14 Search Results

We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODCmore » was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.« less

The desorption of conventional ligands from the surface of halide perovskite nanocrystals (NCs) often causes their structural instability and the deterioration of the optoelectronic properties. To address this challenge, we present an approach of using a bidentate Lewis base ligand, namely, 1,4-bis(diphenylphosphino)butane (DBPP), for the synthesis of CsPbBr₃ NCs. The phosphine group of DBPP has a strong interaction with PbBr₂ precursor, forming a highly crystalline intermediate complex during the reaction. In the presence of oleic acid, the uncoordinated phosphine group of DBPP is converted into the phosphonium cation, which strongly binds with the surface bromide of the formed CsPbBr₃ NCsmore » through hydrogen bonding. Density functional theory calculations suggest that DBPP can strongly bind to the undercoordinated lead and surface bromide ions of CsPbBr₃ NCs through its unprotonated and protonated phosphine groups, respectively. The robust binding of DBPP with the surface of perovskite NCs helps to preserve their structural integrity under various environmental stresses. Moreover, the electron density and energy levels are regulated in DBPP-capped CsPbBr₃ NCs via the efficient transfer of electrons from the ligands to the NCs, resulting in their improved photocatalytic CO₂ reduction performance. Furthermore, our study highlights the potential of using bidentate ligands to stabilize the surface of perovskite NCs and modulate their optical and electronic properties.« less

Polyketide synthases (PKSs) are renowned for the structural diversity of the polyketide natural products they produce, but sulfur-containing functionalities are rarely installed by PKSs. We previously characterized thiocysteine lyase (SH) domains involved in the biosynthesis of the leinamycin (LNM) family of natural products, exemplified by LnmJ-SH and guangnanmycin (GnmT-SH). Here we report a detailed investigation into the PLP-dependent reaction catalyzed by the SH domains, guided by a 1.8 Å resolution crystal structure of GnmT-SH. A series of elaborate substrate mimics were synthesized to answer specific questions garnered from the crystal structure and from the biosynthetic logic of the LNM familymore » of natural products. Here, through a combination of bioinformatics, molecular modeling, in vitro assays, and mutagenesis, we have developed a detailed model of acyl carrier protein (ACP)-tethered substrate-SH, and interdomain interactions, that contribute to the observed substrate specificity. Comparison of the GnmT-SH structure with archetypical PLP-dependent enzyme structures revealed how Nature, via evolution, has modified a common protein structural motif to accommodate an ACP-tethered substrate, which is significantly larger than any of those previously characterized. Overall, this study demonstrates how PLP-dependent chemistry can be incorporated into the context of PKS assembly lines and sets the stage for engineering PKSs to produce sulfur-containing polyketides.« less

Defects and impurities in halide perovskite solar cells can negatively impact device performance and long-term stability. In this study, we identify photonically cured methylammonium (MA) lead iodide films contain a residual adduct, MA₂Pb₃I₈(dimethyl sulfoxide)₂ (MA₂Pb₃I₈(DMSO)₂), that reduces photocurrent generation in perovskite solar cells (PSCs). This is evidenced by a decrease in the external quantum efficiency (EQE) near 400 nm. Similar EQE reductions were observed in PSCs produced using high-speed processes but have not been thoroughly examined. Through X-ray diffraction patterns and Fourier transform infrared spectroscopy, we establish the photo-inactive MA₂Pb₃I₈(DMSO)₂ as the culprit for the EQE reduction. Combined experimental andmore » simulation results reveal that the MA₂Pb₃I₈(DMSO)₂ phase is located at the hole transport layer/ interface, not on the surface, resulting in lower quantum efficiency and surface photovoltage in the short wavelength region. The residual adduct is kinetically trapped due to the short processing time (20 ms) and crystallization direction but can be removed by an additional photonic pulse. Furthermore, this study highlights the need for careful examination of resulting materials beyond device efficiency when transitioning from laboratory processing to industrial high-speed methods.« less

The oxidative [4 + 2] reaction of o-phenylenediamine-derived disulfonamides with fullerene C₆₀ and C₇₀ is reported, in which electron-deficient reactants showed high reactivity. The reaction of C₇₀ exhibited unusual regioselectivity, yielding a [5,6]-adduct as the major product, which was characterized by ¹H, ¹³C NMR and single-crystal X-ray diffraction. Here, DFT calculations revealed the reaction is an inverse-electron-demand Diels–Alder (IEDDA) reaction, and the [5,6]-adduct of C₇₀ is a kinetic product.

