Ketal Group Research Articles

Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups.

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5' and C-6', exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5' and C-6' on this compound's activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5' and C-6'. The R/S configuration of the diastereoisomer at C-13' was further determined through an NOE correlation analysis of CH3 or CH2 at the derivative C-13' position and the H-5' and H-6' by means of a 1D NOE experiment. Further comparative 1H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15-24 and 28-35 demonstrated promising activity against M. marinum, with MIC90 values ranging from 70 to 90 μM, closely approaching the MIC90 of isoniazid. The preliminary structure-activity relationships showed that the ketal groups with aromatic rings at C-5' and C-6' could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance.

Aqueous Developable and CO2‐Sourced Chemical Amplification Photoresist with High Performance

AbstractSeeking high‐performance photoresists is an important item for semiconductor industry due to the continuous miniaturization and intelligentization of integrated circuits. Polymer resin containing carbonate group has many desirable properties, such as high transmittance, acid sensitivity and chemical formulation, thus serving as promising photoresist material. In this work, a series of aqueous developable CO2‐sourced polycarbonates (CO2‐PCs) were produced via alternating copolymerization of CO2 and epoxides bearing acid‐cleavable cyclic acetal groups in the presence of tetranuclear organoborane catalyst. The produced CO2‐PCs were investigated as chemical amplification resists in deep ultraviolet (DUV) lithography. Under the catalysis of photogenerated acid, the acetal (ketal) groups in CO2‐PC were hydrolysed into two equivalents of hydroxyl groups, which change the exposed area from hydrophobicity to hydrophilicity, thus enabling the exposed area to be developed with water. Through normalized remaining thickness analysis, the optimal CO2‐derived resist achieved a remarkable sensitivity of 1.9 mJ/cm2, a contrast of 7.9, a favorable resolution (750 nm, half pitch), and a good etch resistance (38 % higher than poly(tert‐butyl acrylate)). Such performances outperform commercial KrF and ArF chemical amplification resists (i.e., polyhydroxystyrene‐derived and polymethacrylate‐based resists), which endows broad application prospects in the field of DUV (KrF and ArF) and extreme ultraviolet (EUV) lithography for nanomanufacturing.

Aqueous Developable and CO2-Sourced Chemical Amplification Photoresist with High Performance.

Seeking high-performance photoresists is an important item for semiconductor industry due to the continuous miniaturization and intelligentization of integrated circuits. Polymer resin containing carbonate group has many desirable properties, such as high transmittance, acid sensitivity and chemical formulation, thus serving as promising photoresist material. In this work, a series of aqueous developable CO2-sourced polycarbonates (CO2-PCs) were produced via alternating copolymerization of CO2 and epoxides bearing acid-cleavable cyclic acetal groups in the presence of tetranuclear organoborane catalyst. The produced CO2-PCs were investigated as chemical amplification resists in deep ultraviolet (DUV) lithography. Under the catalysis of photogenerated acid, the acetal (ketal) groups in CO2-PC were hydrolysed into two equivalents of hydroxyl groups, which change the exposed area from hydrophobicity to hydrophilicity, thus enabling the exposed area to be developed with water. Through normalized remaining thickness analysis, the optimal CO2-derived resist achieved a remarkable sensitivity of 1.9 mJ/cm2, a contrast of 7.9, a favorable resolution (750 nm, half pitch), and a good etch resistance (38 % higher than poly(tert-butyl acrylate)). Such performances outperform commercial KrF and ArF chemical amplification resists (i.e., polyhydroxystyrene-derived and polymethacrylate-based resists), which endows broad application prospects in the field of DUV (KrF and ArF) and extreme ultraviolet (EUV) lithography for nanomanufacturing.

