Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals.

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

A mild deprotection of isopropylidene ketals from 2-deoxyglycosides using AcOH/H2O/DME: An efficient regioselective deprotection of terminal isopropylidene ketals.

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.

Precisely Programmable Degradation and Drug Release Profiles in Triblock Copolyether Hydrogels with Cleavable Acetal Pendants.

Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.

Dynamic Release from Acetalated Dextran Nanoparticles for Precision Therapy of Inflammation.

Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.

Lethal metabolism of Candida albicans respiratory mutants.

The destructive impact of fungi in agriculture and animal and human health, coincident with increases in antifungal resistance, underscores the need for new and alternative drug targets to counteract these trends. Cellular metabolism relies on many intermediates with intrinsic toxicity and promiscuous enzymatic activity generates others. Fuller knowledge of these toxic entities and their generation may offer opportunities of antifungal development. From this perspective our observation of media-conditional lethal metabolism in respiratory mutants of the opportunistic fungal pathogen Candida albicans was of interest. C. albicans mutants defective in NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain) exhibit normal growth in synthetic complete medium. In YPD medium, however, the mutants grow normally until early stationary phase whereupon a dramatic loss of viability occurs. Upwards of 90% of cells die over the subsequent four to six hours with a loss of membrane integrity. The extent of cell death was proportional to the amount of BactoPeptone, and to a lesser extent, the amount of yeast extract. YPD medium conditioned by growth of the mutant was toxic to wild-type cells indicating mutant metabolism established a toxic milieu in the media. Conditioned media contained a volatile component that contributed to toxicity, but only in the presence of a component of BactoPeptone. Fractionation experiments revealed purine nucleosides or bases as the synergistic component. GC-mass spectrometry analysis revealed acetal (1,1-diethoxyethane) as the active volatile. This previously unreported and lethal synergistic interaction of acetal and purines suggests a hitherto unrecognized toxic metabolism potentially exploitable in the search for antifungal targets.

Selective Peptide Cysteine Manipulation on Demand and Difficult Protein Chemical Synthesis Enabled by Controllable Acidolysis of N,S-Benzylidene Thioacetals.

Although solid-phase peptide synthesis combining with chemical ligation provides a way to build up customized polypeptides in general, many targets are still presenting challenges for the conventional synthetic process, such as hydrophobic proteins. New methods and strategies are still required to overcome these obstacles. In this study, kinetic studies of Cys/Pen ligation and its acidolysis were performed, from which the fast acidolysis of substituted N,S-benzylidene thioacetals (NBTs) was discovered. The study demonstrates the potential of NBTs as a promising Cys switchable protection, facilitating the chemical synthesis of peptides and proteins by efficiently disrupting peptide aggregation. The compatibility of NBTs with other commonly adopted Cys protecting groups and their applications in sequential disulfide bond formation were also investigated. The first chemical synthesis of the native human programmed death ligand 1 immunoglobulin V-like (PD-L1 IgV) domain was achieved using the NBT strategy, showcasing its potential in difficult protein synthesis.

Catalyst-free readily dual-recyclable acetal-based covalent adaptable cellulose networks.

Despite covalent adaptable networks (CANs) imparting the favorable features of crosslinked polymers, as well as the functionality of reprocessing, reshaping and welding, due to exchange reaction enabled topology changes; it is still a huge challenge to design catalyst-free, fast reprocessing, controlled degradation and polymer recyclable biomass base CANs. Herein, for the first time, acetal-based covalent adaptable cellulose networks (ACCs) were utilized to synthesize readily reconstructable cellulose-based thermosets with mechanical tunability. ACCs were synthesized via catalyst-free "click" addition of cellulose and divinyl ether without releasing small molecule byproducts. Different crosslinking densities and crosslinkers were used to explore the structure-property relationship, the mechanical and thermal properties of the ACCs were strongly influenced by these factors. ACCs can obtain enhanced tensile strength or elongation at break by changing the structure of the crosslinker. Furthermore, the reworking, welding and shape memory properties of these ACCs, based on the dynamic exchange reaction of acetal bonds, were investigated. In addition, these ACCs can be degraded under acidic conditions, and closed-loop utilization of polymer was possible. Thus, ACCs can be mechanically and chemically double-cycled, which will contribute to solving the white pollution problem and resource waste as a new class of sustainable plastics.

Effects of sunflower oil infusions of Asparagopsis taxiformis on in vitro ruminal methane production and biohydrogenation of polyunsaturated fatty acids.

