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Carbon dioxide (CO 2 ) injection in unconventional gas-bearing shale reservoirs is a promising method for enhancing methane recovery efficiency and mitigating greenhouse gas emissions. The majority of methane is adsorbed within the micropores and nanopores (≤50 nm) of shale, which possess extensive surface areas and abundant adsorption sites for the sequestration system. To comprehensively discover the underlying mechanism of enhanced gas recovery (EGR) through CO 2 injection, molecular dynamics (MD) provides a promising way for establishing the shale models to address the multiphase, multicomponent fluid flow behaviors in shale nanopores. This study proposes an innovative method for building a more practical shale matrix model that approaches natural underground environments. The grand canonical Monte Carlo (GCMC) method elucidates gas adsorption and sequestration processes in shale gas reservoirs under various subsurface conditions. The findings reveal that previously overlooked pore slits have a significant impact on both gas adsorption and recovery efficiency. Based on the simulation comparisons of absolute and excess uptakes inside the kerogen matrix and the shale slits, it demonstrates that nanopores within the kerogen matrix dominate the gas adsorption while slits dominate the gas storage. Regarding multiphase, multicomponent fluid flow in shale nanopores, moisture negatively influences gas adsorption and carbon storage while promoting methane recovery efficiency by CO 2 injection. Additionally, saline solution and ethane further impede gas adsorption while facilitating displacement. Overall, this work elucidates the substantial effect of CO 2 injection on fluid transport in shale formations and advances the comprehensive understanding of microscopic gas flow and recovery mechanisms with atomic precision for low-carbon energy development.

Surfactant reduces the surface tension of liquids, resulting in improved emulsion stability, and there is great interest in pesticide additives. Ethoxylate is often used as a pesticide emulsifier. However, the degree of ethoxylation and the existence of dioxane byproducts can significantly affect the performance of emulsifiers. Here, a series of polyoxyethylene tallow amines with the addition of different numbers of ethylene oxide (EO) were synthesized and characterized. Their physical and chemical performances were measured. The ability of POEA as a surfactant to reduce water surface tension and the surface adsorption of molecules were assessed based on the static and dynamic surface tensions. The results show that the surfactant molecules preferentially form a saturated adsorption layer in solution, and the mixed-diffusion-kinetics mechanism dominates the adsorption process. With the increase of the EO addition number, the emulsifying property of POEA increases, while the wetting property gradually decreases and the contact angle increases. These results can provide a basis for the selection of pesticide additives. At the same time, the mechanism of removing dioxane by ethoxylate is described, and a simple and low-consumption method is put forward to reduce the dioxane content. It provides a new idea for the removal of dioxane.

The mechanism of sulfate formation during winter haze events in North China remains largely elusive. In this study, the multiple sulfur isotopic composition of sulfate in different grain-size aerosol fractions collected seasonally from sampling sites in rural, suburban, urban, industrial, and coastal areas of North China are used to constrain the mechanism of SO 2 oxidation at different levels of air pollution. The Δ 33 S values of sulfate in aerosols show an obvious seasonal variation, except for those samples collected in the rural area. The positive Δ 33 S signatures (0‰ < Δ 33 S < 0.439‰) observed on clean days are mainly influenced by tropospheric SO 2 oxidation and stratospheric SO 2 photolysis. The negative Δ 33 S signatures (-0.236‰ < Δ 33 S < ∼0‰) observed during winter haze events (PM 2.5 > 200 μg/m 3 ) are mainly attributed to SO 2 oxidation by H 2 O 2 and transition metal ion catalysis (TMI) in the troposphere. These results reveal that both the H 2 O 2 and TMI pathways play critical roles in sulfate formation during haze events in North China. Additionally, these new data provide evidence that the tropospheric oxidation of SO 2 can produce significant negative Δ 33 S values in sulfate aerosols.

Harmful cyanobacterial blooms and the released microcystins (MCs) caused serious environmental and public health concerns to drinking water safety. Photo-oxidation is an appealing treatment option and alternative to conventional flocculation and microbial antagonists, but the performances of current photosensitizers (either inorganic or organic) are unsatisfactory. Here, a polythiophene photosensitizer (PT10) with both high yield of reactive oxygen species (ROS) production (mainly 1 O 2 , Φ Δ = 0.51, > 8 h continuous generation) and moderate photostability was used as a powerful algaecide to inhibit Microcystis aeruginosa . Due to the positive charge of PT10, the algal cells were quickly flocculated, followed by efficient inactivation in 4 h under white light irradiation (96.7%, 10 mW/cm 2 ). Meanwhile, PT10 was self-immolated in about 6 h. Upon biosafety evaluation with adult zebrafish, the low toxicity of PT10 and the degradation products of PT10 and algae (early logarithmic growth stage) were confirmed. In addition, microcystin-LR (MC-LR), a toxic microcystin that will be released during the destruction of the algal cells, was also degraded. Therefore, PT10-based photoinactivation of M. aeruginosa featured both high performance and low secondary pollution. In real-world aquatic systems, PT10 was confirmed to be capable of sunlight-assisted inactivation of M. aeruginosa and prevent algal blooms, thus making it appealing for environmental remediation.