Synthesis of novel L-lactic acid-based plasticizers and their effects on the flexibility, crystallinity, and optical transparency of poly(lactic acid)

Using bio-based plasticizers derived from biomass resources to replace traditional phthalates can avoid the biotoxicity and non-biodegradability caused by the migration of plasticizers during the application of plastics. In this study, L-lactic acid and levulinic acid were employed as the major biomass monomer to successfully fabricate L-lactic acid-based plasticizers (LBL-n, n = 1.0, 1.5, 2.0, 2.5) containing a diverse number of lactate groups. The plasticizing mechanism was explained, manifesting that L-lactic acid-based plasticizers containing a substantial number of lactate groups could effectively improve the flexibility of poly (lactic acid) (PLA), and the elongation at break was 590 %–750 %. Compared to LBL-1.5 plasticized-PLA films, the tensile strength and modulus of ketonized-LBL-1.5 (KLBL-1.5) plasticized-PLA films increased to 59 % and 163 %, indicating the ketal functionality of plasticizers enhanced the strength of PLA. Meanwhile, the increment of lactate groups and the introduction of the ketal group in the plasticizer increased the crystallization, migration, and volatilization stability of plasticized-PLA films and also kept their outstanding optical transparency. Besides, the biodegradability of KLBL-1.5 was investigated by active soil and Tenebrio molitor experiments, and its degradation products were characterized. The findings indicated that KLBL-1.5 was fully decomposed. Taken together, this paper offers new promise for developing high-efficiency and biodegradable plasticizers.

Pincer Nickel-Catalyzed Olefination of Alcohols with Benzylphosphine Oxides.

N,N,P-Pincer nickel complexes effectively catalyze reaction of alcohols with benzylphosphine oxides to form alkenes in good yields. The protocol suits for a wide scope of substrates and generates only E-configurated alkenes. The method also shows good compatibility of functional groups. Methoxy, methylthio, trifluoromethyl, ketal, fluoro, chloro, bromo, thienyl, and furyl groups are tolerated. The mechanism studies support that the reaction proceeds through catalytic dehydrogenation of alcohols to aldehydes or ketones followed by condensation with benzyldiphenylphosphine oxides in the presence of KOtBu.

Aliphatic polycarbonates with acid degradable ketal side groups as multi-pH-responsive immunodrug nanocarriers

Pharmacokinetics of active substances and their biodistribution profiles are crucial aspects for safe and successful administration. Since many immunogenic compounds do not meet all requirements for safe and effective administrations,...

End Group Functionality of 95-99%: Epoxide Functionalization of Polystyryl-Lithium Evaluated via Solvent Gradient Interaction Chromatography.

End group functionality is a key parameter of functional polymer chains. The end-capping efficiency of living polystyryl lithium with various epoxides, namely ethylene oxide (EO), ethoxy ethyl glycidyl ether (EEGE) and isopropylidene glyceryl glycidyl ether (IGG), is investigated with solvent gradient interaction chromatography (SGIC). Generally, end-capping efficiencies >95% are observed. Hydroxy functional polystyrene (PS-OH, PS-EEGE-OH, and PS-IGG-OH) with molar masses ranging from 13.8 to 15.0kgmol-1 are obtained, with dispersities of 1.05-1.06. Deprotection of the acetal (PS-EEGE-OH) and ketal protective group (PS-IGG-OH) is investigated. Nearly quantitative deprotection (>99%) resulting in the corresponding multihydroxy functional PS (PS-(OH)2 and PS-(OH)3 ) are observed via SGIC. Esterification of PS-OH with succinic anhydride shows a conversion of 98% to the corresponding ester. A detailed picture of side reactions during the carbanionic polymer synthesis subsequent epoxide termination is obtained, demonstrating 95-99% terminal functionality. Depending on the polarity of the end group, an elution order of PS-OH<PS-(OH)2 <PS-(OH)3 <PS-COOH is obtained in SGIC. The study demonstrates both the analytical power of SGIC and the exceptionally high terminal functionalization efficiency of anionic polymerization methods.

Chemically Recyclable Poly(β-thioether ester)s Based on Rigid Spirocyclic Ketal Diols Derived from Citric Acid.

Incorporating rigid cyclic acetal and ketal units into polymer structures is an important strategy toward recyclable high-performance materials from renewable resources. In the present work, citric acid, a widely used platform chemical derived from biomass, has been efficiently converted into di- and tricyclic diketones. Ketalization with glycerol or trimethylolpropane afforded rigid spirodiols, which were obtained as complex mixtures of isomers. After a comprehensive NMR analysis, the spirodiols were converted into the respective di(meth)acrylates and utilized in thiol–ene polymerizations in combination with different dithiols. The resulting poly(β-thioether ester ketal)s were thermally stable up to 300 °C and showed glass-transition temperatures in a range of −7 to 40 °C, depending on monomer composition. The polymers were stable in aqueous acids and bases, but in a mixture of 1 M aqueous HCl and acetone, the ketal functional groups were cleanly hydrolyzed, opening the pathway for potential chemical recycling of these materials. We envision that these novel bioderived spirodiols have a great potential to become valuable and versatile bio-based building blocks for several different kinds of polymer materials.

