine‐tuned cyclic ion mobility mass spectrometry (cIM‐MS) method is presented to examine and separate ring conformers of sugar moieties at the μg‐ng scale without purification. We compared ring structures obtained from X‐ray crystallography (solid phase), nuclear magnetic resonance spectroscopy (NMR) (solution phase), and cIM‐MS (gas phase) to assign conformational motifs. We performed detailed gas‐phase conformational calculations, along with experimental and theoretical collisional cross‐section ( CCS ) measurements using various software tools, to identify the most accurate prediction method for carbohydrates. Our analysis revealed that the current CCS calculation tools require further refinement for reliable application to sugars. Thus, the combination of experimental and theoretical methods holds strong potential for confident sugar conformation assignment in the future.

The synthesis of D-glucosamine-1-carboxylic acid based β-sugar amino acids (β-SAAs) is typically performed in nine consecutive steps via an inefficient OAc → Br → CN conversion protocol with low overall yield. Here, we present the improved and more efficient synthesis of both Fmoc-GlcAPC-OH and Fmoc-GlcAPC(Ac)-OH, β-SAAs consisting of only 4-5 synthetic steps. Their active ester and amide bond formation with glycine methyl ester (H-Gly-OMe) was completed and monitored by 1H NMR. The stability of the pyranoid OHs protecting the acetyl groups was investigated under three different Fmoc cleavage conditions and was found to be satisfactory even at high piperidine concentration (e.g. 40%). We designed a SPPS protocol using Fmoc-GlcAPC(Ac)-OH to produce model peptides Gly-β-SAA-Gly as well as Gly-β-SAA-β-SAA-Gly with high coupling efficiency. The products were deacetylated using the Zemplén method, which allows the hydrophilicity of a building block and/or chimera to be fine-tuned, even after the polypeptide chain has already been synthesized.

Complementary to hydrophobic five membered ring β-amino acids (e.g. ACPC), β-sugar amino acids (β-SAAs) have found increasing application as hydrophilic building blocks of foldamers and α/β chimeric peptides. Fmoc-protected β-SAAs [e.g. Fmoc-RibAFU(ip)-OH] are indeed useful Lego elements, ready to use for SPPS. The removal of 1,2-OH isopropylidene protecting group increasing the hydrophilicity of such SAA is presented here. We first used N 3 -RibAFU(ip)-OH model compound to optimize mild deprotection conditions. The formation of the 1,2-OH free product N 3 -RibAFU- OH and its methyl glycoside methyl ester, N 3 -RibAFU(Me)- OMe were monitored by RP-HPLC and found that either 50% TFA or 8 eqv. Amberlite IR-120 H + resin in MeOH are optimal reagents for the effective deprotection. These conditions were then successfully applied for the synthesis of chimeric oligopeptide: -GG- X -GG- [X=RibAFU(ip)]. We found the established conditions to be effective and—at the same time—sufficiently mild to remove 1,2- O -isopropylidene protection and thus, it is proposed to be used in the synthesis of oligo- and polypeptides of complex sequence combination.

The configuration-dependent self-association mode of the two anomers of O-Ac,N-Fmoc-d-glucosamine, a foldamer building block, leading to gel and/or single crystal formation is described. The β-anomer of the sugar amino acid (2) forms a gel from various solvents (confirmed by SEM, rheology measurements, NMR, and ECD spectroscopy), whereas the α-anomer (1) does not form a gel with any solvent tested. Transition from the solution state to a gel is coupled to a concurrent shift of the Fmoc-groups: from a freely rotating (almost symmetrical) to a specific, asymmetric orientation. Whereas the crystal structure of the α-anomer is built as an evenly packed 3D system, the β-anomer forms a looser superstructure of well-packed 2D layers. Modeling indicates that in the lowest energy, but scarcely sampled conformer of the β-anomer, the Fmoc-group bends above the sugar moiety, stabilized by intramolecular CH↔π interactions between the aromatic rings. It is concluded that possessing an extended and promiscuous interaction surface and a conformationally heterogeneous solution state are among the basic requirements of gel formation for a candidate molecule.

The synthesis of α/β-chimeras comprises peptide bond formation from α- to β-, from β- to β-, and from β- to α-amino acid residues. The fine-tuned solid phase synthesis of –GXXG– chimera peptides containing the simplest achiral α-amino acid glycine and two cyclic SAAs of different ring size [X denoting cyclic β-Sugar Amino Acids (β-SAA)] is reported, variants containing Fmoc–RibAFU(ip)–OH a furanoid-, and Fmoc–GlcAPU(Me)–OH a pyranoid-type structural “Lego-element”. Systematic search for the best coupling strategy with both H–β-SAA–OHs is described, including the comparison of the different coupling reagents and conditions. Selecting the optimal reagent (from commonly used PyBOP, HATU and HOBt) was assisted by time-resolved 1H-NMR: formation and stability of the Fmoc protected active esters were compared. We found that PyBOP is the best choice for successfully coupling both H–β-SAA–OH prototypes. The present comparative results open a reasonable route for building efficiently various –β-SAA– containing homo- and heterooligomers.

