Synthesis of Copper Oxide-Based Nanoformulations of Etoricoxib and Montelukast and Their Evaluation through Analgesic, Anti-Inflammatory, Anti-Pyretic, and Acute Toxicity Activities.

Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.

Design, synthesis, and biological evaluation of novel dual FFA1 and PPARδ agonists possessing phenoxyacetic acid scaffold.

The free fatty acid receptor 1 (FFA1/GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have been widely considered as promising targets for type 2 diabetes mellitus (T2DM) due to their respective roles in promoting insulin secretion and improving insulin sensitivity. Hence, the dual FFA1/PPARδ agonists may exert synergistic effects by simultaneously activating FFA1 and PPARδ. The present study performed systematic exploration around previously reported FFA1 agonist 2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (lead compound), leading to the identification of a novel dual FFA1/PPARδ agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic acid (the optimal compound), which displayed high selectivity over PPARα and PPARγ. In addition, the docking study provided us with detailed binding modes of the optimal compound in FFA1 and PPARδ. Furthermore, the optimal compound exhibited greater glucose-lowering effects than lead compound, which might attribute to its synergistic effects by simultaneously modulating insulin secretion and resistance. Moreover, the optimal compound has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg Therefore, our results provided a novel dual FFA1/PPARδ agonist with excellent glucose-lowering effects in vivo.

TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics.

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.

Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.

The protein-protein interaction (PPI) between kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is recognized as a promising target for the prevention and treatment of oxidative stress-related inflammatory diseases. Herein, a series of novel 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs (7p-t and 8c) were designed to further explore the structure-activity relationships of the series. Their activities were measured first with a fluorescence polarization (FP) assay and more potent compounds were further evaluated using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay, demonstrating IC50 values between 7.2 and 31.3 nM. In cytotoxicity studies, the naphthalene derivatives did not show noticeable toxicity to human HepG2-C8 and mouse brain BV-2 microglia cells. Among them, compound 7q bearing oxygen-containing fused rings was shown to significantly stimulate the cellular Nrf2 signaling pathway, including activation of antioxidant response element (ARE)-controlled expression of Nrf2 target genes and proteins. More importantly, 7q suppressed up-regulation of several pro-inflammatory cytokines in lipopolysaccharide (LPS)-challenged BV-2 microglial cells, representing a potential therapeutic application for controlling neuroinflammatory disorders.

Liposomes with Water as a pH-Responsive Functionality for Targeting of Acidic Tumor and Infection Sites.

A lipid named DCPA was synthesized under microwave-assisted heating. DCPA possesses a pyridine betaine, hydrophilic group that can be complexed with water through hydrogen bonding (DCPA-H2 O). DCPA-H2 O liposomes became protonated relatively fast already at pH<6.8, due to the high HOMO binding energy of DCPA-H2 O. In murine models, DCPA-H2 O liposomes had longer blood circulation times than natural DPPC or cationic DCPM liposomes, while after tail-vein injection DCPA-H2 O liposomes targeted faster to solid tumors and intra-abdominal infectious biofilms. Therapeutic efficacy in a murine, infected wound-healing model of tail-vein injected ciprofloxacin-loaded DCPA-H2 O liposomes exceeded the ones of clinically applied ciprofloxacin as well as of ciprofloxacin-loaded DPPC or DCPM liposomes.

Synthesis of 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their protective activity against oxidative stress.

A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their S-alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group-possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone-induced oxidative stress.

(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors.

As rate-limited enzyme of polyol pathway, aldose reductase (ALR2) is one of the key inhibitory targets for alleviating diabetic complications. To reduce the toxic side effects of the inhibitors and to decrease the level of oxidative stress, the inhibitory selectivity towards ALR2 against detoxicating aldehyde reductase (ALR1) and antioxidant activity are included in the design of multifunctional ALR2 inhibitors. Hydroxypyridinone derivatives were designed, synthesized and evaluated their inhibitory behavior and antioxidant activity. Notably, {2-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-4-oxo-4H-pyridin-1-yl}-acetic acid (7l) was the most potent, with IC50 values of 0.789 µM. Moreover, 7l showed excellent selectivity towards ALR2 with selectivity index 25.23, which was much higher than that of eparlestat (17.37), the positive control. More significantly, 7l performed powerful antioxidative action. At a concentration of 1 µM, phenolic compounds 7l scavenged DPPH radical with an inhibitory rate of 41.48%, which was much higher than that of the well-known antioxidant Trolox, at 11.89%. Besides, 7l remarkably suppressed lipid peroxidation with a rate of 88.76% at a concentration of 100 µM. The binding mode derived from molecular docking proved that the derivatives were tightly bound to the activate site, suggesting strongly inhibitory action of derivatives against ALR2. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors capable with potency for both selective ALR2 inhibition and as antioxidants.