We describe the Mass Spectrometry Adduct Calculator (MSAC), an automated Python tool to calculate the adduct ion masses of a parent molecule. Here, adduct refers to a version of a parent molecule [M] that is charged due to addition or loss of atoms and electrons resulting in a charged ion, e.g. [M+H]⁺. MSAC includes a database of 2,341 potential ions and their mass-to-charge ratios (m/z) as extracted from the NIST/EPA/NIH Mass Spectral Library (NIST17), the Global Natural Products Social Molecular Networking Public Spectral Libraries (GNPS), and MassBank of North America (MoNA). The calculator relies on user-selected subsets of the combinedmore » database to calculate expected m/z for adducts of molecules supplied as formulas This tool is intended to help researchers create identification libraries to collect evidence for the presence of molecules in mass spectrometry data. While the included adduct database focuses on adducts typically detected during liquid chromatography-mass spectrometry analyses, users may supply their own lists of adducts and charge states for calculating expected m/z. We also analyzed statistics on adducts from spectra contained in the three selected mass spectral libraries. MSAC is freely available at https://github.com/pnnl/MSAC.« less

Here, the syntheses and molecular structures of new Sm^II and Tm^IIN,N-dimethylaminodiboranate (DMADB) complexes are described. Treating SmI₂(THF)₂ with Na(H₃BNMe₂BH₃) in THF results in the formation of Sm(H₃BNMe₂BH₃)₂(THF)₃ (1), which can be readily converted to Sm(H₃BNMe₂BH₃)₂(DME)₂ (DME = 1,2-dimethoxyethane) or Sm(H₃BNMe₂BH₃)₂(diglyme) by exchange with the corresponding ether. We also show that Sm(H₃BNMe₂BH₃)₂(THF)₃ can be prepared by reduction of the SmIII compound Sm(H₃BNMe₂BH₃)₃(THF) with KC₈ and that addition of 18-crown-6 to this reaction mixture results in the formation of the Sm^II compound Sm(H₃BNMe₂BH₃)₂(18-crown-6). In a similar fashion, two new Tm^II complexes have been synthesized: treatment of TmI₂ in THF with Na(H₃BNMe₂BH₃) resultsmore » in the formation of Tm(H₃BNMe₂BH₃)₂(THF)₂ and Tm(H₃BNMe₂BH₃)₂(THF)₃, which form a cocrystal. IR data and elemental analyses are reported for all the new compounds, as are their crystal structures. ¹H and ¹¹B NMR data are provided where available.« less

Annotation of untargeted high-resolution full-scan LC-MS metabolomics data remains challenging due to individual metabolites generating multiple LC-MS peaks arising from isotopes, adducts and fragments. Adduct annotation is a particular challenge, as the same mass difference between peaks can arise from adduct formation, fragmentation, or different biological species. To address this, here we describe a Buffer Modification Workflow (BMW), in which the same sample is run by LC-MS in both liquid chromatography solvent with ¹⁴NH₃-acetate buffer, and in solvent with the buffer modified with ¹⁵NH₃-formate. Buffer switching results in characteristic mass and signal intensity changes for adduct peaks, facilitating their annotation.more » This relatively simple and convenient chromatography modification annotated yeast metabolomics data with similar effectiveness to growing the yeast in isotope-labeled media. Application to mouse liver data annotated both known metabolite and known adduct peaks with 95% accuracy. Altogether, it identified 26% of ~ 27,000 liver LC-MS features as putative metabolites, of which ~ 2600 showed HMDB or KEGG database formula match. This workflow is well-suited to biological samples that cannot be readily isotope labeled, including plants, mammalian tissues, and tumors.« less

A droplet imbibition experiment is proposed to study interfacial effects, which appears to be the main factor influencing reaction acceleration in charged microdroplets produced by electrospray ionization (ESI). One reagent is deposited onto the surface of rapidly moving microdroplets containing the second reagent to be reacted. In this manner, reactions are hindered from reaching equilibrium and monitored in real time by mass spectrometry. We demonstrated this phenomenon using Katritzky chemistry, which is known to proceed either by the solvent-stabilized 2H-pyran intermediate or via the surface-active pseudobase intermediate. Additionally, comparisons with reactions performed using ESI show obvious surface effects in favormore » of the droplet imbibition experiment. By keeping reactant mole ratio constant, it was demonstrated that similar interfacial effects observed in the droplet imbibition experiment can be reached by allowing ESI microdroplets containing premixed reagents to traverse a distance >16 mm. At such spray distance, molecular diffusion and droplet lifetime become comparable allowing reactants to be enriched at droplet surface. Reactions were also conducted in rapid mixing, theta capillary-based droplets, which showed markedly reduced yields compared with the interfacial droplet imbibition experiment.« less

The fleeting lifetimes of reactive intermediates in C–H functionalization chemistry often prevent their direct characterization. For example, the critical nitrenoid intermediates that mediate Rh₂-catalyzed C–H amination have eluded characterization for more than 40 years. In the absence of structural characterization of these species, methodological development is often computationally guided. Here we report the first X-ray crystal structure of a reactive Rh₂ nitrenoid, enabled by N₂ elimination from an organic azide ligand within a single-crystal matrix. The resulting high-resolution structure displays metrical parameters consistent with a triplet nitrene complex of Rh₂. Furthermore, the demonstration of facile access to reactive metal nitrenoidsmore » within a crystalline matrix provides a platform for structural characterization of the transient species at the heart of C–H functionalization.« less