Exploiting pH mismatch in preparative high-performance liquid chromatographic recovery of ertapenem from mother liquor streams

Preparative chromatography was successfully employed to recover ertapenem from mother liquor streams. The recovery process involved concentration of mother liquor stream by evaporation, purification by reversed-phase preparative high-performance liquid chromatography (HPLC), and removal of chromatographic solvents in the recovered fractions by evaporation. HPLC feed was prepared by stripping off the organic solvents from the mother liquor using a wiped-film evaporator. Purification was first carried out on a 25 cm x 0.46 cm analytical column packed with 10-microm Kromasil C8 particles and then scaled up to a 25 cm x 5 cm preparative column. Gram-level recovery of ertapenem with high purity was achieved by exploiting a novel approach based on pH mismatch between the feed and the eluent. Purified ertapenem streams from preparative HPLC runs were combined, evaporated and recycled into the crystallizer for ertapenem isolation.     

Chromatographic resolution of closely related species: Drug metabolites and analogs

In this study, we investigate the separation of a variety of mixtures of drugs, metabolites, and related analogs including representatives of the carbamazepine, methylated xanthine, steroid hormone, nicotine, and morphine families using several automated chromatographic method development screening systems including ultra high performance liquid chromatography, core–shell HPLC, achiral supercritical fluid chromatography (SFC), and chiral SFC. Of the 138 column and mobile phase combinations examined for each mixture, a few chromatographic conditions afford the best overall performance, with a single achiral SFC method (4.6 × 250 mm, 3.0 μm GreenSep Ethyl Pyridine, 25 mM isobutylamine in methanol/CO₂) affording good separation for all samples. Four of these mixtures were also resolved by achiral SFC on the Luna HILIC and chiral SFC Chiralpak IB columns using methanol or ethanol with 25 mM isobutylamine as polar modifiers. Modifications of standard chromatography screening conditions afforded fast separation methods (from 1 to 5 min) for baseline resolution of all components of each of these challenging sets of closely related compounds.     

Enhancing the Anticancer Potential of Targeting Tumor-Associated Metalloenzymes via VEGFR Inhibition by New Triazolo[4,3-a]pyrimidinone Acyclo C-Nucleosides Multitarget Agents

The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents. Despite their transient efficacy, these agents are often susceptible to resistance. This set the stage to introduce dual inhibitors of correlated MMPs and CAs. The next step is expected to target the common vital signaling nodes as well. In this regard, VEGFR-2 is central to various tumorigenesis events involving both families, especially MMP-2 and CA II. Herein, we report simultaneous inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed hybrid 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides. The promising derivatives were nanomolar inhibitors of VEGFR-2 (8; IC₅₀ = 5.89 nM, 9; IC₅₀ = 10.52 nM) and MMP-2 (8; IC₅₀ = 17.44 nM, 9; IC₅₀ = 30.93 nM) and submicromolar inhibitors of CA II (8; IC₅₀ = 0.21 µM, 9; IC₅₀ = 0.36 µM). Docking studies predicted their binding modes into the enzyme active sites and the structural determinants of activity regarding substitution and regioselectivity. MTT assay demonstrated that both compounds were 12 folds safer than doxorubicin with superior anticancer activities against three human cancers recording single-digit nanomolar IC₅₀, thus echoing their enzymatic activities. Up to our knowledge, this study introduces the first in class triazolopyrimidinone acyclo C-nucleosides VEGFR-2/MMP-2/CA II inhibitors that deserve further investigation.     

SEM-mapped micro-photoluminescence studies of highly luminescent micro-clusters in erbium-doped silicon-rich silicon oxide

This paper reports on the formation of unique micrometer-scale clusters in erbium-doped silicon-rich silicon oxide (ErSRSO) thin films produced by thermal evaporation. Through scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX), we identify these micro-clusters as structures where the film curves away from the substrate to encase erbium-rich aggregates. Even though erbium aggregation has been reported to cause quenching, we demonstrate that the micro-clusters as a whole can exhibit significantly enhanced erbium photoluminescence (PL), with emissions over 24 times brighter than the surrounding non-cluster region. Mapping micro-photoluminescence measurements onto SEM images reveals that the erbium aggregates alone do not generate the enhanced PL, but rather the thin film encasing the aggregates is the origin of the emissions. Analysis of the PL Stark splitting shows a correlation between the micro-clusters’ fine structure and the strength of their PL. Taken together, the above evidence indicates that the micro-clusters’ strong PL is produced by changes in the local environment of the Er³⁺ inside the thin film surrounding the erbium-rich aggregates.     