Bio-Degradable Polyesters with Rigid Cyclic Diester from Camphor and Tartaric Acid.

Despite their excellent, useful, and stable properties, thermoplastics are constantly subject to environmental risks because of their low degradability under thermal, chemical, and mechanical stresses. To overcome the aforementioned issues, we hereby introduce an eco-friendly camphor (Ct) cyclic diester. The Ct diester is designed as a monomer, including a ketal group from the Ct, and shows high thermal stability via a rigid spiro-ring and a bridged bicyclic structure. A series of polyester was synthesized using the Ct diester, including various types of diols and dimethyl terephthalate. PETxCty copolyesters showed appropriate thermal stability up to 414 °C and a high glass transition temperature. This thermal behavior led to amorphous regions as the Ct diester content increased. Regarding the proportion of the Ct diester in the polyester, it was sensitive to hydrolysis and contributed to the degradation of the polyester in acid buffer conditions.Graphical

PH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss.

Bone tissue undergoes continuous remodeling via osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An imbalance in this process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, we developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers an osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier is further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in ovariectomized mice and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis.

Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology

Pneumococcal conjugate vaccines (PCVs) are formed by bioconjugation of a carrier protein to the purified capsular polysaccharide (Ps) from multiple serological strains of Streptococcus pneumoniae. The associated bioconjugation chemistry relies on initial selective modifications to the Ps backbone structure. Among these modifications, removal of a ketal functional group, termed deketalization, is one that is important for pharmaceutical PCV production. Herein, we report a process monitoring investigation into the deketalization of a polysaccharide relevant to PCV process development. We have applied process analytical technology (PAT) for in situ process monitoring to study the deketalization reaction in real time. We find that in situ FTIR spectroscopy elucidates multiple classes of reaction kinetics, one of which correlates strongly with the deketalization reaction of interest. This PAT approach to real time reaction monitoring offers the possibility of improved process monitoring in the pharmaceutical production of PCVs. To our knowledge, this report represents the first PAT investigation into Ps deketalization. Our findings suggest that broader application of PAT to the chemical modifications associated with PCV bioconjugation, as well as other pharmaceutically relevant bioconjugation processes, carries the power to enhance process understanding, control, and efficiency through real time process monitoring.

Effect of ketal group in castor oil acid‐based plasticizer on the properties of poly(vinyl chloride)

AbstractTwo castor oil acid esters containing a ketal or ketone group (KCL or CL), as alternative plasticizers for poly(vinyl chloride) (PVC), were prepared. The structures were confirmed by1H NMR and FTIR spectroscopies. The effects of the presence of a ketal or ketone group in these compounds on PVC plasticization were examined. The DMA and SEM results showed that both plasticizers were miscible with PVC and exhibited excellent plasticizing properties, compared to those of dioctyl phthalate (DOP). The PVC plasticized by KCL displayed a lowerTgvalue of 20.6°C, which was lower than that of PVC plasticized with DOP (22.3°C) and PVC plasticized with CL (40.5°C). Tensile tests indicated that PVC plasticized using KCL showed a 37% higher of elongation at break than PVC plasticized by CL and 30% higher than PVC plasticized by DOP. The plasticizing mechanism was also investigated. Moreover, exudation, volatility, and extraction tests, along with TGA indicated that the presence of ketal groups effectively improved the migration resistance of plasticizer and the thermal stability of PVC blends. Taken together, introducing ketal groups into plasticizer might be an effective strategy for improving its plasticizing efficiency.

Development of an Acid-Labile Ketal Linked Amphiphilic Block Copolymer Nanoparticles for pH-Triggered Release of Paclitaxel.