Asparagopsis taxiformis inhibits ruminal methane (CH4) production due to its bromoform (CHBr3) content. The immersion of A. taxiformis in edible vegetable oils allows the extraction and stabilization of the highly volatile CHBr3 in the oil phase. The objectives of this study were to explore the effects of adding sunflower oils with increasing concentrations of CHBr3 on in vitro ruminal methanogenesis and biohydrogenation. Five batches of 48-h in vitro incubations were performed in 14 fermentation bottles, using rumen inocula collected shortly after the slaughter of young crossbred bulls and 1 g of dry matter (DM) from a total diet of mixed feed without added oil (control) or with 60 µL of sunflower oil per gram of DM as the substrate. The treatments were the CHBr3 content in the oil added: 0 µg (B0), 25 µg (B25), 50 µg (B50), 75 µg (B75), 100 µg (B100), and 150 µg (B150) of CHBr3 per gram of substrate DM. Organic matter (OM) degradability, total gas, CH4, volatile fatty acids (VFA), long-chain fatty acids, and dimethyl acetals (DMA) were analyzed at the end of each incubation. Data were analyzed with a model considering the treatments as the fixed effect and the run as a random block and using orthogonal contrasts. Degradability of OM was higher in the control group and was unaffected by CHBr3 concentration. Total gas production per gram of degraded OM was unaffected by treatments and averaged 205 ± 29.8 mL/g. Methane (mL) production decreased linearly with increasing CHBr3 concentrations, with 33%, 47%, and 87% reductions for B75, B100, and B150, respectively. Total VFA concentration was unaffected by oil inclusion but was reduced by 20% in CHBr3-containing treatments, although without any dose-response pattern. The molar percentage of acetate decreased linearly, whereas propionate and butyrate increased linearly with the increasing CHBr3 dosage. Including oil in the diet decreased the branched-chain fatty acids and DMA content. Increasing CHBr3 concentrations did not affect branched-chain fatty acids, but linearly increased most of the identified DMA. Adding oil to the control diet increased the 18:2n-6, whereas increasing the concentration of CHBr3 had no effect on 18:2n-6 but decreased linearly the 18:0 and increased the trans-18:1 isomers. The results obtained provide evidence that oil immersions of A. taxiformis can successfully inhibit ruminal production of CH4 in vitro at doses of 100 and 150 µg/g DM, and simultaneously modulate biohydrogenation.

Acetal Formation of Flavoring Agents with Propylene Glycol in E-Cigarettes: Impacts on Indoor Partitioning and Thirdhand Exposure.

The widespread use of flavored e-cigarettes has led to a significant rise in teenage nicotine use. In e-liquids, the flavor carbonyls can form acetals with unknown chemical and toxicological properties. These acetals can cause adverse health effects on both smokers and nonsmokers through thirdhand exposure. This study aims to explore the impacts of these acetals formed in e-cigarettes on indoor partitioning and thirdhand exposure. Specifically, the acetalization reactions of commonly used flavor carbonyls in laboratory-made e-liquids were monitored using proton nuclear magnetic resonance (1H NMR) spectroscopy. EAS-E Suite and polyparameter linear free energy relationships (PP-LFERs) were employed to estimate the partitioning coefficients for species. Further, a chemical two-dimensional partitioning model was applied to visualize the indoor equilibrium partitioning and estimate the distribution of flavor carbonyls and their acetals in the gas phase, aerosol phase, and surface reservoirs. Our results demonstrate that a substantial fraction of carbonyls were converted into acetals in e-liquids and their chemical partitioning was significantly influenced. This study shows that acetalization is a determinant factor in the exposure and toxicology of harmful carbonyl flavorings, with its impact extending to both direct exposure to smokers and involuntary exposure to nonsmokers.

Evaluation of polymethyl-methacrylate and acetal denture base resins processed by two different techniques before and after nano-chlorohexidine surface treatment.