Gel formation is widely spread in nature, essential for living organisms.Gels of natural and synthetic sources are also used in various fields of industry (e.g.pharmateuticals, food science, cosmetics, nano materials).Low molecular weight gelators (LMWGs) are of particular interest, having advantageous physico-chemical properties.For understanding and designing their characteristics, efforts are made to establish the molecular level criteria of gelation, including key interactions governing gel formation.Carbohydrate derivatives having versatile configuration, molecular folds and self-assembly behaviours, are promising candidates of designing biocompatible LMWGs.Interactions stabilizing the gel structure were proposed for N-Fmoc-glucosamines, establishing a model for a group of free hydroxyl-containing hydrogels.Here we present a comparative study of alpha and beta anomers of fully O-acetylated derivative of N-Fmocglucosamine.The beta anomer readily forms gels from different solvent mixtures, presenting solution-gelcrystalline transformation pathway.Interestingly the alpha anomer crystallizes from solution skipping the gel formation.This molecule pair makes a unique system to understand details of gelation, as they differ only in their anomeric configuration.We applied a combination of various methods for characterizing phase transformation processes of both anomers.Crystal structures along with results of NMR and ECD studies as well as in silico conformational analysis are presented.Key conformers as well as intra-and intermolecular interactions were identified proposing a possible explanation of the configuration dependent gelation ability of the protected Dglucosamines.

Pyranuronic β‐sugar amino acids (β‐SAAs) are biocompatible and tuneable building blocks of foldamers and chimera‐peptides. The scalable and economical total synthesis of two building blocks is described here. These C‐4 epimers, Fmoc‐GlcAPU(Me)‐OH (7) and Fmoc‐GalAPU(Me)‐OH (8), which are suitable for solid phase peptide synthesis, were prepared via a common oxime intermediate 16. The new synthesis uses nine consecutive steps, starting from methyl α‐d‐glucopyranoside (6). The synthesis is fine‐tuned, optimized, and ready for large‐scale and cost‐efficient production.

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 cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–t X–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–c X–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 –t X– or –c X– 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–t X–Aaa– or –Aaa–t X–t X–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–c X–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

The "classical" challenge, raised by Emil Fischer as to why one monosaccharide arylhydrazone adopts a cyclic structure but another an acyclic structure, is answered here. The present comprehensive analysis of hexose and hexosamine arylhydrazones, based on 2D NMR spectroscopy and theoretical modeling, has established that the chain of hydrogen bonds needed for conformational selection can only be completed for D-glucosamine derivatives. Thus, D-glucosamine 4-nitrophenyl-hydrazone exclusively adopts its cyclic form, but any configurational changes imply the formation of acyclic structures. In conclusion, three criteria dominate structure selection, namely 1) an amino function at the C-2 position, 2) the "all-equatorial" substitution mode of the pyranoid ring, and 3) an electron-withdrawing group on the arylhydrazone are all needed to get the cyclic form only.

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.

Crystalline complexes of D-ribose, D-ribono-1,4-lactone and methyl β-D-ribopyranoside with sodium halides were synthesized and some of their crystal structures determined. Crystal structures of two lactone complexes and a methyl β-D-ribopyranoside reveal the mode of the salt binding and the intricate interplay of cation coordination and hydrogen bonding in these complexes. When complexed with NaBr, the ribopyranoside is in the (1)C(4) shape whereas ribose with no salt present has the (4)C(1) shape. It is also demonstrated that such complexes can be easily prepared in solid state reaction using a ball mill.

2-Acetamido-2-deoxypentonolactones were synthesized from per-O-acetylated formazans of D-ribose, D- and L-arabinose, respectively. In dimethyl sulfoxide, a novel spontaneous transformation of the per-O-acetyl-pentose formazans into new 3,4,5-tri-O-acetyl-pent-2-enose formazans has been recognized. Additional examples for the occurrence of the isomerism between pseudo-aromatic chelate and open phenylazo-phenylhydrazone system were demonstrated by (1)H NMR spectroscopy in both the unprotected pentose formazans and 3,4,5-tri-O-acetyl-pent-2-enose formazans. Computational calculations supported higher stability of the ring form.