Here, we report on the construction of biodegradable poly(ethylene oxide monomethyl ether) (MPEO)-b-poly(ε-caprolactone) (PCL) nanoparticles (NPs) having acid-labile (acyclic ketal group) linkage at the block junction. In the presence of acidic pH, the nanoassemblies were destabilized as a consequence of cleaving this linkage. The amphiphilic MPEO-b-PCL diblock copolymer self-assembled in PBS solution into regular spherical NPs. The structure of self-assemble and disassemble NPs were characterized in detail by dynamic (DLS), static (SLS) light scattering, small-angle X-ray scattering (SAXS), and transmission electron microscopy (TEM). The key of the obtained NPs is using them in a paclitaxel (PTX) delivery system and study their in vitro cytostatic activity in a cancer cell model. The acid-labile ketal linker enabled the disassembly of the NPs in a buffer simulating an acidic environment in endosomal (pH ~5.0 to ~6.0) and lysosomal (pH ~4.0 to ~5.0) cell compartments resulting in the release of paclitaxel (PTX) and formation of neutral degradation products. The in vitro cytotoxicity studies showed that the activity of the drug-loaded NPs was increased compared to the free PTX. The ability of the NPs to release the drug at the endosomal pH with concomitant high cytotoxicity makes them suitable candidates as a drug delivery system for cancer therapy.

A Novel Acid-Degradable PEG Crosslinker for the Fabrication of pH-Responsive Soft Materials.

The design and synthesis of a novel acid-degradable polyethylene glycol-based N-hydroxysuccinimide (NHS) ester-activated crosslinker is reported. The crosslinker is reactive towards nucleophiles and features a central ketal functional group that is stable at pH >7.5 and rapidly hydrolyses at pH >6.0. The crosslinker is used to (i) fabricate acid-degradable polysaccharide hydrogels that exhibit controlled degradation upon exposure to an acidic environment or via endogenous enzyme activity; and (ii) construct hydrogel-filled protein-polymer microcompartments (termed proteinosomes) capable of pH-dependent membrane disassembly. Taken together the results provide new opportunities for the fabrication of pH-responsive soft materials with potential applications in drug delivery, tissue engineering, and soft-matter bioengineering.

Asymmetric Hydrogenation of Racemic 6-Aryl 1,4-Dioxaspiro[4.5]decan-7-ones to Functionalized Chiral β-Aryl Cyclohexanols via a Dynamic Kinetic Resolution.

A ruthenium-catalyzed asymmetric hydrogenation method for the synthesis of functionalized β-aryl cyclohexanols is described. With chiral spiro ruthenium catalyst (Ra,S,S)-5c, a series of racemic α-aryl cyclohexanones bearing a β-monoethylene ketal group were hydrogenated to the corresponding functionalized β-aryl cyclohexanols in high yields with enantioselectivity of up to 99% ee via a dynamic kinetic resolution. This protocol can be conducted on a decagram scale and provide potential approaches for the synthesis of optically active and densely functionalized aryl cyclohexanols.

Daphnane-type diterpenoids from Euphorbia fischeriana Steud and their cytotoxic activities

Two new daphnane-type diterpenoids fischerianin A (1) and fischerianin B (2), as well as two known ones langduin A (3) and langduin A6 (4), were isolated from the extracts of Euphorbia fischeriana Steud dry roots. Their structures including the absolute stereochemistry were determined by various spectroscopic methods and comparing their experimental and calculated CD spectra. 1 and 2 harbor a ketal group and a 9,13-oxide bridge in their C ring which is rare in daphnane-type diterpenoids. In cytotoxic assays, moderately inhibitory activities of 1–4 against human cancer cell lines (human malignant melanoma cell line, A375; human liver carcinoma cell line, HepG2; human promyelocytic leukemia cell line, HL-60; human Caucasian chronic myelogenous leukemia cell line, K562; human cervix epithelioid carcinoma cell line, HeLa) were observed, with IC50 values ranging from 5.31 to 21.46 μM.

Complete Genome of Nocamycin-Producing Strain Saccharothrix syringae NRRL B-16468 Reveals the Biosynthetic Potential for Secondary Metabolites.

