Acid Oxime Research Articles

Preparation of double network antibacterial hydrogel modified by hydroxamic acid gelatin/polyacrylamide and high efficiency uranium extraction from seawater

Uranium extracted from seawater can solve the problem of the shortage of uranium on land and provide potential resources for the nuclear power industry. However, the high salinity and low uranium concentration in seawater, coupled with the presence of competing ions and bacteria, pose significant challenges to this technology. In this study, a hydroxyl oxime acid modified gelatin/polyacrylamide double network (Gel/PAM(DN)-HA) hydrogel developed for efficient uranium extraction from seawater. The adsorption capacity of Gel/PAM(DN)-HA hydrogel for uranium in 15 ppm uranium solution was as high as 397.04 mg-U/g-Ads, with a reuse rate of 78.46 % ± 5.84 % after 5 cycles of adsorption-desorption. Gel/PAM(DN)-HA was immersed in natural seawater for 24 days to evaluate its adsorption capacity. Gel/PAM(DN)-HA demonstrated an impressive uranium extraction capacity of 4.801 mg·g−1. Antibacterial experiments demonstrated that Gel/PAM(DN)-HA can effectively inhibit the Escherichia coli (E. coli ATCC25922) and Staphylococcus aureus (S. aureus ATCC6538). The results highlight the adsorbent's significant potential for extensive utilization in extracting uranium from seawater.

Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

Highly Efficient Electrosynthesis of Glycine over an Atomically Dispersed Iron Catalyst.

Glycine is a nonessential amino acid that plays a vital role in various biological activities. However, the conventional synthesis of glycine requires sophisticated procedures or toxic feedstocks. Herein, we report an electrochemical pathway for glycine synthesis via the reductive coupling of oxalic acid and nitrate or nitrogen oxides over atomically dispersed Fe-N-C catalysts. A glycine selectivity of 70.7% is achieved over Fe-N-C-700 at -1.0 V versus RHE. Synergy between the FeN3C structure and pyrrolic nitrogen in Fe-N-C-700 facilitates the reduction of oxalic acid to glyoxylic acid, which is crucial for producing glyoxylic acid oxime and glycine, and the FeN3C structure could reduce the energy barrier of *HOOCCH2NH2 intermediate formation thus accelerating the glyoxylic acid oxime conversion to glycine. This new synthesis approach for value-added chemicals using simple carbon and nitrogen sources could provide sustainable routes for organonitrogen compound production.

Visible-Light-Induced Decarboxylative Aminosulfonylation of (Hetero)aryl Carboxylic Oxime Esters.

Sulfonamides are important structures in pharmaceuticals, agrochemicals, and organocatalysts, yet the rapid and benign synthesis of these compounds is still a great challenge. Herein we report a photoinduced method for synthesizing sulfonamides from (hetero)aryl carboxylic acid oxime esters. This reaction proceeds via one-pot cascade radical-radical cross-coupling by energy-transfer-mediated photocatalysis. A wide substrate scope including (hetero)aryl substrates and late-stage modification of pharmaceutical molecular entities reveal its generality.

Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies.

(1) Background: The aim of the presented work was to obtain a set of oleanolic acid derivatives with a high level of anticancer activity and a low level of toxicity by applying an economic method. Three types of oleanolic acid derivatives were obtained: (i) derivatives of methyl oleanonate oxime, (ii) derivatives of methyl oleanonate oxime with an additional 11-oxo function, and (iii) derivatives of morpholide of oleanonic acid oxime. (2) Methods: The above oximes were acylated with aliphatic or aromatic carboxylic acid. The newly obtained compounds were subjected to ADMETox analysis and were also tested for cytotoxicity activity on the HeLa, KB, MCF-7, A-549, and HDF cell lines with the MTT assay. (3) Results: Among the tested acylated oximes of oleanolic acid, some derivatives, particularly those with two nitro groups attached to the aromatic ring, proved to be the most potent cytotoxic agents. These triterpene derivatives significantly inhibited the growth of the HeLa, KB, MCF-7, and A-549 cancer cell lines in micromolar concentrations. (4) Conclusions: The introduction of different moieties, particularly the 3,5-dinitro group, resulted in the synthesis of highly potent cytotoxic agents with favorable SI and ADMETox parameters.

Photocatalytic Unsymmetrical Diamination of Styrenes, Indoles, and Benzofurans Facilitated by Benzotriazolyl and Iminyl Radicals.