Cancer immunotherapy, such as the Toll-like receptor (TLR) agonist including CpG oligodeoxynucleotide, has shown potency in clinical settings. However, it is still confronted with multiple challenges, which include the limited efficacy and severe adverse events caused by the rapid clearance and systemic diffusion of CpG. Here we report an improved CpG-based immunotherapy approach composed of a synthetic extracellular matrix (ECM)-anchored DNA/peptide hybrid nanoagonist (EaCpG) via (1) a tailor designed DNA template that encodes tetramer CpG and additional short DNA moieties, (2) generation of elongated multimeric CpG through rolling circle amplification (RCA), (3) self-assembly of densely packaged CpG particles composed of tandem CpG building blocks and magnesium pyrophosphate, and (4) incorporation of multiple copies of ECM binding peptide through hybridization to short DNA moieties. The structurally well-defined EaCpG shows dramatically increased intratumoral retention and marginal systemic dissemination through peritumoral administration, leading to potent antitumor immune response and subsequent tumor elimination, with minimal treatment-related toxicity. Combined with conventional standard-of-care therapies, peritumor administration of EaCpG generates systemic immune responses that lead to a curative abscopal effect on distant untreated tumors in multiple cancer models, which is superior to the unmodified CpG. Taken together, EaCpG provides a facile and generalizable strategy to simultaneously potentiate the potency and safety of CpG for combinational cancer immunotherapies.

A highly diastereo- and enantioselective phosphine-catalyzed sequential [3 + 2]/[3 + 2] annulation of allenoates with arylidenemalononitriles has been developed. This reaction allows for the facile construction of multifunctionalized cis -fused bicyclic[3,3,0]octene scaffolds, encompassing three consecutive stereogenic centers with one quaternary carbon center, in a one-step operation from readily available materials. The reported protocol is scalable, operates under mild reaction conditions, and creates the core structural motif of a number of natural products.

Ultraviolet radiation (UVR) is both useful to human beings and can cause irreversible harm of varying degrees (UVA, UVB, and UVC). Especially, in areas with excessive sunlight, the appearance of UVB results in an increased risk of skin cancer. On the other hand, UV lamps (254 nm, UVC) are widely used in disinfection (air, water, and factory food) and hospital sterilization; the leakage of UVC is thus sometimes inevitable, which may cause fatal injuries to the related staff. Therefore, low-cost UV dosimetry-based personal protective equipment (PPE) and industrial monitoring devices are of great importance. Here, for the first time, we found that 3,3',5,5'-tetramethylbenzidine (TMB) could be rapidly oxidized upon UVB and UVC irradiation in a dose-dependent manner, in which TMB acts as a self-photosensitizer. Since TMB is a typical and widely used chromogenic substrate in enzyme-linked immunosorbent assay (ELISA), it is well-commercialized with low cost and vast availability worldwide, which permitted the development of low-cost naked-eye UVB and UVC dosimetry. A wearable bracelet mounted with TMB-loaded paper was developed for successful indication of whether the UVB exposure in the sunlight exceeded the minimum erythema dose (MED). In addition, we also developed a clock dial equipped with a TMB solution for unattended detection of UVC leakage from UVC disinfection lamps. The UVB- and UVC-selective coloration and low cost of TMB offered remarkable potential in facile detection of UVR in our daily life.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is an important analysis technique that can gather vast amounts of information from surfaces. Recently, machine learning was combined with ToF-SIMS to successfully extract useful information from mass spectra. However, the descriptor generation required for ToF-SIMS analysis using machine learning remains challenging because it requires a lot of effort, is time-consuming, and significantly limits the versatility and practicality of the machine learning approach for ToF-SIMS analysis. Herein, we proposed a new approach to avoid the descriptor generation: to regard ToF-SIMS spectra as images and apply the convolutional neural network (CNN) to analyze these spectral images. We applied and assessed this approach for the identification of silane coupling agents in multicomponent films. Furthermore, the CNN showed higher accuracy than descriptor-based approaches, suggesting its usefulness in achieving the automation and standardization of the ToF-SIMS analysis.

