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Item Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic insights and rational design to overcome limitations(American Chemical Society, 2024-08-28) Ho, Tam D.; Lee, Byung Joo; Buchanan, Travis L.; Heikes, Micah E.; Steinert, Ryan M.; Milem, E. Grace; Goralski, Sean T.; Wang, Ya-Nong; Lee, SangHyun; Lynch, Vincent M.; Rose, Michael J.; Mitchell-Koch, Katie R.; Hull, Kami L.Herein, we report mechanistic investigations into the Cu-catalyzed three-component carboamination of alkenes with ?-halo carbonyls and aryl amines via an oxocarbenium intermediate. Monitoring the reaction reveals the formation of transient atom transfer radical addition (ATRA) intermediates with both electron-neutral and deficient vinyl arenes as well as unactivated alkenes. Based on our experimental studies and density functional theory calculations, the oxocarbenium is generated through atom transfer and subsequent intramolecular substitution. Further, mechanistic factors that dictate the regioselectivity of the nucleophilic attack onto the oxocarbenium to afford the ?-amino ester, ?-iminolactone, or ?-lactone are discussed. A strategy to overcome scope limitation with respect to unactivated alkenes is developed using the mechanistic insights gained herein. Finally, we demonstrate that under modified conditions, our Cu catalyst enables the ATRA reaction between a variety of alkyl halides and vinyl arenes/?-olefins, and we present a one-pot, two-step carbofunctionalization with an array of nucleophiles through ATRA/SN2. © 2024 American Chemical SocietyItem Structure-guided design of potent coronavirus inhibitors with a 2-pyrrolidone scaffold: Biochemical, crystallographic, and virological studies(American Chemical Society, 2024) Dampalla, Chamandi S.; Kim, Yunjeong; Zabiegala, Alexandria; Howard, Dennis; Nguyen, Harry Nhat; Madden, Trent K.; Thurman, Hayden A.; Cooper, Anne; Liu, Lijun; Battaile, Kevin P.; Lovell, Scott; Chang, Kyeong-Ok; Groutas, William C.Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CL$^{pro}$ embodying an N-substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3-S4 subsites and connected to an invariant Leu-Gln P2-P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CL$^{pro}$ were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors. © 2024 American Chemical Society.Item In vitro characterization of dopaminergic toxins: A laboratory exercise suitable for a senior undergraduate biochemistry laboratory curriculum(American Chemical Society, 2023) Le, Viet Q.; Adjei, Joseph; Eldani, Maya; Oluwatosin, Adetuyi; Wimalasena, KandategeThe objective of this study was to introduce a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay and a fluorometric 4',6-diamidino-2-phenylindole (DAPI) apoptotic assay that are suitable to adopt into an undergraduate biochemistry laboratory curriculum to identify and characterize dopaminergic toxins in the common working environments. Here, we used commercially available Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP$^+$), as a model dopaminergic toxin and tested its selective dopaminergic toxicity in MN9D cells against non-neuronal HepG2 cells in an upper-level undergraduate biochemistry laboratory class. Overall, this laboratory exercise helped students to develop skills in quantitative in vitro toxicity measurements using a simple colorimetric MTT assay and gain an understanding of the mechanism of toxicity by DAPI fluorescence imaging techniques for apoptosis. Required experimental data analyses will also allow students to gain an understanding of the use of appropriate statistical analyses of biochemicals in biomedical studies. More importantly, this exercise will allow students to better understand the intimate relationship between the environment and human health. The high relevance of this study to environmental effects of human health will certainly result in high interest leading to increased student engagement and interest for advanced learning. © 2024 American Chemical Society and Division of Chemical Education, Inc.Item Unprecedented mid-infrared nonlinear optical materials achieved by crystal structure engineering, a case study of (KX)P2S6 (X = Sb, Bi, Ba)(Royal Society of Chemistry, 2022-02-02) Nguyen, Vivian; Ji, Bingheng; Wu, Kui; Zhang, Bingbing; Wang, JianThree acentric type-I phase-matchable infrared nonlinear optical materials KSbP2S6, KBiP2S6, and K2BaP2S6, showing excellent balance between the second harmonic generation coefficient, bandgap, and laser damage threshold, were synthesized via a high-temperature solid-state method. KSbP2S6 is isostructural to KBiP2S6, which both crystallize in the β-KSbP2Se6 structure type. K2BaP2S6 was discovered for the first time, which crystallizes in a new structure type. KSbP2S6 and KBiP2S6 exhibit close structural similarity to the parent compound, centrosymmetric Ba2P2S6. The [P2S6] motifs, isotypic to ethane, exist in Ba2P2S6, KSbP2S6, KBiP2S6, and K2BaP2S6. The mixed cations, K/Sb pair, K/Bi pair, and K/Ba pair, play a dual-role of aligning the [P2S6] structure motifs, contributing to a high SHG coefficient, as well as enlarging the bandgap. KSbP2S6, KBiP2S6, and K2BaP2S6 are direct bandgap semiconductors with a bandgap of 2.9(1) eV, 2.3(1) eV and 4.1(1) eV, respectively. KSbP2S6, KBiP2S6, and K2BaP2S6 exhibit a high second harmonic response of 2.2× AgGaS2, 1.8× AgGaS2, and 2.1× AgGaS2, respectively, coupled with a high laser damage threshold of 3× AgGaS2, 3× AgGaS2, and 8× AgGaS2, respectively. The DFT calculations also confirm that the large SHG coefficient mainly originates from [P2S6] anionic motifs.Item Synthesis, crystal growth, electronic properties and optical properties of Y6IV2.5S14 (IV=Si, Ge)(Wiley, 2021-12-06) Ye, Zhengyang; Bardelli, Stefano; Wu, Kui; Sarkar, Arka; Swindle, Andrew; Wang, JianTwo isostructural ternary acentric sulfides, Y6Si2.5S14 (1) and Y6Ge2.5S14 (2) were re-investigated to understand the origin of the chemical flexibility of RE6BxCyCh14(RE=Y, La−Lu; B=Si, Ge, Sn, Al, Ga; C=monovalent M+ (Ag, Na, Li, etc.), divalent M2+ (Mg, Cr, Ni, Zn, etc.), trivalent M3+ (Al, In, Ga, etc.), tetravalent M4+ (Si, Ge, Sn) and pentavalent M5+ (Sb), Ch=S, Se), which consists of ∼444 isostructural compounds. Y6IV2.5S14 (IV=Si, Ge) were synthesized by a high-temperature salt flux method. The crystal structures of Y6IV2.5S14 (IV=Si, Ge) are constructed by [YS8] polyhedra, [Si1S6] octahedra, and [Si2S4] tetrahedra. The Si1 atom displaces from the center of [Si1S6] octahedra with partial occupancy, which can be replaced by various metals, and mainly accounts for the chemical flexibility of the RE6BxCyCh14 family. The bonding pictures of Y6Si2.5S14 were studied by electron localization function (ELF) and crystal orbital Hamilton population (COHP) calculations. Y6Si2.5S14 is evaluated as an indirect semiconductor with a bandgap of 2.4(1) eV measured by UV-Vis. The indirect bandgap of Y6Ge2.5S14 is 1.7(1) eV. Y6IV2.5S14 (IV=Si, Ge) are not type-I phase-matchable materials. For samples of 47 μm particle size, Y6Si2.5S14 and Y6Ge2.5S14 own good second harmonic generation (SHG) responses of ∼3.0×AGS and ∼2.8×AGS respectively. Y6Si2.5S14 and Y6Ge2.5S14 possess high laser damage threshold (LDT) of ∼5.5×AGS and ∼5.2×AGS respectively.