Design and synthesis of 6-C-alkyl-DMDP type nanomolar inhibitors of ß-galactosidase and ß-glucosidase based on broussonetine S and related derivatives.

Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Standard treatment for early-stage or locoregionally advanced non-small cell lung cancer (NSCLC) includes surgical resection. Recurrence after surgery is commonly reported, but a summary estimate for postsurgical recurrence-free survival (RFS) in patients with NSCLC is lacking. RESEARCH QUESTION: What is the RFS after surgery in patients with stage I-III NSCLC at different time points, and what factors are associated with RFS? STUDY DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE, and Cochrane databases between January 2011 and June 2021. The primary outcome was RFS at 1, 2, 3, and 5 years postresection. Single-arm, random-effects meta-analyses were done to calculate effect estimates and 95% CIs. Analyses were stratified by stage/substage as per the AJCC Cancer Staging Manual, and RFS was estimated (1) after pooling studies, using seventh or eighth edition staging criteria; and (2) among studies using only the eighth edition. Meta-regressions were performed to assess associations between RFS and patient demographic/clinical characteristics of interest. RESULTS: Data from 471 studies comprising 1,060 surgical study arms were extracted. RFS estimates from 60,695 patients staged with the seventh or eighth edition were analyzed. RFS ranged from 96% at 1 year postresection to 82% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III. Estimates for patients staged using only eighth edition criteria were slightly higher. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographic region (North America/Europe vs Asia) were significantly associated with worse RFS. INTERPRETATION: This study presents a comprehensive assessment of reported RFS from published clinical literature, offering estimates at multiple postsurgical time points and by geographic region. Findings can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC.

An umbrella review of the surgical performance of Harmonic ultrasonic devices and impact on patient outcomes.

BACKGROUND: For thirty years, the Harmonic scalpel has been used for precise dissection, sealing and transection. There are numerous meta-analyses on individual surgical procedures with Harmonic, but no overarching review covering all the areas. This umbrella review seeks to summarize the clinical results from the use of Harmonic across surgical fields and broadly quantify its effects on patient outcomes. METHODS: MEDLINE, EMBASE, and Cochrane Databases were searched for meta-analyses (MAs) of randomized controlled trials (RCTs) comparing Harmonic devices to conventional techniques or advanced bipolar (ABP) devices. For each procedure type, the most comprehensive MAs were evaluated. RCTs not already analysed in a MA were also included. Operating time, length of stay, intraoperative blood loss, drainage volume, pain, and overall complications were evaluated, and the methodological quality and certainty of evidence were assessed. RESULTS: Twenty-four systematic literature reviews were identified on colectomy, hemorrhoidectomy, gastrectomy, mastectomy, flap harvesting, cholecystectomy, thyroidectomy, tonsillectomy, and neck dissection. There were also 83 RCTs included. In every MA evaluated, Harmonic devices were associated with either statistically significant or numerical improvements in every outcome compared with conventional techniques; most MAs reported a reduction in operating time of ≥ 25 min. Harmonic versus ABP device MAs in colectomy and thyroidectomy showed no significant differences in outcomes. CONCLUSION: Across surgical procedures, Harmonic devices demonstrated improved patient outcomes for operating time, length of stay, intraoperative bleeding, drainage volume, pain, and overall complications compared to conventional techniques. Additional studies are required to assess differences between Harmonic and ABP devices.

Design and Pharmacological Chaperone Effects of N-(4'-Phenylbutyl)-DAB Derivatives Targeting the Lipophilic Pocket of Lysosomal Acid α-Glucosidase.

This study provides the first example of a strategy to design a practical ligand toward lysosomal acid α-glucosidase (GAA) focusing on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed a Ki value of 0.73 µM, which was 353-fold higher affinity than N-butyl-DAB (3f) without a terminal phenyl group. Docking analysis showed that the phenyl part of 5g was accommodated in a lipophilic pocket. Furthermore, the p-trifluoromethyl group effectively suppresses the fluctuation of the phenyl group, allowing it to produce a stable bonding form with GAA. 5g increased the midpoint of the protein's protein denaturation temperature (Tm) by 6.6 °C above that in the absence of the ligand and acted as a "thermodynamic stabilizer" to improve the thermal stability of rhGAA. 5g dose-dependently increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation; its effect was comparable to that of DNJ, which is under clinical trials.

Stereotactic body radiation therapy and thermal ablation for treatment of NSCLC: A systematic literature review and meta-analysis.