O -Acetylation is a common modification of sialic acids that can occur at carbons 4-, 7-, 8-, and/or 9. Acetylated sialosides are employed as receptors by several betacoronaviruses and toroviruses, and by influenza C and D viruses. The molecular basis by which these viruses recognize specific O -acetylated sialosides is poorly understood, and it is unknown how viruses have evolved to recognize specific O -acetylated sialosides expressed by their host. Here, we describe a chemoenzymatic approach that can readily provide sialoglycan analogues in which acetyl esters at C4 and/or C7 are replaced by stabilizing acetamide moieties. The analogues and their natural counterparts were used to examine the ligand requirements of the lectin domain of coronaviral hemagglutinin-esterases (HEs). It revealed that HEs from viruses targeting different host species exhibit different requirements for O -acetylation. It also showed that ester-to-amide perturbation results in decreased or loss of binding. STD NMR and molecular modeling of the complexes of the HE of BCoV with the acetamido analogues and natural counterparts revealed that binding is governed by the complementarity between the acetyl moieties of the sialosides and the hydrophobic patches of the lectin. The precise spatial arrangement of these elements is important, and an ester-to-amide perturbation results in substantial loss of binding. Molecular Dynamics simulations with HEs from coronaviruses infecting other species indicate that these viruses have adapted their HE specificity by the incorporation of hydrophobic or hydrophilic elements to modulate acetyl ester recognition.

In recent decades, epidemiological, clinical, and experimental studies have demonstrated that a diet with antioxidant or anti-inflammatory function plays a central role in the prevention of atherosclerosis (AS). The purpose of this study was to explore the effects of Cannabis seed oil (CO) administration on in vitro antioxidant capacity as well as blood lipid profiles, lipid peroxidation, inflammatory response, and endothelial cell integrity. Female ApoE -/- mice were fed a high-cholesterol diet and administrated with CO or phosphate-buffered saline (PBS) and seal oil by gavage for 8 weeks. The results show that CO administration reduced the levels of serum triglycerides and low-density lipoprotein cholesterol at week 6. Additionally, a decrease in serum tumor necrosis factor α and nitric oxide was also observed. Moreover, results from CD31 staining and scanning electron microscopy revealed that CO treatment alleviated the endothelial cell damage and lipid deposition induced by a high-cholesterol diet. The ratio of lesion area to the total aorta area was 19.57% for the CO group, which was lower than the PBS control group (24.67%). Collectively, CO exerted anti-atherosclerotic effects by modulating serum lipid profiles and inflammatory responses and improving endothelial cell integrity and arterial lipid deposition. The results provide a promising preventive strategy for the early progression of AS.

D 2 O plays important roles in a variety of fields (such as the nuclear industry and bioorganic analysis), and thus its isotopic purity (H 2 O contents) is highly concerned. Due to its highly similar physical properties to H 2 O and large excess amounts of H 2 O over D 2 O, it is challenging to distinguish D 2 O from H 2 O. On the basis of the characteristic NIR-II phosphorescence of singlet oxygen ( 1 O 2 ), and the fact that H 2 O is a more efficient quencher for 1 O 2 than D 2 O, here, we proposed to simply use the 1275 nm emission of 1 O 2 for the analysis of the isotopic purity of D 2 O. In normal cases (a xenon lamp for excitation), such steady-state emission is extremely weak for valid analytical applications, we thus employed laser excitation for intensification. To this goal, a series of photosensitizers were screened, and eventually polythiophene PT10 was selected with high singlet oxygen quantum yield (Φ Δ = 0.51), high H 2 O/D 2 O contrast, and excellent photostability. Upon excitation with a 445 nm laser, a limit of detection (LOD, 3σ) of 0.1% for H 2 O in D 2 O was achieved. The accuracy of the proposed method was verified by the analysis of the isotopic purity of several D 2 O samples (with randomly added H 2 O). More interestingly, the hygroscopicity of D 2 O was sensitively monitored with the proposed probe in a real-time manner; the results of which are important for strengthening the care of D 2 O storage and the importance of humidity control during related investigations. Besides D 2 O isotopic purity evaluation, this work also indicated the potential usefulness of the NIR-II emission of singlet oxygen in future analytical detection.