The bacterium Saccharothrix syringae NRRL B-16468 is the producer of nocamycin I and nocamycin II which feature tetramic acid and bicyclic ketal groups. In this study, we presented the complete genome of S. syringae NRRL B-16468 obtained from ARS Culture Collection. It contains a circular chromosome of 10,929,570bp with an average GC content of 73.49%, 9316 genes, 12 rRNAs and 54 tRNAs. Bioinformatics analyses of the genome has demonstrated that it harbors 55 putative biosynthetic gene clusters (BGCs) involved in synthesizing diverse secondary metabolites. The backbones of the natural products synthesized by these BGCs encoding for type I polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and hybrid type I PKS-NRPS were analyzed, furthermore, the natural products synthesized by these BGCs with > 40% similarity to known BGCs were described in detail. The complete genome of S. syringae reveals its capacity in producing diverse bioactive natural products, and it will also shed lights on mining novel secondary metabolites from S. syringae through rational strategies.

Xylariaopyrones E–I, five new α-pyrone derivatives from the endophytic fungus Xylariales sp. (HM-1)

Five new α-pyrones, xylariaopyrones E–I (1–5), along with three known analogues (6–8) were isolated from the cultivation broth of the endophytic fungus Xylariales sp. (HM-1). The structures of the new compounds including their absolute configurations were elucidated by comprehensive spectroscopic methods and quantum ECD calculations. Xylariaopyrone E (1) is the first example of α-pyrone derivative with a novel [3, 2, 0] bridge ring system via a ketal function group in the side chain. In bioactivity assays, xylariaopyrones E–G (1–3) showed moderate inhibiting activities against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa with MIC values from 25.4 to 64.5 μg/mL, whereras xylariaopyrone G (3) exhibited significant inhibition of monoamine oxidase B with an IC50 value of 15.6 μmol/L. Xylariaopyrone H (4) and the known compound 7 showed moderate toxicity against brine shrimp larvae with inhibition rates of 42.8% and 44.5%, respectively.

Reductive methylation of triphthaloylbenzene: Isolation and characterization of hexamethoxy-trinaphthylene and two unexpected trinaphthylene derivatives

With the aim of developing new π-conjugated materials for application in electronics, the reductive methylation of triphthaloylbenzene is presented. Several new products are obtained: 5,6,11,12,17,18-hexamethoxy-trinaphthylene (1a) and two unexpected compounds, i.e., the corresponding monohydroxy-pentamethoxy-trinaphthylene (1b) and a peculiar trinaphtylene derivative (2) possessing hydroxy, methoxy, carbonyl, and ketal groups and a tetrahydrofuran moiety fused on the core. X-ray crystallographic analysis of 1b and 2 reveals that both compounds exhibit deformed frameworks. The investigation of their optical properties shows that the lowest-energy absorption bands for 1a and 1b are a shoulder band around 350 nm, whereas 2 gives rise to a one broad and weak band at 573 nm. All the molecules have negligible fluorescence. Addition of 1,8-diazabicyclo[5.4.0]undec-7-ene into a solution of 2 causes a color change from purple to olive brown, which renders it suitable as a pH indicator.

Biodegradable pH-responsive micelles loaded with 8-hydroxyquinoline glycoconjugates for Warburg effect based tumor targeting

Biodegradable triblock copolymer poly(ethylene glycol)-b-polycarbonate-b-oligo([R]-3-hydroxybutyrate) was prepared via metal-free ring-opening polymerization of ketal protected six-membered cyclic carbonate followed by esterification with bacterial oligo([R]-3-hydroxybutyrate) (oPHB). Amphiphilic triblock copolymer self-organizes into micelles with a diameter of ~25 nm. Acid-triggered hydrolysis of ketal groups to two hydroxyl groups causes an increase in hydrophilicity of the hydrophobic micelle core, resulting in the micelles swell and drug release. oPHB was added as core-forming block to increase the stability of prepared micelles in all pH (7.4, 6.4, 5.5) studied. Doxorubicin and 8-hydroxyquinoline glucose- and galactose conjugates were loaded in the micelles. In vitro drug release profiles in PBS buffers with different pH showed that a small amount of loaded drug was released in PBS at pH 7.4, while the drug was released much faster at pH 5.5. MTT assay showed that the blank micelles were non-toxic to different cell lines, while glycoconjugates-loaded micelles, showed significantly increased ability to inhibit the proliferation of MCF-7 and HCT-116 cells compared to free glycoconjugates. The glycoconjugation of anti-cancer drugs and pH-responsive nanocarriers have separately shown great potential to increase the tumor-targeted drug delivery efficiency. The combination of drug glycoconjugation and the use of pH-responsive nanocarrier opens up new possibilities to develop novel strategies for efficient tumor therapy.