RATIONALE: Stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early stage non-small cell lung cancer (NSCLC). Use of image guided thermal ablation (IGTA; including microwave ablation [MWA] and radiofrequency ablation [RFA]) has increased in NSCLC, however there are no studies comparing all three. OBJECTIVE: To compare the efficacy of IGTA (including MWA and RFA) and SBRT for the treatment of NSCLC. METHODS: Published literature databases were systematically searched for studies assessing MWA, RFA, or SBRT. Local tumor progression (LTP), disease-free survival (DFS), and overall survival (OS) were assessed with single-arm pooled analyses and meta-regressions in NSCLC patients and a stage IA subgroup. Study quality was assessed with a modified methodological index for non-randomized studies (MINORS) tool. RESULTS: Forty IGTA study-arms (2,691 patients) and 215 SBRT study-arms (54,789 patients) were identified. LTP was lowest after SBRT at one and two years in single-arm pooled analyses (4% and 9% vs. 11% and 18%) and at one year in meta-regressions when compared to IGTA (OR = 0.2, 95%CI = 0.07-0.63). MWA patients had the highest DFS of all treatments in single-arm pooled analyses. In meta-regressions at two and three-years, DFS was significantly lower for RFA compared to MWA (OR = 0.26, 95%CI = 0.12-0.58; OR = 0.33, 95%CI = 0.16-0.66, respectively). OS was similar across modalities, timepoints, and analyses. Older age, male patients, larger tumors, retrospective studies, and non-Asian study region were also predictors of worse clinical outcomes. In high-quality studies (MINORS score ≥ 7), MWA patients had better clinical outcomes than the overall analysis. Stage IA MWA patients had lower LTP, higher OS, and generally lower DFS, compared to the main analysis of all NSCLC patients. CONCLUSIONS: NSCLC patients had comparable outcomes after SBRT and MWA, which were better than those with RFA.

Production of d-aldotetrose from l-erythrulose using various isomerases.

d-Aldotetroses are rare sugars that are obtained via chemical synthesis in low yield. In this study, we demonstrated that d-aldotetroses could be produced using 3 isomerases. First, l-erythrulose was epimerized using d-tagatose 3-epimerase from Pseudomonas cichorii ST-24. The specific optical rotation of the reaction solution gradually decreased to zero, indicating that approximately 50% of the l-erythrulose was converted to d-erythrulose. d, l-Erythrulose mixture was isomerized with d-arabinose isomerase from Klebsiella pneumoniae 40bXX to produce d-threose, resulting in a conversion rate of 9.35%. d-Erythrose production using l-rhamnose isomerase from Pseudomonas stutzeri LL172 resulted in a conversion rate of 12.9%. Because of the low purity of the purchased d-erythrose, the product was reduced by the Raney nickel catalyst compared with authentic erythritol. We confirmed the products using HPLC and 13C-NMR spectra. This is the first report of d-aldotetrose production using an enzymatic reaction.

Design and synthesis of iso-allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase.

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 µM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.

Design, synthesis and glycosidase inhibition of DAB derivatives with C-4 peptide and dipeptide branches.

A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver ß-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed the most potent ß-galactosidase inhibition (IC50 = 0.66 µM). Molecular docking studies revealed different docking modes of compound 23b compared to those of other DAB-peptides, and partial similarity of compound 23b to DGJ.

Adopting a portfolio of ultrasonic and advanced bipolar electrosurgery devices from a single manufacturer compared to currently used ultrasonic and advanced bipolar devices: a probabilistic budget impact analysis from a Spanish hospital perspective.

AIMS: Advanced energy devices are commonly used in electrosurgery, including ultrasonic and advanced bipolar (ABP) devices. Smoke evacuation and reusable dispersive electrodes are also utilized during electrosurgery to improve staff and patient safety. This study assessed the budget impact of adopting a portfolio of Ethicon energy devices compared to devices from other manufacturers from a Spanish hospital perspective. METHODS: The main analysis compared the Ethicon advanced energy device portfolio (ultrasonic and ABP devices) to Non-Ethicon advanced energy devices. It was assumed that 4,000 procedures using one advanced energy device each were performed annually, and the cost impact of operating room time, length of stay, and transfusions were considered. A probabilistic budget impact analysis with 10,000 iterations was conducted for generalizability to other hospitals in Spain and Europe. Secondary analysis assessed whether cost savings from the Ethicon advanced energy device portfolio could offset costs of adopting smoke evacuation and reusable dispersive electrodes (Full Ethicon energy portfolio). RESULTS: In the main analysis, the annual budget impact of introducing the Ethicon advanced energy device portfolio was cost saving in 79.8% of probabilistic iterations (mean: -€945,214; 95% credible interval [CrI]: -€3,242,710; €1,285,942) with a mean budget impact per procedure of -€236 (95% CrI: -€811; €321). In the secondary analysis, adding smoke evacuation and reusable dispersive electrodes was still cost saving in 75.3% of iterations compared to Non-Ethicon advanced energy devices (mean: -€778,208; 95% CrI: -€3,075,086; €1,464,728) with a mean budget impact per procedure of -€97 (95% CrI: -€384; €183). Savings resulted from differences in operating room time, length of hospital stay, and volume of disposable electrodes. CONCLUSIONS: Adopting Ethicon advanced energy devices demonstrated economic benefits compared to non-Ethicon devices. Introducing the advanced portfolio may improve surgical care quality and the full portfolio was cost saving while improving OR safety for staff and patients.