Facile preparation of a novel Ga-67-labeled NODAGA-conjugated lactam-cyclized alpha-MSH peptide at room temperature for melanoma targeting.

In this study, the melanoma targeting property of 67Ga-NODAGA-GGNle-CycMSHhex {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH2} was determined on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NODAGA as a radiometal chelator for facile room temperature radiolabeling of NODAGA-GGNle-CycMSHhex. The IC50 value of NODAGA-GGNle-CycMSHhex was 0.87 ± 0.12 nM on B16/F10 melanoma cells. 67Ga-NODAGA-GGNle-CycMSHhex was readily prepared at room temperature with greater than 98% radiolabeling yield and displayed MC1R-specific binding on B16/F10 melanoma cells. The B16/F10 melanoma uptake of 67Ga-NODAGA-GGNle-CycMSHhex was 10.31 ± 0.78, 14.96 ± 1.34, 13.7 ± 3.33 and 10.4 ± 2.2% ID/g at 0.5, 2, 4 and 24 h post-injection, respectively. Approximately 85% of the injected dose was cleared out the body via urinary system at 2 h post-injection. 67Ga-NODAGA-GGNle-CycMSHhex showed high tumor/blood, tumor/muscle and tumor/skin uptake ratios after 2 h post-injection. Overall, 67Ga-NODAGA-GGNle-CycMSHhex could be easily prepared at room temperature and exhibited favorable melanoma targeting property, suggesting the potential use of NODAGA as a radiometal chelator for facile room temperature radiolabeling of α-MSH peptides.

Physicochemical Insight into Coordination Systems Obtained from Copper(II) Bromoacetate and 1,10-Phenanthroline.

Two different coordination compounds of copper were synthesized from the same building blocks (1,10-phenanthroline, bromoacetate anions, and copper cations). The synthesis parameters were carefully designed and evaluated to allow the change of the resulting compounds molecular structure, i.e., formation of mononuclear (bromoacetato-O,O')(bromoacetato-O)aqua(1,10-phenanthroline-N,N')copper(II) and dinuclear (µ-bromido-1:2κ2)bis(µ-bromoacetato-1κO,2κO')bis(1,10-phenanthroline-N,N')dicopper(II) bromoacetate bromoacetic acid solvate. The crystal, molecular and supramolecular structures of the studied compounds were determined and evaluated in Hirshfeld analysis. The UV-Vis-IR absorption and thermal properties were studied and discussed. For the explicit determination of the influence of compounds structure on radiation absorption in UV-Vis range, density functional theory and time-dependent density functional theory calculations were performed.

Mechanistic insights into ceramidase inhibitor LCL521-enhanced tumor cell killing by photodynamic and thermal ablation therapies.

Our recent investigation uncovered that the acid ceramidase inhibitor LCL521 enhances the direct tumor cell killing effect of photodynamic therapy (PDT) treatment. The present study aimed at elucidating the mechanisms underlying this effect. Exposing mouse squamous cell carcinoma SCCVII cells treated with temoporfin-based PDT to LCL521 (rising ceramide concentration) produced a much greater decrease in cell survival than comparable exposure to the sphingosine kinase-1 inhibitor PF543 (that reduces sphingosine-1-phosphate concentration). This is consistent with recognizing the rising levels of pro-apoptotic sphingolipid ceramide as being more critical in promoting the death of PDT-treated cells than the reduction in the availability of pro-survival acting sphingosine-1 phosphate. This pro-apoptotic impact of LCL521, which was suppressed by the apoptosis inhibitor bongkrekic acid, involves the interaction with the cellular stress signaling network. Hence, inhibiting the key elements of these pathways markedly influenced the adjuvant effect of LCL521 on the PDT response. Particularly effective was the inositol-requiring element-1 (IRE1) kinase inhibitor STF-083010 that dramatically enhanced the killing of cells treated with PDT plus LCL521. An important role in the survival of these cells was exhibited by master transcription factors STAT3 and HIF-1α. The STAT3 inhibitor NSC 74859 was especially effective in further reducing the cell survival rates, suggesting its possible exploitation for therapeutic gain. An additional finding in this study is that LCL521-promoted PDT-mediated cell killing through ceramide-mediated lethal effects is extended to the interaction with other cancer treatment modalities with a rapid cellular stress impact such as photothermal therapy (PTT) and cryoablation therapy (CAT).