We carried out molecular studies of 15 unrelated Hungarian families diagnosed with Fabry disease (FD). Genetic analysis of the α-galactosidase A gene was performed in 22 hemizygous males and 34 females. One of the female patients with severe disease phenotype showed homozygosity for the recurrent c.644A > G mutation due to parental consanguinity. The c.644A > G mutation that has previously been found mostly in patients with the cardiac variant of FD, was associated with renal but not cardiac involvement in this female and in two other family members. In nine families, eight novel sequence variants such as small deletions (c.363delT, c.477delT, c.746delAC) and single nucleotide changes (c.107T > C, c.493G > C, c.796G > T, c.866T > G, c.871G > A) were found in addition to six previously described private mutations. This report contributes to the identification of novel disease-causing mutations in FD, and increases our knowledge on demographics and molecular characteristics of this rare lysosomal storage disorder. This is the first comprehensive overview of molecular genetic features of Hungarian patients with FD.

The presence of the fern species Anogramma leptophylla was detected in the Zempleni Mountains (NE Hungary) in 1991. The species was known neither from the country nor from the whole Carpatho-Pannonian Region (also known as Carpathian Basin) previously. Its habitat is situated oil a roadside hank. cut into an unstable rhyolite Surface, above the valley of the Creek Kemen conear the village of Palhaza. The fern is it cosmopolitan taxon restricted to humid environments and is considered to be all oceanic-suboceanic (Atlantic) element in Europe. The occurrence in Hungary is located more than 1000 kill from the closest populations, thus. this is one of the most remote inland occurrences of this (sub)oceanic species. This striking presence of the fern may be Clue to the peculiar microclimatological conditions of the habitat, which are described here in order to give in exact explanation for this outstanding occurrence. The chromosomes were also counted in some individuals of the Hungarian population and wore found to be n=26(11) for each sample.

Noise suppression has been a long-standing problem in digital speech processing. For average signal-to-noise ratio (SNR) and stationary noise there are commercially available software products or equipment. Therefore, the subject of the recent research is the enhancement of noisy speech in case of non-stationary noise. The noise suppression algorithm, presented in this paper, is based on dimension-embedding, and separates speech from noise in the transformed domain. The algorithm has been tested on several noisy versions of a Hungarian sentence using three different noise-types and seven different SNRs. The gains achieved correspond to the published data.

The ploidy level and karyotype ofMuscari botryoides (s.l.) samples from Hungary (25 localities) and Romania (1 locality:locus classicus ofM. transsilvanicum) were determined. The Romanian sample proved to be diploid (2n=18), while in Hungary both diploid and tetraploid (2n=36) populations occurred. The karyotypes of all diploid populations were similar: 2 pairs of long acrocentric (one of them usually with satellites) + 3 pairs of medium-sized submetacentric-metacentric + 4 pairs of short ± metacentric chromosomes. All diploid populations in Hungary can be identified asM. transsilvanicum. There is no reason to support the taxonM. botryoides subsp.hungaricum because it does not differ from the sample collected at thelocus classicus ofM. transsilvanicum (Romania, Sibiu-Guşteriţa) in any of the characteristics mentioned in its protologue. Its karyotype also corresponds to that ofM. transsilvanicum. Contrary to the former assumptions, the tetraploidM. botryoides is also native to Hungary. The tetraploid karyotype seems to be somewhat of a duplication of the diploid one. Morphological characters used in the identification keys are not suitable for unambiguous separation of the taxa mentioned above, though morphometric analyses revealed some quantitative differences between diploids and tetraploids. Their separation on species level can only be supported by the supposed reproductive barriers caused by different ploidy level and chorology. In HungaryM. transsilvanicum is restricted mostly to the Eupannonian Region, the Mecsek and Villány Mts.M. botryoides does not occur in the Eupannonicum, instead it inhabits the subatlantic hilly W and SW part of Hungary and the Northern Mountain Range. The latter territory (including also the Slovak localities) seems to be the easternmost extension of the area ofM. botryoides.

New classes of sugar derivatives of the antibacterial drug norfloxacin (1) were synthesized by substituting the N‐4′ of the piperazinyl moiety of the molecule. Direct coupling with gluco‐ and galactopyranosyl units afforded glycosylamines 2–5. Introduction of urea or thiourea linkage between glycosyl and norfloxacin units was produced with the corresponding glycosyl isocyanates or isothiocyanates. For the synthesis of unprotected sugar urea compounds, a new approach was applied by using 1,2‐N, O‐carbonyl‐β‐D‐glycopyranoses. Hydrazinocarbonyl‐methyl‐ and ‐propyl spacers also were found appropriate for linking norfloxacin with sugar units. Dedicated to Professor A. Messmer on the occasion of his 80th anniversary.