Using pure shift HSQC to characterize microgram samples of drug metabolites

Difficulties in isolating samples from complex biological matrices and sensitivity limitations have long stymied the utilization of heteronuclear 2D NMR for the characterization of drug metabolites. Small diameter cryogenic NMR probes have largely ameliorated sensitivity limitations and the recently reported pure shift HSQC 2D NMR pulse sequence offers a further and marked improvement in both resolution and sensitivity. Using a 7.4 μg sample of the commercially available metabolite 3-hydroxy carbamazepine dissolved in 30 μL of deuterated solvent and a 600 MHz NMR equipped with a 1.7 mm cryogenic NMR probe, it was possible to acquire high signal-to-noise pure shift HSQC data in just over 30 min. A conventional HSQC spectrum acquired with identical parameters had approximately half the signal-to-noise of the pure shift HSQC spectrum. Collapsing the vicinal homonuclear couplings in the pure shift HSQC spectrum also significantly improves resolution. A practical, real world application of the technique is illustrated with the chromatographically isolated metabolite 3-hydroxy amiodarone from incubation with CYP2J2 recombinant enzyme. High quality pure shift HSQC data were recorded in slightly over 14 h for a 3 μg sample of the metabolite.     

Some contributions to the thin-layer chromatographic analysis of complex natural phospholipid and neutral lipid mixtures

We have isolated a minor phosphatidyl ethanolamine component from pancreas and a minor phosphatidyl choline component from retina, which were revealed by their separate thin-layer chromatographic properties on silica gel and aluminum oxide sheets, respectively. We have described in some detail a number of modifications in thin-layer chromatography methodology which enhances the opportunity for assessing the glycerophospholipid and neutral lipid composition of tissues, as attested by a diverse set of examples, and have pointed out some of the associated technical problems.     

The Physicochemical Characteristics of Gelam Honey and Its Outcome on the Female Reproductive Tissue of Sprague–Dawley Rats: A Preliminary Study

Gelam honey (GH) is a prized natural product synthesized from the nectar of flowers from Gelam trees (Melaleuca sp.). Gelam is an evergreen tree species that grows in tropical regions such as Malaysia. GH is a multifloral honey with proven antioxidant and anti-inflammatory properties. However, the beneficial effect of GH on female reproductive tissue has yet to be substantiated. Herein, we investigated the effects of GH administration on the uterine and vaginal epithelial thickness of sexually mature Sprague–Dawley rats. Epithelia thickness could be an indicator of an atrophy manifesting as a symptom of a cardio syndrome. Rats were given oral doses of GH in four groups for 14 days; the lowest dose was 0.2 g GH/kg body weight (bw) rat/day and the highest dose was 8 g GH/kg bw rat/day. The physicochemical characteristics of GH were assessed through hydroxymethylfurfural and moisture content determination and sugar identification. GH attenuated the atrophy of the uterine and vaginal epithelia and increased the thickness of the endometrial stroma and endometrial surface endothelial layer. However, the dissonance observed in the effect of GH administration on the vaginal epithelium requires further investigation. Nevertheless, GH may have a strong potential in attenuating uterine and vaginal atrophies.     

New cytotoxic bio-transformed sesquiterpene by Rhizopus oryzae fungus

Due to the rapidly increasing number of pathogenic bacteria, viruses, and tumor cells that possess resistance toward established therapies, lead structures for the development of new drugs are in high demand. The plant material of Tanacetum sinaicum is considered a prolific source of the potent biologically active sesquiterpene Tanacetolide A ( 1 ). In our research, we focused on the structural transformation of the substrate Tanacetolide A (compound 1 ) by suspended culture of the novel locally isolated terrestrial fungus Rhizopus oryzae KX685359. The fungal transformation resulted in the formation of 1β,3α-dihydroxy-6α-hydroperoxy-eudsm-4(15)-ene 12-oic acid ( 2 ) with higher antiproliferative activity against colon cancer cell line (Caco-2) than that of the parent compound ( 1 ).     

Recent advances in phase matching of second‐order nonlinearities in monolithic semiconductor waveguides

Techniques used to assist phase matching of second‐order nonlinearities in semiconductor waveguides are reviewed. The salient points of each method are highlighted, with their strengths and weaknesses with regard to various key applications discussed. Recent progress in these techniques is also reviewed. Emphasis is placed on two techniques, namely quasi‐phase matching via domain disordering utilizing quantum well intermixing, and exact phase matching using Bragg reflection waveguides.