Scalable Green Approach Toward Fragrant Acetates.

The advantageous properties of ethylene glycol diacetate (EGDA) qualify it as a useful substitute for glycerol triacetate (GTA) for various green applications. We scrutinised the lipase-mediated acetylation of structurally diverse alcohols in neat EGDA furnishing the range of naturally occurring fragrant acetates. We found that such enzymatic system exhibits high reactivity and selectivity towards activated (homo) allylic and non-activated primary/secondary alcohols. This feature was utilised in the scalable multigram synthesis of fragrant (Z)-hex-3-en-1-yl acetate in 70% yield. In addition, the Lipozyme 435/EGDA system was also found to be applicable for the chemo-selective acetylation of (hydroxyalkyl) phenols as well as for the kinetic resolution of chiral secondary alcohols. Lastly, its discrimination power was demonstrated in competitive experiments of equimolar mixtures of two isomeric alcohols. This enabled the practical synthesis of 1-pentyl acetate isolated as a single product in 68% yield from the equimolar mixture of 1-pentanol and 3-pentanol.

Development of Facile and Selective Fluorescent Probe for Physiological Phosphates based on Aggregation-induced Emission.

In this work, two new fluorescence chemosensors 2-(4-(1,2,2-triphenylvinyl)phenoxy) acetic acid (TPE-COOH) and 2,2'-(((1,2-diphenylethane-1,2-diyl)bis(4,1-phenylene))bis(oxy))diacetic acid (TPE-(COOH)2) were synthesized and applied for the facile detection of physiological phosphates. Due to the aggregation-induced emission (AIE) character, the emission can be turned on after label free interaction with polyethyleneimine (PEI). When the physiological phosphates were introduced to the system, the AIEgens/PEI complex was dissociated due to stronger electrostatic interaction between PEI and phosphates, which resulted in the significant fluorescence quenching of AIEgens. As the four kinds of phosphates cytidine-5'-diphosphate disodium salt (CDP), adenosine-5 (ADP), sodium pyrophosphate (PPi) and guanosine-5'-diphosphate disodium salt (GDP) had different interaction with PEI, also the TPE-COOH and TPE-(COOH)2 had different interaction with PEI, the fluorescence quenching effect was distinct for four phosphates. The unique pattern of fluorescence variations was differentiated by chemometric methods including principal component analysis and linear discriminant analysis. The robustness of the sensor array was proved by discrimination of four kinds of phosphates in serum samples with different concentrations, and the discrimination capacity was not influenced in complicated samples Graphical abstract.

Lipase-catalyzed synthesis of propyl-phenyl acetate: a kinetic and thermodynamic study.

This study focuses on the synthesis of propyl-phenyl acetate via esterification reaction in the presence of immobilized Candida antartica lipase-B (CAL-B). In this work, the effect of relevant factors (kinetics and thermodynamic) on total percent conversion and process optimization was studied. The reaction was performed in heptane medium with 1:2 molar ratio of benzoic acid: n-propanol with 0.6% (w/v) biocatalyst loading at 40 °C to attain a maximum conversion of 96.1% within 40 min of reaction time. Effect of increase in temperature on ∆G values indicates that lipase is more promising at moderate temperature (40 °C). A second-order kinetic model was proposed to evaluate apparent kinetic constants that indicate a good agreement between the experimental and theoretical data (0.94 ≤ R2 ≤ 0.99) with high initial reaction rate (113.5 mM/min). Finally, the catalyst CAL-B was successfully reused eight times without any significant decrease in relative activity.

A class of carbonic anhydrase IX/XII - selective carboxylate inhibitors.

A small series of 2,4-dioxothiazolidinyl acetic acids was prepared from thiourea, chloroacetic acid, aromatic aldehydes, and ethyl-2-bromoacetate. They were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, the cytosolic hCA I and II, and the transmembrane hCA IX and XII, involved among others in tumorigenesis (hCA IX and XII) and glaucoma (hCA II and XII). The two cytosolic isoforms were not inhibited by these carboxylates, which were also rather ineffective as hCA IX inhibitors. On the other hand, they showed submicromolar hCA XII inhibition, with KIs in the range of 0.30-0.93 µM, making them highly CA XII-selective inhibitors.