BACKGROUND: Flexible denture base polymers have gained popularity in modern dentistry however, their biofilm formation tendency, adversely affecting the oral tissue heath, remains a concern. Consequently, this study aimed to evaluate surface roughness and biofilm formation tendency of two types of denture base resins manufactured with two techniques before and after surface coating with chlorohexidine (CHX) NPs. MATERIALS AND METHODS: Acetal (AC) and Polymethyl-methacrylate (PMMA) resins manufactured by conventional and CAD/CAM methods were shaped into disk (10 X 10 X 1 mm). They were dipped for 8 h and 24 h in colloidal suspension prepared by mixing aqueous solution of CHX digluconate and hexa-metaphosphate (0.01 M). Surface roughness, optical density (OD) of microbial growth media and biofilm formation tendency were evaluated directly after coating. Elutes concentrations of released CHX were evaluated for 19 days using spectrophotometer. Three-way ANOVA and Tukey's post-hoc statistical analysis were used to assess the outcomes. RESULTS: AC CAD/CAM groups showed statistically significant higher roughness before and after coating (54.703 ± 4.32 and 77.58 ± 6.07 nm, respectively). All groups showed significant reduction in OD and biofilm formation tendency after surface coating even after 19 days of CHX NPs release. CONCLUSIONS: Biofilm formation tendency was highly relevant to surface roughness of tested resins before coating. After CHX NPs coating all tested groups showed significant impact on microbial growth and reduction in biofilm formation tendency with no relation to surface roughness. Significant antimicrobial effect remained even after 19 days of NPs release and specimens storage.

Exploration of the Linkages between Lignin and Carbohydrates in Kraft Pulp from Wheat Straw Using a 13C/2H Isotopic Tracer.

To further our understanding of the change in association between lignin and carbohydrates after kraft pulping, isotope-labeled kraft pulp (KP) was prepared using 13C and D double-isotope-labeled wheat straw, and it was subjected to enzymatic hydrolysis and ionic liquid treatment to explore the linkages between lignin and carbohydrate complexes in wheat straw. Isotope abundance determination showed that 13C and D abundances in the experimental groups were substantially higher than those in the control group, indicating that the injected exogenous coniferin-[α-13C], coniferin-[γ-13C], and d-glucose-[6-D2] were effectively absorbed and metabolized during wheat internode growth. Solid-state CP/MAS 13C-NMR spectroscopy showed that lignin was mainly linked to polysaccharides via acetal, benzyl ether, and benzyl ester bonds. Kraft pulp (KP) from the labeled wheat straw was degraded by cellulase. The obtained residue was fractionated using the ionic liquid DMSO/TBAH to separate the cellulose-lignin complex (KP-CLC) and xylan-lignin complex (KP-XLC). X-ray diffractometer determination showed that the KP-CLC regenerated cellulose type II from type I after the ionic liquid conversion. The 13C-NMR spectrum of Ac-En-KP-CLC showed that the cellulose-lignin complex structure was chemically bonded between the lignin and cellulose through acetal and benzyl ether bonds. The 13C-NMR spectrum of En-KP-XLC showed a lignin-hemicellulose complex structure, wherein lignin and xylan were chemically bonded by benzyl ether and acetal bonds. These results indicate that the cross-linking between lignin and carbohydrates exists in lignocellulosic fibers even after kraft pulping.

N,O-Benzylidene Acetal Dipeptides (NBDs) Enable the Synthesis of Difficult Peptides via a Kinked Backbone Strategy.

Proteins with highly hydrophobic regions or aggregation-prone sequences are typically difficult targets for chemical synthesis at the current stage, as obtaining such type of peptides via solid-phase peptide synthesis requires sophisticated operations. Herein, we report N,O-benzylidene acetal dipeptides (NBDs) as robust and effective building blocks to allow the direct synthesis of difficult peptides and proteins via a kinked backbone strategy. The effectiveness and easy accessibility of NBDs have been well demonstrated in our chemical syntheses of various challenging peptides and proteins, including chemokine, therapeutic hormones, histone, and glycosylated erythropoietin.

Design of Cationic Lipids with Acetal Linkers: Conformational Preferences, Hydrolytic Stability, and High Drug-Loading Abilities.

Lipids are key constituents of numerous biomedical drug delivery technologies. Here, we present the design, synthesis and biophysical characterizations of a library of cationic lipids containing an acetal residue in their linker region. These cationic acetal lipids (CALs) were conveniently prepared through a trans-acetalization protocol from commercially available precursors. NMR studies highlighted the conformational rigidity at the acetal residue and the high hydrolytic stability of these CALs. Fluorescence anisotropy studies revealed that the CAL with a pyridinium headgroup (CAL1) formed highly cohesive vesicular aggregates in water. These structural and self-assembly features of the CAL1 allowed up to 196 % w/w loading of curcumin (Cur) as a representative hydrophobic drug. A reconstitutable formulation of Cur was obtained as a result, which could deliver the drug inside mammalian cells with very high efficiency. The hemocompatibility and cytocompatibility of CAL1 was significantly enhanced by creating a coating of polydopamine (PDA) onto its vesicular assemblies to produce hybrid lipid-polymer nanocapsules. This work demonstrates rapid access to the useful synthetic lipid formulations with high potential in drug and gene delivery applications.

Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy.

As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.