This study created an economic model to calculate whether using modern electrical surgical tools with features to make cutting tissue and stopping bleeding faster and easier could save Spanish hospitals money. The electrical surgery tools from one manufacturer were compared to those from various other companies. Differences in how long surgery took to perform, how long patients stayed in hospital after their surgery, and how many blood transfusions they needed were considered in the model. The model was tested 10,000 times with random changes in the costs and settings used to be surer about the range of possible results. The results showed the devices from one manufacturer could save a Spanish hospital money in almost 80% of model runs and that savings worked out to €236 per surgery. In another analysis, savings were enough to cover the cost of introducing safety devices to remove surgical smoke from the operating room and reusable patient grounding electrodes that prevent some injuries potentially caused by small sticky electrodes. In conclusion, the model showed that Spanish hospitals may be able to save money by switching to the modern electrical surgery tools from Ethicon.

Nanomolar ß-glucosidase and ß-galactosidase inhibition by enantiomeric α-1-C-alkyl-1,4-dideoxy-1,4-imino-arabinitol derivatives.

A series of α-1-C-alkyl DAB (1,4-dideoxy-1,4-imino-d-arabinitol) and LAB (1,4-dideoxy-1,4-imino-l-arabinitol) derivatives with aryl substituents have been designed as analogues of broussonetine W (12), and assayed as glycosidase inhibitors. While the inhibition spectrum of α-1-C-alkyl DAB derivative 16 showed a good correlation to that of broussonetine W (12), introduction of substituents on the terminal aryl (17a-f) or hydroxyl groups at C-1' position of the alkyl chains (18a-e) decreased their α-glucosidase inhibitions but greatly improved their inhibitions of bovine liver ß-glucosidase and ß-galactosidase. Furthermore, epimerization of C-1' configurations of compounds 18a-e clearly lowered their inhibition potency of bovine liver ß-glucosidase and ß-galactosidase. Notably, some of the α-1-C-alkyl DAB derivatives were also found to have potent human lysosome ß-glucosidase inhibitions. In contrast, enantiomers of compounds 18a-e and 1'-epi-18a-e generally showed increased α-glucosidase inhibitions, but sharply decreased bovine liver ß-glucosidase and ß-galactosidase inhibitions. Molecular docking calculations unveiled the novel two set of binding modes for each series of compounds; introduction of C-1' hydroxyl altered the conformations of the pyrrolidine rings and orientation of their long chains, resulting in improved accommodation in the hydrophobic grooves. The compounds reported herein are very potent ß-glucosidase and ß-galactosidase inhibitions with novel binding mode; and the structure-activity relationship provides guidance for design and development of more pyrrolidine pharmacological chaperones for lysosomal storage diseases.

Economic analysis of n-butyl cyanoacrylate compared with ethylene vinyl alcohol copolymer liquid embolic embolization of brain arteriovenous malformations (bAVMs) from a US hospital perspective.

BACKGROUND: In US hospitals, the liquid embolic systems (LESs) n-butyl cyanoacrylate (n-BCA) and ethylene vinyl alcohol copolymer (EVOH) are used for brain arteriovenous malformation (bAVM) embolization to achieve presurgical devascularization. The aim of this study was to perform an economic analysis comparing four techniques for bAVM embolization based on LES, ancillary device, and angiography suite time costs. METHODS: An economic model was developed comparing the embolization costs for n-BCA, EVOH with the plug and push technique, EVOH with detachable-tip microcatheters, and EVOH with balloon microcatheters. Per procedure costs were calculated for bAVMs with one to four pedicles. Annual cohort analyses were performed to evaluate the potential impact for low and high-volume centers. Sensitivity analyses were performed to determine cost drivers. RESULTS: The analyses showed that the n-BCA technique was the least costly of the four techniques. Total per procedure costs for one to four embolized pedicles ranged from $5941 to $10,074 for the n-BCA technique, $8428 to $30,345 for the EVOH balloon microcatheter technique, $12,711 to $47,477 for the EVOH plug and push technique, and $13,900 to $52,233 for the EVOH detachable-tip microcatheter technique. Cohort analyses costs for 52 annual cases ranged from $308,953 to $523,838 with the n-BCA technique and from $722,816 to $2,716,096 with the EVOH detachable-tip microcatheter technique. CONCLUSIONS: Procedure costs associated with n-BCA are lower than those with each of the three EVOH techniques examined. Future cost analyses should compare the costs of new LES products once available.

