High flux novel polymeric membrane for renal applications.

Biocompatibility and the ability to mediate the appropriate flux of ions, urea, and uremic toxins between blood and dialysate components are key parameters for membranes used in dialysis. Oxone-mediated TEMPO-oxidized cellulose nanomaterials have been demonstrated to be excellent additives in the production and tunability of ultrafiltration and dialysis membranes. In the present study, nanocellulose ionic liquid membranes (NC-ILMs) were tested in vitro and ex vivo. An increase in flux of up to two orders of magnitude was observed with increased rejection (about 99.6%) of key proteins compared to that of polysulfone (PSf) and other commercial membranes. NC-ILMs have a sharper molecular weight cut-off than other phase inversion polymeric membranes, allowing for high throughput of urea and a uremic toxin surrogate and limited passage of proteins in dialysis applications. Superior anti-fouling properties were also observed for the NC-ILMs, including a > 5-h operation time with no systemic anticoagulation in blood samples. Finally, NC-ILMs were found to be biocompatible in rat ultrafiltration and dialysis experiments, indicating their potential clinical utility in dialysis and other blood filtration applications. These superior properties may allow for a new class of membranes for use in a wide variety of industrial applications, including the treatment of patients suffering from renal disease.

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKß ubiquitin-like domain (ULD).

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKß subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and in vitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI50 values < 2 µM). Two analogs, the benzyl carbamate 7b and the phenethyl carbamate7k, were the most active compounds. Lead compound 7b inhibited cell proliferation in M9 ENL AML cells, and in TMD-231, OV-MD-231 and SUM149 breast cancer cell lines. Interestingly, mechanistic studies showed that 7b did not inhibit p65 phosphorylation in M9 ENL AML and OV-MD-231 cells, but did inhibit phophorylation of both p65 and IκBα in SUM149 cells. 7b also reduced NFκB binding to DNA in both OV-MD-231 and SUM149 cells. Molecular docking studies indicated that 7b and 7k are both predicted to interact with the ubiquitin-like domain (ULD) of the IKKß subunit. These data suggest that in SUM149 cells, 7b is likely acting as an allosteric inhibitor of IKKß, whereas in M9 ENL AML and OV-MD-231 cells 7b is able to inhibit an event after IκB/p65/p50 phosphorylation by IKKß that leads to inhibition of NFκB activation and reduction in NFκB-DNA binding. Analog 7b was by far the most potent compound in either carbamate series, and was considered an important lead compound for further optimization and development as an anticancer agent.

7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands.

A series of N-benzyl-7-azaindolequinuclidinone (7-AIQD) analogs have been synthesized and evaluated for affinity toward CB1 and CB2 cannabinoid receptors and identified as a novel class of cannabinoid receptor ligands. Structure-activity relationship (SAR) studies indicate that 7-AIQD analogs are dual CB1/CB2 receptor ligands exhibiting high potency with somewhat greater selectivity towards CB2 receptors compared to the previously reported indolequinuclidinone (IQD) analogs. Initial binding assays showed that 7-AIQD analogs 8b, 8d, 8f, 8g and 9b (1 µM) produced more that 50% displacement of the CB1/CB2 non-selective agonist CP-55,940 (0.1 nM). Furthermore, Ki values determined from full competition binding curves showed that analogs 8a, 8b and 8g exhibit high affinity (110, 115 and 23.7 nM, respectively) and moderate selectivity (26.3, 6.1 and 9.2-fold, respectively) for CB2 relative to CB1 receptors. Functional studies examining modulation of G-protein activity demonstrated that 8a acts as a neutral antagonist at CB1 and CB2 receptors, while 8b exhibits inverse agonist activity at these receptors. Analogs 8f and 8g exhibit different intrinsic activities, depending on the receptor examined. Molecular docking and binding free energy calculations for the most active compounds (8a, 8b, 8f, and 8g) were performed to better understand the CB2 receptor-selective mechanism at the atomic level. Compound 8g exhibited the highest predicted binding affinity at both CB1 and CB2 receptors, and all four compounds were shown to have higher predicted binding affinities with the CB2 receptor compared to their corresponding binding affinities with the CB1 receptor. Further structural optimization of 7-AIQD analogs may lead to the identification of potential clinical agents.

Oxone®-Mediated TEMPO-Oxidized Cellulose Nanomaterial Ultrafiltration and Dialysis Mixed-Matrix Hollow Fiber Membranes.

Recent exploration of cellulose nanomaterials has resulted in the creation of Oxone®-Mediated TEMPO-Oxidized Cellulose Nanomaterials (OTO-CNMs). These materials, when incorporated into a polymer matrix, have properties showing increased flux, decreased membrane resistance, and improved clearance, making them an ideal material for dialysis. This study is the first to focus on the implementation of OTO-CNMs into hollow fiber membranes and a comparison of these membranes for ultrafiltration and dialysis. Ultrafiltration and dialysis were performed using bovine serum albumin (BSA), lysozyme, and urea to analyze various properties of each hollow fiber membrane type. The results presented in this study provide the first quantitative evaluation of the clearance and sieving characteristics of Oxone®-Mediated TEMPO-Oxidized Cellulose-Nanomaterial-doped cellulose triacetate mixed-matrix hemodialyzers. While the cellulose nanomaterials increased flux (10-30%) in ultrafiltration mode, this was offset by increased removal of albumin. However, in dialysis mode, these materials drastically increased the mass transfer of components (50-100%), which could lead to significantly lower dialysis times for patients. This change in the performance between the two different modes is most likely due to the increased porosity of the cellulose nanomaterials.

Oxone®-Mediated TEMPO-Oxidized Cellulose Nanomaterials form I and form II.

The 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) oxidation of cellulose, when mediated with Oxone® (KHSO5), can be performed simply and under mild conditions. Furthermore, the products of the reaction can be isolated into two major components: Oxone®-mediated TEMPO-oxidized cellulose nanomaterials Form I and Form II (OTO-CNM Form I and Form II). This study focuses on the characterization of the properties of OTO-CNMs. Nanoparticle-sized cellulose fibers of 5 and 16 nm, respectively, were confirmed through electron microscopy. Infrared spectroscopy showed that the most carboxylation presented in Form II. Conductometric titration showed a two-fold increase in carboxylation from Form I (800 mmol/kg) to Form II (1600 mmol/kg). OTO-CNMs showed cellulose crystallinity in the range of 64-68% and crystallite sizes of 1.4-3.3 nm, as shown through XRD. OTO-CNMs show controlled variability in hydrophilicity with contact angles ranging from 16 to 32°, within or below the 26-47° reported in the literature for TEMPO-oxidized CNMs. Newly discovered OTO-CNM Form II shows enhanced hydrophilic properties as well as unique crystallinity and chemical functionalization in the field of bio-sourced material and nanocomposites.

Fellutamide B Synthetic Path Intermediates with in Vitro Neuroactive Function Shows Mood-Elevating Effect in Stress-Induced Zebrafish Model.

Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A-D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A-D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders.

Highly sulphated cellulose: a versatile, reusable and selective desilylating agent for deprotection of alcoholic TBDMS ethers.

A mild, efficient and rapid protocol was developed for the deprotection of alcoholic TBDMS ethers using a recyclable, eco-friendly highly sulphated cellulose sulphate acid catalyst in methanol. This acid catalyst selectively cleaves alcoholic TBDMS ethers in bis-TBDMS ethers containing both alcoholic and phenolic TBDMS ether moieties.