Blueberry anthocyanins are well known for their beneficial biological activities. However, the poor bioavailability of anthocyanins limits their functional capacity in vivo . Our current study aimed to detect the effects of α-casein on the absorption of blueberry anthocyanins and their metabolites in rats. Blueberry anthocyanins with and without α-casein were intragastrically administered to two groups of rats and their blood samples were collected within 24 h. Results illustrated that rapid absorption of anthocyanins was observed in the rat plasma, but their concentration was relatively low. With the complexation of α-casein, the maximum concentration ( C max ) of bioavailable anthocyanins and metabolites could increase by 1.5-10.1 times ( P < 0.05 or P < 0.01). The promotional effect on the plasma absorption of malvidin-3- O -galactoside and vanillic acid was outstanding with the C max increasing from 0.032 to 0.323 and from 0.360 to 1.902 μg/mL, respectively ( P < 0.01). Besides, the molecular docking models presented that anthocyanins could enter the structural cavity and interact with amino acid residues of α-casein, which was in accordance with the improved bioavailability of anthocyanins. Therefore, α-casein could assist more blueberry anthocyanins and their metabolites to enter blood circulation.

Snow serves as a vital scavenging mechanism to gas-phase and particle-phase organic nitrogen substances in the atmosphere, providing a significant link between land-atmosphere flux of nitrogen in the surface-earth system. Here, we used optical instruments (UV-vis and excitation-emission matrix fluorescence) and a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) to elucidate the molecular composition and potential precursors of snow samples collected simultaneously at four megacities in North China. The elemental O/N ratio (≥3), together with the preference in the negative ionization mode, indicates that the one and two nitrogen atom-containing organics (CHON 1 and CHON 2 ) in snow were largely in the oxidized form (as organic nitrates, -ONO 2 ). This study assumed that scavenging of particle-phase and gas-phase organic nitrates might be significant sources of CHON in precipitation. A gas-phase oxidation process and a particle-phase hydrolysis process, at a molecular level, were used to trace the potential precursors of CHON. Results show that more than half of the snow CHON molecules may be related to the oxidized and hydrolyzed processes of atmospheric organics. Potential formation processes of atmospheric organics on a molecular level provide a new concept to better understand the sources and scavenging mechanisms of organic nitrogen species in the atmosphere.

We report the results of a VAMAS (Versailles Project on Advanced Materials and Standards) interlaboratory study on the identification of peptide sample TOF-SIMS spectra by machine learning. More than 1000 time-of-flight secondary ion mass spectrometry (TOF-SIMS) spectra of six peptide model samples (one of them was a test sample) were collected using 27 TOF-SIMS instruments from 25 institutes of six countries, the U. S., the U. K., Germany, China, South Korea, and Japan. Because peptides have systematic and simple chemical structures, they were selected as model samples. The intensity of peaks in every TOF-SIMS spectrum was extracted using the same peak list and normalized to the total ion count. The spectra of the test peptide sample were predicted by Random Forest with 20 amino acid labels. The accuracy of the prediction for the test spectra was 0.88. Although the prediction of an unknown peptide was not perfect, it was shown that all of the amino acids in an unknown peptide can be determined by Random Forest prediction and the TOF-SIMS spectra. Moreover, the prediction of peptides, which are included in the training spectra, was almost perfect. Random Forest also suggests specific fragment ions from an amino acid residue Q, whose fragment ions detected by TOF-SIMS have not been reported, in the important features. This study indicated that the analysis using Random Forest, which enables translation of the mathematical relationships to chemical relationships, and the multi labels representing monomer chemical structures, is useful to predict the TOF-SIMS spectra of an unknown peptide.

Horseradish peroxidase (HRP)-based assays feature particular interests because of the simple colorimetric readout. In these assays, 3,3',5,5'-tetramethylbenzidine (TMB) is the most widely used chromogenic substrates for HRP. The later research in nanozyme and DNAzyme also used TMB (the chosen substrate) because they are both HRP-mimics. It should be noted that the substrate of HRP is not just limited to TMB but, in fact, a broad range of benzidine derivatives. However, except decreased carcinogenicity due to tetrasubstitution of benzidine, the rationale for the chosen substrate TMB is not clear yet. Here, we addressed such a fundamental issue from the chemistry point of view. Nine benzidine derivatives featuring varied properties (different substitution groups and varied number of substitutions) were selected and investigated with four typical TMB-involved chromogenic systems. Among the existing benzidine substrates that are used for peroxidase-based assays, TMB exhibited the highest sensitivity, better color purity of colored products, and reasonable stability of oxidation products. Moreover, two tetrasubstituted benzidine derivatives other than TMB ( 4OCH 3 and 2OCH 3 2CH 3 ) were synthesized for comparison. It turned out that the performances (sensitivity, color purity, and stability of the colored products) of TMB are still superior, thus chemically confirming its status of "the chosen substrate" in colorimetric assays.