C-6 fluorinated casuarines as highly potent and selective amyloglucosidase inhibitors: Synthesis and structure-activity relationship study.

A series of C-6 fluorinated casuarine derivatives have been synthesized via organocatalytic stereoselective α-fluorination of iminosugar-based aldehydes or direct nucleophilic fluorination of polyhydroxylated pyrrolizidines. Glycosidase assays against various glycosidases allowed systematic structure-activity relationship (SAR) study using molecular docking calculations. Introduction of fluorine atom(s) at C-6 position removed the trehalase and maltase inhibitory activities of all casuarine derivatives, and greatly increased their specificity towards amyloglucosidase. Inhibition of the fluorinated casuarines depended on the configuration of C-6 fluorine, of which 6-deoxy-6-epi-6-fluoro-casuarine (24) was found approximately 40-fold potent than its parent compound 6-epi-casuarine (2) as a potent and specific inhibitor of amyloglucosidase. Molecular docking calculations showed that replacement of the C-6 hydroxyls by fluorine atom(s) removed the original interactions with trehalase, but helped to reinforce the binding with amyloglucosidase via newly established fluorine related hydrogen bonding or untypical anion-π interactions. To further investigate the quantitative SARs of casuarine derivatives, the CoMFA and CoMSIA models on amyloglucosidase were established, indicating the dominating effect of electrostatic field in amyloglucosidase inhibition. The 3D-QSAR models were validated to be reliable and can be used for further optimization of casuarine-related iminosugars, as well as design and development of anti-diabetic and immunomodulatory drugs.

Stable D-xylose ditriflate in divergent syntheses of dihydroxy prolines, pyrrolidines, tetrahydrofuran-2-carboxylic acids, and cyclic ß-amino acids.

Double nucleophilic displacement of D-xylo-ditriflate by amines, water and alkyl cyanoacetates, respectively, gave a series of bicyclic divergent intermediates for the synthesis of a wide range of highly functionalized targets, including hydroxylated prolines, pyrrolidines, furanoic acids, and cyclopentanes.

Introduction of C-alkyl branches to L-iminosugars changes their active site binding orientation.

L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value of 0.060 µM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were introduced. Docking simulation analysis revealed that the alkyl chains of 5-C-alkyl-L-ido-DNJs were stored in three different pockets, depending on their length, thereby the molecular orientation was changed. Comparison of the binding poses of DNJ and 5-C-methyl-L-ido-DNJ showed that they formed a common ionic interaction with Asp404, Asp518, and Asp616, but both the binding orientation and the distance between the ligand and each amino acid residue were different. 5-C-Methyl-L-ido-DNJ dose-dependently increased intracellular GAA activity in Pompe patient fibroblasts with the M519V mutation and also promoted enzyme transport to lysosomes. This study provides the first example of a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and L-sugar-type iminosugars to change the orientation of binding.

trans, trans-2-C-Aryl-3,4-dihydroxypyrrolidines as potent and selective ß-glucosidase inhibitors: Pharmacological chaperones for Gaucher disease.

Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives (trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines), designed as ß-glucosidase inhibitors by molecular docking calculations, have been synthesized in 2 steps from l- and d-tartaric acid derived enantiomeric cyclic nitrones 29L and 29D, respectively. Both series of C-4 hydroxymethyl depleted DAB and LAB derivatives 28Da-e and 28La-e, which are structurally trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines, were potent and selective human lysosome acid ß-glucosidase (GCase) inhibitors, of which 28Dd and 28Ld with C-4 biphenyls showed the highest potency relative to other compounds of the same series. The work provided a series of pyrrolidine-type potent and selective GCase inhibitors with minimal hydroxyl substitutions and synthetic procedures. Structure-activity relationship study revealed not only the rationality of hydrophobic and aromatic properties of the binding sites in GCase, but also the great potential of pyrrolidine family in development of new GCase inhibitors with minimized undesirable side effects. The results indicate a strategy for the development of drugs for the treatment of related diseases targeting acid ß-glucosidase, such as Gaucher disease and Parkinson's disease.

