Monosaccharides and Analogues from Simple Achiral Unsaturated Compounds

We present herein a selection of ingenious methods that have been developed to convert inexpensive furan, pyrrole and unsaturated hydrocarbons into enantiomerically enriched monosaccharides and analogues of biological interest

Total asymmetric synthesis of monosaccharides and analogues

Since the discovery of the 'formose reaction' by Butlerow,[1] total synthesis of carbohydrates has undergone rapid development. The most important methods for the asymmetric synthesis of monosaccharides and analogues of biological importance are presented. Nowadays any natural and non-natural monosaccharide can be prepared pure in both enantiomeric forms starting from inexpensive starting materials. Metal-based asymmetric catalysis and organocatalysis have been successfully applied, alone or in combination with chemoenzymatic methods. Alternative methods rely upon substrate- or reagent- controlled diastereo- and enantioselective reactions. Suitably protected carbohydrates have been prepared by total synthesis, thus allowing their direct use in the preparation of oligosaccharides and analogues

Synthesis of Novel 3-Amino(Hydroxy)methyl-l-fuco-Azafagomines as Leads for Selective Inhibitors of α-l-Fucosidases

The synthesis of 3-substituted l-fuco-azafagomines from d-lyxose is reported. They represent the first example of aza-C-glycosides having a biimino (-NH-NH-) moiety. The key step of the synthesis is the introduction of the hydrazine moiety by reductive hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. Their glycosidase inhibitory properties are also reported.Ministerio de Ciencia e Innovación of Spain CTQ2008-01565/BQUJunta de Andalucía FQM-345 and P07-FQM-0305

Syntheses and biological activities of 1,4-iminoalditol derivatives as α-L-fucosidase inhibitors

A review dealing with 1,4-iminoalditol (hydroxylated pyrrolidine) derivatives as inhibitors of α-l-fucosidases including the different synthetic approaches for their preparation as well as their inhibitory properties is presented

Synthesis and cancer growth inhibitory activities of 2-fatty-alkylated pyrrolidine-3,4-diol derivatives

n/

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Synthesis of Novel 3-Deoxy-3-C-Triazolylmethyl-Allose Derivatives and Evaluation of Their Biological Activity

Recently, monosaccharide-triazole conjugates have proved to possess a large variety of useful biological activities. This paper describes synthesis of a new series of 3-deoxy-3-C-triazolylmethyl-allose derivatives. These latter are obtained from acetonide-protected 3-deoxy-3-azidomethyl allose and commercial alkynes via Cu(I) catalyzed 1,3-dipolar cycloaddition. The obtained molecular scaffolds differ from those described earlier by methylene linker (-CH2-) between the C(3) of allose and triazole moiety. It was demonstrated that acetonide-protected monosaccharide, 3-deoxy-3-C-(4-phenyl-1H-1,2,3-triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-D-allofuranose, inhibited α-L-fucosidase for 26% at 0.1 mM concentration, but a deprotected analog, 3-deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)methyl-β-D-allofuranose, showed 15% inhibition of β-glucosidase at 1 mM concentration

The regioselectivity of the addition of benzeneselenyl chloride to 7-azanorborn-5-ene-2-yl derivatives is controlled by the 2-substituent: new entry into 3-and 4-hydroxy-5-substituted prolines

The electrophilic addition of benzeneselenyl chloride to the alkene moiety of 7-azabicyclo[2.2.1]hept-5en-2-yl derivatives has been studied. With camphanates 8 and 9 N-Boc-5-endo-chloro-6-exo-phenylseleno-7-azanorborn-2-yl camphanates 10 and 11 are obtained with high regioselectivity due to a steric control. With N-Boc-7-azanorbor-5-en-2-one (2) the corresponding 6-endo-chloro-5-exo-phenylseleno derivative 15 is obtained in high yield due to a kinetic control attributed to the electron-releasing ability of the homoconjugated carbonyl group. Bicyclic adducts 10 and 11 and 15 are readily converted into 4-hydroxy-(14) and 3-hydroxy-5-substituted proline derivatives 19, respectively. (C) 2010 Elsevier Ltd. All rights reserved

Amide Formation in One Pot from Carboxylic Acids and Amines via Carboxyl and Sulfinyl Mixed Anhydrides

An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method