Utilizing energy transfer catalysis, this research employed the bifunctional reagents benzotriazole carboxylic acid oxime esters to simultaneously generate benzotriazole and imine radicals. The synthesis of two distinct C-N bonds in a single conversion is showcased through radical addition and radical-radical cross-coupling processes between benzotriazole carboxylic acid oxime ester and olefins. This process facilitates the intermolecular two-component unsymmetrical diamination reaction of olefins. Using this approach, more than 40 benzotriazole-containing molecules were successfully synthesized using styrene, indole, and benzofuran as acceptors, with yields ranging from moderate to excellent.

Photoinduced EnT-mediated sulfonamidylimination of alkenes and (hetero)arenes with iminophenylacetic acid oxime esters.

A photoinduced EnT-mediated generation of sulfonamidyl radicals has been accomplished using rationally designed iminophenylacetic acid oxime ester reagents under metal-free conditions. This approach offers a mild, regio- and diastereoselective synthesis of N-sulfonyl diamines via diamination of alkenes and (hetero)arenes.

Difunctionalization of gem-difluoroalkenes for amination and heteroarylation via metal-free photocatalysis.

gem-Difluoroalkenes are widely used building blocks in fluorine chemistry. Herein, a metal-free photocatalytic amination and heteroarylation method of gem-difluoroalkenes with heteroaryl carboxylic acid oxime esters as substrates is reported. This environmentally benign reaction proceeds via radical-radical cross-coupling in energy-transfer-mediated photocatalysis and can be used in the rapid construction of heteroaryl difluoroethylamine scaffolds and late-stage modification of complex pharmaceutical structures.

Unlocking the Potential: Novel NSAIDs Hybrids Unleash Chemopreventive Power toward Liver Cancer Cells through Nrf2, NF-κB, and MAPK Signaling Pathways.

HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates of non-steroidal anti-inflammatory drugs (NSAIDs)-Ibuprofen and Ketoprofen-with oleanolic acid oximes derivatives (OAO) were synthesized, and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells, and HCC-derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells, treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB, it was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivative conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.

Characterization, crystal structure, and quantum chemical parameters of diaqua bis-(2-hydroxyiminopropanoato) iron (II): A comparative study

A new di-aqua bis-(2-hydroxyiminopropanoato) iron (II) or iron pyruvic acid oxime complex [Fe(PAO)2(H2O)2] was revealed by single crystal X-ray diffraction. Density Functional Theory (DFT), with B3LYP, was utilized for the computational studies. The crystal morphology, spectroscopic analysis by FT-IR, and vis. UV was carried out. Hirshfeld surface investigation was accomplished to inspect the intermolecular forces and the packing of crystals. Moreover, computational calculations of [Fe(PAO)2(H2O)2] were acquired by the Gaussian 16W program, and by quantum mechanical procedures with Density Functional Theory (DFT) and the 6–311++G (2d, 2p) basis set. The experimental FT-IR spectrum is highly associated with the calculated vibrational spectra. The energies of the frontier orbitals, HOMO and LUMO, were utilized to estimate the electronegativity, hardness, and softness to attain an estimation of chemical behavior for the [Fe(PAO)2(H2O)2] complex.

Photosensitized Vicinal Sulfonylamination of Alkenes with Oxime Ester and DABCO·(SO2)2.

A metal-free photosensitized three-component reaction of oxime esters, alkenes, and DABCO·(SO2)2 was developed. This protocol could accommodate a wide substrate scope, including activated and unactivated alkenes and aryl and aliphatic carboxylic acid oxime esters, delivering a broad range of β-amino sulfones in moderate to high yields. The insertion of SO2 as a linker moiety allows the manipulation of the functionality in the reaction process, expanding the utility of oxime esters as bifunctional reagents.

Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain

The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving transmembrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding; side chain should contain hydrogen donor group; the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids.

Multidentate Coordination Induced Crystal Growth Regulation and Trap Passivation Enables over 24% Efficiency in Perovskite Solar Cells

AbstractCrystal growth regulation has become an effective solution to reduce the defects at grain boundaries (GBs) and surfaces of perovskite films for better photovoltaic performances. Oxime acid materials are maturely used as selective collectors in the flotation separation of oxide minerals. Such materials, showing a strong coordination effect and high selectivity with lead, may have great potential in controlling the crystal growth and passivating the defect of perovskite film, which are rarely applied in perovskite solar cells (PerSCs). Herein, an oxime acid‐based material with multi‐coordination sites, ethyl 2‐(2‐aminothiazole‐4‐yl)‐2‐hydroxyiminoacetate (EHA), is incorporated into the PbI2 precursor solution to fabricate high‐performance PerSCs using a two‐step method. The multidentate coordination effect of EHA can link and integrate the PbI2 colloidal clusters to achieve pre‐aggregation in the PbI2 precursor solution, facilitating the sequent crystal growth progress of perovskite film. Meanwhile, EHA can connect grains and fill GBs, which is favorable for charge transfer and passivating both Pb‐I anti‐site and iodine vacancy defects. As a result, the optimal devices show an enhanced efficiency of 24.1% and excellent humidity and thermal stability. This work affords a promising strategy to fabricate efficient and stable PerSCs via multidentate coordination‐induced crystallization control and GB passivation.