Application of Lipase Purified from Aspergillus fumigatus in the Syntheses of Ethyl Acetate and Ethyl Lactate.

Microbial lipases are used for the synthesis of various short chain esters such as octyl acetate, methyl salicylate, ethyl acetate and ethyl lactate. In this study, a purified lipase of Aspergillus fumigatus was utilized for the synthesis of two esters i.e. ethyl acetate and ethyl lactate. The purified lipase from Aspergillus fumigatus performed esterification of ethanol and acetic acid (at a molar ratio of 1:1) when incubated at 40℃ under shaking (130 min-1) for 12 h resulting in the formation of ethyl acetate (89%). In case of ethyl lactate maximum esterification (87.32%) was achieved when ethanol and lactic acid (500:100 mM ) was used in heptane resulting in the synthesis of ethyl lactate at 40°C under shaking (120 rpm) after 12 h of reaction time. These esters of short chain carboxylic acid and alcohols belong to the highly important natural aroma compounds and are used as green solvents in food and pharmaceutical industry.

Synthesis and X-Ray Crystal Structures of Trinuclear Nickel(II) Complexes Derived from Schiff Bases and Acetate Ligands with Biological Activity.

The reactions of Ni(OAc)2 2H2O with Schiff base ligands 5-bromo-2-((cyclopentylimino)methyl)phenol (HL1) and 5-bromo-2-(((2-(isopropylamino)ethyl)imino)methyl)phenol (HL2) in methanol afforded two discrete trinuclear com-plexes [Ni3(L1)2(?2-?1:?1-OAc)2(DMF)2(BrSal)2] (1) and [Ni3(L2)2(?2-?1:?1-OAc)2(?2-?2:?1-OAc)2] (2), where BrSal is the monoanionic form of 4-bromosalicylaldehyde. The complexes were characterized by elemental analysis, IR and UV-Vis spectroscopy. The crystal structures of the complexes have been determined by X-ray crystallography. In both com-plexes, the nickel atoms are in octahedral coordination geometries. The L1 ligand coordinates to the nickel atoms through the phenolate O and imino N atoms, and the L2 ligand coordinates to the nickel atoms through the phenolate O, imino N and amino N atoms. The antimicrobial activities of the complexes were assayed.

Polyethylene glycol (PEG-400) promoted one-pot, five-component synthesis of (E)-ethyl2-(2-((E)-2-(1-(4-methyl-2-(phenylamino)thiazol-5yl)ethylidene)hydrazinyl)-4-oxothiazol-5(4H)-ylidene)acetates.

A facile, inexpensive and eco-friendly synthesis of functionalised (E)-ethyl2-(2-((E)-2-(1-(4-methyl-2-(phenylamino)thiazol-5yl)ethylidene)hydrazinyl)14-oxothiazol-5(4H)-ylidene)acetates has been developed via one-pot five-component approach. The title compounds were synthesized by the reaction of anilines, 3-chloropentane-2,4-dione, ammoniumthiocyanate, thiosemicarbazide and dialkylacetylene dicarboxylate using polyethylene glycol as green and recyclable solvent. The domino reaction proceeded smoothly in good-to-excellent yields.

Synthesis of n-butyl acetate via reactive distillation column using Candida Antarctica lipase as catalyst.

The reactive distillation process for the synthesis of n-butyl acetate via transesterification of ethyl acetate with n-butyl alcohol catalyzed by immobilized lipase was simulated and experimentally tested in this work. Based on the reaction kinetics, a reactive distillation process model was developed. The effects of theoretical stages number in the reaction section, the rectifying section and stripping section, reflux ratio, feed molar ratio and relative feed position on the transesterification distillation process were investigated. The transesterification of ethyl acetate with n-butyl alcohol was carried out in a small-scale reactive distillation column. The results showed that the optimal operating conditions are as follows: reaction section stages were 13, rectifying section stages were six, stripping section stages were five, reflux ratio was 1, mole ratio of ethyl acetate and n-butanol was 3:1, the feeding positions of n-butanol and ethyl acetate were at the top and bottom of the reaction section, respectively. Compared to the batch reaction with only 60% conversion of n-butanol, the reactive distillation column can improve the conversion of n-butanol (up to 93.6%).At the same time, the experiment verified that the conversion of n-butanol could still reach 72.5%, after the lipase-loaded packing storage in the reaction system at 70 °C for 120 days.

A multimeric MRI contrast agent based on a closo-borane scaffold bearing modified AAZTA chelates on the periphery.

A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.