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia.

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, such as Alzheimer's disease. (2) Methods. A mouse BV-2 microglia cell line was activated using LPS and the anti-inflammatory cucumber-derived iminosugar amino acid idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, was used alongside dexamethasone as the control to determine whether it could reduce the inflammatory responses. (3) Results. A dose-dependent reduction in the LPS-induced production of the proinflammatory factors TNFα, IL-6, and nitric oxide and the transcription factor NF-κB was found. (4) Conclusions. Further investigations of the anti-inflammatory effects of idoBR1 in other models of neurodegenerative diseases are warranted.

Diastereoselective Synthesis, Glycosidase Inhibition, and Docking Study of C-7-Fluorinated Casuarine and Australine Derivatives.

C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, were synthesized with organocatalytic stereoselective α-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are due to the interaction modes dominated by fluorine atoms in these iminosugars with the amino acids' residues of the corresponding enzymes. Steady interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase by untypical anion-π interactions. These unexpected docking modes and related structure-activity relationship studies emphasize the value of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.

Quantitative chemical exchange saturation transfer imaging of nuclear overhauser effects in acute ischemic stroke.

PURPOSE: In chemical exchange saturation transfer imaging, saturation effects between - 2 to - 5 ppm (nuclear Overhauser effects, NOEs) have been shown to exhibit contrast in preclinical stroke models. Our previous work on NOEs in human stroke used an analysis model that combined NOEs and semisolid MT; however their combination might feasibly have reduced sensitivity to changes in NOEs. The aim of this study was to explore the information a 4-pool Bloch-McConnell model provides about the NOE contribution in ischemic stroke, contrasting that with an intentionally approximate 3-pool model. METHODS: MRI data from 12 patients presenting with ischemic stroke were retrospectively analyzed, as well as from six animals induced with an ischemic lesion. Two Bloch-McConnell models (4 pools, and a 3-pool approximation) were compared for their ability to distinguish pathological tissue in acute stroke. The association of NOEs with pH was also explored, using pH phantoms that mimic the intracellular environment of naïve mouse brain. RESULTS: The 4-pool measure of NOEs exhibited a different association with tissue outcome compared to 3-pool approximation in the ischemic core and in tissue that underwent delayed infarction. In the ischemic core, the 4-pool measure was elevated in patient white matter ( 1.20±0.20 ) and in animals ( 1.27±0.20 ). In the naïve brain pH phantoms, significant positive correlation between the NOE and pH was observed. CONCLUSION: Associations of NOEs with tissue pathology were found using the 4-pool metric that were not observed using the 3-pool approximation. The 4-pool model more adequately captured in vivo changes in NOEs and revealed trends depending on tissue pathology in stroke.

Design, synthesis and glycosidase inhibition of C-4 branched LAB and DAB derivatives.

Two series of C-4 alkylated and arylated LAB (1,4-dideoxy-1,4-imino-l-arabinitol) and DAB (1,4-dideoxy-1,4-imino-d-arabinitol) derivatives, synthesized in 6 steps from enantiomeric cyclic nitrones derived from l- and d-tartaric acid, were designed and assayed against various glycosidases. C-4 Branched LAB alkyl and phenyl derivatives 5La-d showed potent α-glucosidase inhibition, particularly against human lysosomal acid α-glucosidase; C-4 DAB derivatives 5Da-d, with small alkyl groups, showed enhanced inhibition of rat intestinal maltase and sucrase. Both enantiomeric C-4 arylated derivatives 5Lf-l and 5Df-l exhibited potent and selective α-glucosidase inhibition; and compound 5Li with a para-electron donating group (EDG) on its C-4 aryl group, showed the most potent rat intestinal sucrase inhibition. Docking studies showed similar hydrogen bonding modes for the iminosugar skeletons of DAB (1) and LAB (2) with ntMGAM,. While C-4 alkylated LAB derivatives showed high similarity in their binding modes with the active site of ntMGAM, binding modes of the DAB derivatives relied on the size of C-4 alkyl groups with methyl and butyl showed the optimum interactions. Furthermore, C-4 arylation improved the interactions of LAB derivatives with enzymes by T-shaped π-π stack with residue Trp-406; for C-4 arylated DAB derivatives, the π-π stack interactions were found with distinct planar distortions caused by EDGs or EWGs on the C-4 aryls. The results reported herein provided insights for the design and development of DAB and LAB related α-glucosidase inhibitors, and may also contribute to the future development of anti-viral, anti-diabetic and anti-Pompe disease drugs.