Synthesis, Biological Evaluation, and Docking Studies of Open-Chain Carbohydrate Amides as Acetylcholinesterase Inhibitors.

INTRODUCTION: Alzheimer's disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. METHODS: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4- lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. RESULTS: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. CONCLUSION: Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives.

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3-O-saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N,N'-bis(tert-butoxycarbonyl)-N''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3-O-methyl-branched N-benzyltriazole isonucleosides and a guanidinomethyltriazole 3'-O-dodecyl xylofuranos-5'-yl isonucleoside were accessed. The guanidinomethyltriazole derivative and a 3-O-dodecyl (N-Boc)guanidino xylofuranose were revealed as selective inhibitors of acetylcholinesterase (Ki =22.87 and 7.49 µM, respectively). The latter also showed moderate antiproliferative effects in chronic myeloid leukemia (K562) and breast cancer (MCF-7) cells. An aminomethyltriazole 5'-isonucleoside was the most potent molecule with low micromolar GI50 values in both cells (GI50 =6.33 µM, 8.45 µM), similar to that of the drug 5-fluorouracil in MCF-7 cells. Moreover, the most bioactive compounds showed low toxicity in human fibroblasts, further indicating their interest as promising lead molecules.

RECURRENT VARICOSE VEINS FOLLOWING SMALL SAPHENOUS VEIN SURGERY: A 5-YEAR FOLLOW-UP DUPLEX ULTRASOUND STUDY.

INTRODUCTION: Chronic venous disease (CVD) of the lower limbs is a very prevalent medical condition with important socioeconomic repercussions. Small saphenous vein (SSV) incompetence, although less frequent than great saphenous vein (GSV) incompetence, presents a more challenging treatment, with higher rates of complication and recurrence. OBJECTIVES: To determine the incidence and associated risk factors of varicose veins recurrence in patients submitted, for the first time and exclusively, to SSV surgery with 5 years of follow-up. METHODS: Retrospective analysis of all exclusively first-time SSV surgeries, at Angiology and Vascular Surgery Service of Hospital Beatriz Ângelo, between January 1st, 2013, and December 31st, 2014. In March 2019, the authors performed clinical and venous doppler ultrasound reassessment of all included patients. RESULTS: A total of 23 limbs were evaluated, 56.5% were female and the mean age was 51.8 years. All patients were symptomatic and underwent ligation of the saphenopopliteal junction (SPJ), 26.1% and 43.5% had total and partial SSV stripping, respectively. After venous doppler ultrasound at 5-year follow-up, we found that 21.7% did not present a correct SPJ ligation due to failure to identify its location, with a statistically significant association between SPJ ligation and varicose vein recurrence. In follow-up, we also diagnosed GSV incompetence in 21.7% for the first time, which is in agreement with the fact that this is a chronic disease. Finally, we found that all patients with symptomatic recurrence at 5-year follow-up had CVD, however, some asymptomatic patients also had ultrasound changes. CONCLUSION: Routine preoperative localization of the SPJ by doppler ultrasound guidance could have an impact in minimizing varicose vein recurrence. Imaging recurrence does not always translate into clinical recurrence. Because this is a chronic disease, patients should keep general care to prevent disease progression, even after surgery.

MAJOR PULMONARY SURGERY IN PATIENTS WITH COMPROMISED LUNG FUNCTION.

INTRODUCTION: The risk stratification of lung resection is fundamentally based on the results of pulmonary function tests. In patients considered to be at risk, major surgery is generally denied, opting for potentially less curative therapies. OBJECTIVE: To evaluate the postoperative outcomes of major lung surgery in a group of patients deemed high risk. METHODS: We performed a retrospective review of clinical records of all patients submitted to lobectomy, bilobectomy or pneumonectomy in a 3-year period in a reference Thoracic Surgery Unit. The patients were then divided in two groups: group A composed of patients with normal preoperative pulmonary function and group B which included patients with impaired lung function, defined as FEV1 and/or DLCO ≤60%. RESULTS: A total of 234 patients were included, 181 (77.4%) in group A and 53 (22.6%) in group B. In group B, patients had more smoking habits, were more often associated with chronic obstructive pulmonary disease and were also more frequently submitted to thoracotomy. When surgery was motivated by primary lung cancer this group had a more advanced clinical stage of the disease. In the postoperative period, these patients had longer hospital stay, longer chest drainage time and greater need for oxygen therapy at home, however, no statistically significant difference was noted in morbidity or mortality. CONCLUSIONS: Major thoracic surgery can be safely performed in selected patients considered to be high risk for resection by pulmonary function tests. A potentially curative surgery should not be denied based on respiratory function tests alone.

sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo.

Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp2-iminosugar glycolipids (sp2-IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp2-IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp2-IGLs: unlike MGCs, DSO2-ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO2-ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp2-IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.

Tn Antigen Mimics Based on sp(2)-Iminosugars with Affinity for an anti-MUC1 Antibody.

The first examples of amino acid (Ser/Thr)-sp(2)-iminosugar glycomimetic conjugates featuring an α-O-linked pseudoanomeric linkage are reported. The key synthetic step involves the completely diastereoselective α-glycosylation of Ser/Thr due to strong stereoelectronic and conformational bias imposed by the bicyclic sp(2)-iminosugar scaffold. Mucin-related glycopeptides incorporating these motifs were recognized by the monoclonal antibody (mAb) scFv-SM3, with activities depending on both the hydroxylation pattern (Glc/Gal/GlcNAc/GalNAc) of the sp(2)-iminosugar and the peptide aglycone structure (Ser/Thr).

Influence of the configurational pattern of sp(2)-iminosugar pseudo N-, S-, O- and C-glycosides on their glycoside inhibitory and antitumor properties.

The synthesis of a complete series of cyclic carbamate-type sp(2)-iminosugar N-, S-, O- and C-octyl pseudoglycosides related to nojirimycin, mannojirimycin and galactonojirimycin, all having the α-pseudoanomeric configuration, is reported. The gem-diamine-type N-pseudoglycosides can be accessed directly from the corresponding reducing sp(2)-imisosugar precursors by reaction with octylamine in methanol, whereas per-O-acetyl or 1-fluoro derivatives were used as pseudoglycosyl donors for the preparation of S-pseudoglycosides or O- and C-pseudoglycosides, respectively. Evaluation of their inhibitory properties against a panel of glycosidases evidenced selectivity profiles that strongly depend on the configurational pattern and the nature of the glycosidic linkage. On the contrary, the antiproliferative activity determined against a panel of tumor cell lines was largely independent of the relative orientation of the hydroxyl groups in the sp(2)-iminosugar moiety. Indeed, sp(2)-iminosugar representatives exhibiting significant growth inhibition potencies were identified in all three configurationally different types of compounds studied, namely α-d-gluco, α-d-manno and α-d-galacto glycoside analogs. Interestingly, none of the compounds affected viability and mortality of normal cells at the used concentrations. Altogether, the results strongly suggest that the anticancer activity of amphiphilic sp(2)-iminosugar glycosides might be unrelated, or not solely related, to their glycosidase inhibitory activity.

o-Xylylene protecting group in carbohydrate chemistry: application to the regioselective protection of a single vic-diol segment in cyclodextrins.

A systematic study of the suitability of α,α'-dibromo-o-xylene as a reagent for cyclic o-xylylene protection of vic-diols in different monosaccharide substrates is reported. The installation of this protecting group, formally equivalent to a di-O-benzylation reaction, proceeds with good regioselectivity toward 1,2-trans-diequatorial diol systems in pyranose and furanose rings. Initially, the benzyl ether-type derivative of the more acidic hydroxyl is preferentially formed. Subsequent intramolecular etherification toward the equatorial-oriented vicinal OH is kinetically favored. The methodology has been implemented for the simultaneous protection of the secondary O-2 and O-3 positions of a single d-glucopyranosyl unit in cyclic oligosaccharides of the cyclodextrin (CD) family (cyclomaltohexa-, -hepta-, and -octaose; α, ß, and γCD).