A reliable and high yielding synthetic pathway for the synthesis of the biologically highly important class of nucleoside diphosphate sugars (NDP-sugars) was developed by using various cycloSal-nucleotides 1 and 9 as active ester building blocks. The reaction with anomerically pure pyranosyl-1-phosphates 2 led to the target NDP-sugars 20-45 in a nucleophilic displacement reaction, which cleaves the cycloSal moiety in anomerically pure forms. As nucleosides cytidine, uridine, thymidine, adenosine, 2'-deoxy-guanosine and 2',3'-dideoxy-2',3'-didehydrothymidine were used while the phosphates of D-glucose, D-galactose, D-mannose, D-NAc-glucosamine, D-NAc-galactosamine, D-fucose, L-fucose as well as 6-deoxy-D-gulose were introduced.
Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy treatment. However, mechanisms of resistance are only incompletely understood. We have recently shown that repeated administration of the AED phenytoin allows selecting resistant and responsive rats from the amygdala kindling model of epilepsy, providing a tool to study mechanisms of AED resistance. We now tested whether individual amygdala-kindled rats also differ in their anticonvulsant response to the major AED valproate (VPA) and which mechanism may underlie the different response to VPA. VPA has been proposed to act, at least in part, by reducing spontaneous activity in the substantia nigra pars reticulata (SNr), a main basal ganglia output structure involved in seizure propagation, seizure control, and epilepsy-induced neuroplasticity. Thus, we evaluated whether poor anticonvulsant response to VPA is correlated with low efficacy of VPA on SNr firing rate and pattern in kindled rats. We found (1) that good and poor VPA responders can be selected in kindled rats by repeatedly determining the effect of VPA on the electrographic seizure threshold, and (2) a significant correlation between the anticonvulsant response to VPA in kindled rats and its effect on SNr firing rate and pattern. The less VPA was able to raise seizure threshold, the lower was the VPA-induced reduction of SNr firing rate and the VPA-induced regularity of SNr firing. The data demonstrate for the first time an involvement of the SNr in pharmacoresistant experimental epilepsy and emphasize the relevance of the basal ganglia as target structures for new treatment options.
Recently, we reported an efficient chemical method for the synthesis of a variety of naturally occurring nucleoside diphosphate (NDP) sugars. This method, which is based on the cycloSal approach, can also be used, in principle, for the preparation of rare or even nonnatural NDP sugars. Herein, the syntheses of sulfoquinovose‐, glucose‐6‐sulfate‐, L‐galactose‐, and 2‐fluoroglycopyranoside‐containing NDP sugars are presented, as well as the synthesis of NDP sugars with non‐natural nucleosides. The reactions described gavestereoisomerically defined NDP sugars in high yields and short reaction times.
The cycloSal approach has been used in the past for the synthesis of a range of phosphorylated bioconjugates. In those reports, cycloSal nucleotides were allowed to react with different phosphate nucleophiles. With glycopyranosyl phosphates as nucleophiles, diphosphate-linked sugar nucleotides were formed. Here, cycloSal-nucleotides were used to prepare monophosphate-linked sugar nucleotides successfully in high anomeric purity and high chemical yield. The method was successfully used for the synthesis of three nucleotide glycopyranoses as model compounds. The method was then applied to the syntheses of CMP-N-acetyl-neuraminic acids (CMP-Neu5NAc) and of four derivatives with different modifications at their amino functions (N-propanoyl, N-butanoyl, N-pentanoyl and N-cyclopropylcarbonyl). The compounds were used for initial enzymatic studies with a bacterial polysialyltransferase (polyST). Surprisingly, the enzyme showed marked differences in terms of utilisation of the four derivatives. The N-propanoyl, N-butanoyl, and N-pentanoyl derivatives were efficiently used in a first transfer with a fluorescently labelled trisialo-acceptor. However, elongation of the resulting tetrasialo-acceptors worsened progressively with the size of the N-acyl chain. The N-pentanoyl derivative allowed a single transfer, leading to a capped tetramer. The N-cyclopropylcarbonyl derivative was not transferred.
α2,8‐Linked polysialic acid (polySia) is an oncofoetal antigen with high abundance during embryonic development. It reappears in malignant tumours of neuroendocrine origin. Two polysialyltransferases (polySTs) ST8SiaII and IV are responsible for polySia biosynthesis. During development, both enzymes are essential to control polySia expression. However, in tumours ST8SiaII is the prevalent enzyme. Consequently, ST8SiaII is an attractive target for novel cancer therapeutics. A major challenge is the high structural and functional conservation of ST8SiaII and ‐IV. An assay system that enables differential testing of ST8SiaII and ‐IV would be of high value to search for specific inhibitors. Here we exploited the different modes of acceptor recognition and elongation for this purpose. With DMB‐DP3 and DMB‐DP12 (fluorescently labelled sialic acid oligomers with a degree of polymerisation of 3 and 12, respectively) we identified stark differences between the two enzymes. The new acceptors enabled the simple comparative testing of the polyST initial transfer rate for a series of CMP‐activated and N‐substituted sialic acid derivatives. Of these derivatives, the non‐transferable CMP‐Neu5Cyclo was found to be a new, competitive ST8SiaII inhibitor.
The risk for children and adolescents to be exposed to a potentially traumatic event (PTE) is high. The present study examines the frequency of PTEs in children and adolescents with Posttraumatic Stress Disorder (PTSD), the type of index trauma, and its relation to PTSD symptom severity and gender. A clinical sample of 159 children and adolescents between 7-16 years was assessed using the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). All reported PTEs from the checklist were analyzed according to frequency. The index events were categorized according to the following categories: cause (random vs. intentional), relation to offender (intrafamilial vs. extrafamilial), patient's role (victim, witness or vicarious traumatization), and type of PTE (physical or sexual violence). Relation between categories and PTSD symptom severity and sex were analyzed with inferential statistics. On average participants reported five PTEs, most frequently physical violence without weapons (57.9%), loss of loved person through death (45.9%), and sexual abuse/assaults (44%). The most frequent index traumata were intentional (76.7%). Regarding trauma type, there was a significant difference concerning higher symptom severity in children and adolescents who experienced sexual abuse/assault compared to physical violence (t=-1.913(109), p=0.05). A significantly higher symptom severity was found for girls compared to boys for the trauma categories extrafamilial offender (z=-2,27, p=0.02), victim (z=-2,11, p=0,04), and sexual abuse/assault (z=-2,43, p=0,01). Clinical and diagnostic implications are discussed in relation to the amendments of PTSD diagnostic criteria in DSM-5.
A new access for the synthesis of nucleoside diphosphate glycopyranoses has been developed based on the cycloSal-concept. Using this approach, excellent chemical yields were obtained within short reaction times. In comparison to other methods the cycloSal-concept allows a fast and efficient preparation of anomerically defined nucleoside diphosphate glycopyranoses.
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