Photocatalytic Modular Cyanoalkylamination of Alkenes Involving Two Different Iminyl Radicals.

The modular cyanoalkylamination of alkenes using bench-stable and easy-to-handle α-imino-oxy acid oxime esters as difunctional reagents creates new synthetic avenues. A metal-free photosensitization protocol for the installation of both amino and cyanoalkyl functionalities onto alkene feedstocks in a single step via two differently reactive nitrogen-centered radicals was developed via energy-transfer catalysis. Excellent functional group tolerance and mild reaction conditions also render this protocol suitable for the cyanoalkylamination of pharmaceutically relevant molecule-derived alkenes.

Abstract 106: Diclofenac hybrids with oleanolic acid oximes modulate key signaling pathways in pancreatic cancer cells

Abstract Pancreatic cancer is characterized by constitutive activation of mitogen-activated protein kinases (MAPKs) like JNK and p38 determining its malignant phenotypes. Overexpression of NF-κB and COX-2 involved in inflammation contributes to increased cell growth and invasiveness. The latter might be related to the activated AKT pathway. Nonsteroidal anti-inflammatory drugs were suggested for pancreas cancers prophylaxis. Naturally occurring oleanolic acid (OA) was shown to possess anti-inflammatory and anti-tumorigenic activities. Coupling its analogs with NSAIDs may enhance this effect. Our study aimed to evaluate the effect of two oleanolic acid oximes derivatives conjugated with diclofenac (DCL), 4c (3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester) and 4d (3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide) on inflammation-related pathways, MAPK and NF-κB, cell cycle arrest and ROS formation in PSN-1 pancreatic cancer cells. PSN-1 cells were incubated with DCL, 4c or 4d at the concentration of 30µM. Activation of NF-κB was assessed by measuring binding of its p50 and p65 subunits to DNA using ELISA method. Their nuclear concentrations were determined by Western blot. RT-PCR was used to evaluate NF-κB subunits and COX-2 mRNA levels. Bead-based immunoassay determined the cytosolic levels of p38, JNK, CREB, AKT, P70S6K and STAT3 proteins. Cell cycle distribution and ROS formation were assessed using flow cytometry. Conjugate 4d significantly reduced nuclear level of p65 subunit and its mRNA expression, although compound 4c had more significant impact on COX-2 expression. Both derivatives significantly diminished p65 DNA binding, but only 4d had significant effect on p50. Both compounds reduced ROS production, but neither of them affected the cell cycle arrest. We observed decreased cytosolic AKT level along with increased levels of unphosphorylated JNK and p38 kinases which may have an antagonistic effect on proliferation by reducing activity of inflammatory mediators acting as tumor promoters. AKT decrease after treatment with 4d derivative might be the cause of increased unphosphorylated CREB level. Accumulation of p38 and JNK in cytosol could be a result of decreased ROS production and/or cause increased CREB protein level. Additionally, increased STAT3 cytosolic level suggests inhibition of mTORC1 pathway that explains reduced p70S6 kinase. Overall, these results suggest that OAO-DCL morpholide conjugate may affect both NF-κB and MAPK signaling pathways in pancreatic cancer cells. Further studies are required to explain detailed mechanism of these modifications. Funding: Studies were supported by Polish National Science Centre grant 2016/21/B/NZ7/01758. Acknowledgments: Authors thank Dr. Gary Gorbsky, Chair of Cell Cycle & Cancer Biology Program in Oklahoma Medical Research Foundation for supporting financing Maria Narozna conference participation. Citation Format: Maria Narozna, Violetta Krajka-Kuzniak, Robert Kleszcz, Wanda Baer-Dubowska. Diclofenac hybrids with oleanolic acid oximes modulate key signaling pathways in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 106.

Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells.

Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic cancer (PC) cells. Cultured PSN-1 cells were exposed for 24 h (30 µM) to OA oxime (OAO) derivatives substituted with benzyl or morpholide groups and their conjugates with indomethacin (IND) or diclofenac (DCL). The activation of NF-κB and Nrf2 was assessed by the evaluation of the translocation of their active forms into the nucleus and their binding to specific DNA sequences via the ELISA assay. The expression of NF-κB and Nrf2 target genes was evaluated by R-T PCR and Western blot analysis. The conjugation of IND or DCL with OAO derivatives increased cytotoxicity and their effect on the tested signaling pathways. The most effective compound was the DCL hybrid with OAO morpholide (4d). This compound significantly reduced the activation and expression of NF-κB and enhanced the activation and expression of Nrf2. Increased expression of Nrf2 target genes led to reduced ROS production. Moreover, MAPKs and the related pathways were also affected. Therefore, conjugate 4d deserves more comprehensive studies as a potential PC therapeutic agent.

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells. Highlights Oleanolic acid oxime ester derivatives (3a–3t) were synthesised and screened against α-glucosidase and α-amylase. Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM. Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM. Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

Selective C-C Bond Cleavage of Cycloalkanones by NaNO2/HCl.

A novel selective fragmentation of cycloalkanones by NaNO2/HCl has been established. The C-C bond cleavage reaction proceeds smoothly under mild conditions, selectively affording versatile keto acids or oxime acids. The methodology can streamline the synthesis of valuable chiral molecules and isocoumarins from readily available feedstocks.

Conjugation of Diclofenac with Novel Oleanolic Acid Derivatives Modulate Nrf2 and NF-κB Activity in Hepatic Cancer Cells and Normal Hepatocytes Leading to Enhancement of Its Therapeutic and Chemopreventive Potential.

Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling pathways. This study focused on the synthesis and biological evaluation of four diclofenac (DCL)–OAO derivative conjugates in the context of these pathways’ modification and hepatic cells survival. Treatment with the conjugates 4d, 3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide, and 4c, 3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester significantly reduced cell viability in comparison to the DCL alone. In THLE-2, immortalized normal hepatocytes treated with these conjugates resulted in the activation of Nrf2 and increased expression in SOD-1 and NQO1, while the opposite effect was observed in the HepG2 hepatoma cells. In both cell lines, reduced activation of the NF-κB and COX-2 expression was observed. In HepG2 cells, conjugates increased ROS production resulting from a reduced antioxidant defense, induced apoptosis, and inhibited cell proliferation. In addition, the OAO morpholide derivative and its DCL hybrid reduced the tumor volume in mice bearing xenografts. In conclusion, our study demonstrated that conjugating diclofenac with the OAO morpholide and a benzyl ester might enhance its anti-cancer activity in HCC.

Abstract 1289: Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells

Abstract Chronic inflammation is a key factor in the etiology of neoplastic diseases, including pancreatic cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) were approved for the chemoprevention of colon tumors and suggested for pancreas cancers prophylaxis. Anti-inflammatory and anti-tumorigenic activities are also exerted by naturally occurring and synthetic triterpenoids. Coupling of triterpenoid analogues with NSAIDs may enhance this effect and prevent the unfavorable side effects related to NSAIDs long-term use. In this study novel oleanolic acid oxime (OAO) derivatives conjugated with indomethacin (IND) differing in substitution group at position C-17 were evaluated in the context of their possible modulating effect of Nrf2-ARE and NF-κB signaling pathways in pancreatic cancer cells.PSN-1 cells were incubated for 24h with IND and OAO-IND derivatives at the concentrations of 10µM and 20µM selected based on the results of the MTT assay. The activation of Nrf2 and NF-κB was assessed by the evaluation of its translocation into the nucleus and binding to specific DNA sequences by the ELISA assay. Expression of Nrf2, SOD-1, NF-κBp50, NF-κBp65 and COX-2 was evaluated by RT-PCR and Western blot methods.Cell viability was affected mostly by 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide and 3-indomethacinoxyiminoolean-en-28-oic acid benzyl ester. The level of Nrf2 in the nucleus and binding to ARE sequence was decreased in PSN-1 cells, similarly as was NF-κBp50 and NF-κBp65 binding and nuclear accumulation. As result of diminished activation of these transcription factors decreased expression of SOD-1 and COX-2 i.e. mRNA and protein levels were found. These results indicate that the OAO-IND derivatives, particularly morpholide and benzyl ester conjugates, are more potent suppressors of NF-κB signaling pathway than IND alone. Moreover, conjugation of IND with novel OAO may protect cancer cells against chemoresistance through inhibition of the Nrf2-ARE pathway. Those novel compounds might be considered the potential modulators of hepatocellular carcinoma therapy and chemopreventive agents. Funding: This work was supported by Polish National Science Centre, grant 2016/21/B/NZ7/01758. Citation Format: Wanda Baer-Dubowska, Maria Narozna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar. Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1289.