A multicomponent reaction of styrenes, aryldiazonium tetrafluoroborates, sulfur dioxide, nitriles, and water in the presence of a photocatalyst at room temperature is performed. This vicinal aminosulfonylation of styrenes with the insertion of sulfur dioxide under visible light irradiation proceeds efficiently with excellent chemoselectivity, giving rise to the corresponding β-sulfonyl amides in moderate to good yields.

The iridium-catalyzed hydroarylation of alkenyl ethers developed by Nishimura and co-workers (Ebe, Y.; Onoda, M.; Nishimura, T.; Yorimitsu, H. Angew. Chem. Int. Ed. 2017, 56, 5607-5611) represents a rare example of regio- and enantioselective hydroarylation of challenging internal alkenes. In the present study, density functional theory calculations were performed in order to investigate the detailed reaction mechanism and the origins of the experimentally observed regio- and enantioselectivities. The computations show that the initial C-H oxidative addition and the isomerization between the allylic ethers and the 1-alkenyl ethers via the migratory insertion into the Ir-H bond/β-hydride elimination are both feasible. The reaction was found to proceed through the modified Chalk-Harrod-type mechanism via the migratory insertion into the Ir-C bond/C-H reductive elimination. The migratory insertion into the Ir-C bond constitutes the rate- and selectivity-determining step of the overall reaction. The calculations reproduced quite well the experimentally observed regio- and enantioselectivities. The enantioselectivity of the reaction was found to arise from the reactions of the (E)- and (Z)-1-alkenyl ethers, which afford the opposite enantiomers of product with the aryl group installed at the α-position to the alkoxy group. It turns out that the strong electron-donating character of the alkoxy group plays an important role in determining the regioselectivity, since it can stabilize the developed positive charge of the α-insertion transition state, leading to the aryl group being selectively installed at the α-position.

A series of tetrasubstituted fluoroalkenes were synthesized in good yield and high E/Z selectivity (up to 96/4) by Wittig reaction between α-heterosubstituted ketones and α-fluorophosphonium ylides. A detailed study of factors that control stereoselectivity in these reactions shows that stereoselectivity is the result of stabilizing CH···F and N···C═O interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity for reactions of stabilized ylides with α-alkoxy aldehydes.

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.

The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.

A regiocontrolled intermolecular Diels-Alder reaction of an o-benzoquinone followed by an intramolecular nitrile oxide cyclization is employed to prepare the BCD fragment of viridin. The AE segment is attached to it by means of an intramolecular Diels-Alder reaction of an o-benzoquinone monoketal generated in situ from tricycle 15 and 5-trimethylsilyl-2E,4E-pentadienol 20. The silyl substituent at C-1 of the pentacyclic product directs the dihydroxylation of the C2-C3 double bond to its beta-face. Various transformations of the 1alpha-trimethylsilyl-2beta,3beta-dihydroxy pentacycle into several others with oxygen substituents in ring A are described. One of these products 40 possesses the same structure and relative stereochemistry in rings A, B, and E as that of the natural product wortmannolone 3.

(RS)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 5) and the selective AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA, 7) have been used as leads for the design and synthesis of a number of potential AMPA receptor antagonists. Two parallel series of AMOA analogs were synthesized, containing either a distal carboxylic acid (compounds 8b-g and 11b) or a phosphonic acid (compounds 9a-g, 10c, and 11c). Pharmacological characterization of the synthesized compounds was carried out using a series of receptor binding assays and by in vitro electrophysiological experiments using the rat cortical slice model. The two analogs with a tert-butyl substituent, (RS)-2-amino-3-[5-tert-butyl-3-(carboxymethoxy)-4-isoxazolyl]pr opi onic acid (ATOA, 8b) and the corresponding phosphonic acid analog ATPO (9b), were the most potent and selective AMPA antagonists within each series. ATOA and ATPO showed IC50 values of 150 and 28 microM, respectively, toward AMPA-induced depolarizations in the cortical slice model compared to IC50 = 320 microM for the parent compound, AMOA. These two new competitive AMPA antagonists were significantly more selective than AMOA, showing no antagonism (up to 1 mM) toward NMDA-induced responses, whereas AMOA (at 1mM) showed weak (19%) inhibition toward NMDA-induced responses. The structure-activity relationships for the two series of compounds revealed considerable differences with respect to the substituents effects, and the phosphonic acid analogs generally exhibited significantly higher potencies compared to the carboxylic acid analogs.