Department of Chemistry

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    Dissymmetry Factor Spectral Analysis Can Provide Useful Diastereomer Discrimination_Chiral Molecular Structure of an Analogue of (-)-Crispine A
    (ACS Omega, 2019-04) Johnson, Jordan L.; Nair, Divya Sadasivan; Pillai, Sarath Muraleedharan; Johnson, Didimos; Kallingathodii, Zabeera; Ibnusaud, Ibrahim; Polavarapu, Prasad L.
    (1R,10bR)-1'-((R) - 1,2- Dihydroxyethyl) -1-hydrox-8,9-dmiethoxy1,5,6,10b-tetrahydropyrrolo [2,1-a]-isoquinolin-3(2H)-one, an analogue of (-)-crispine A, with three stereogenic centers is synthesized and its absolute configuration (AC) established using the combined information derived from the synthetic scheme and single crystal X-ray diffraction data. The experimental chiroptical spectra (namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD)) and the corresponding quantum chemical (QC) predicted spectra for all diastereomers are used to evaluate the AC. The AC of the synthesized compound could be correctly established using any one of the three chiroptical spectroscopic methods (ORD, ECD, or VCD) when the relative configuration is constrained to be that derived from X-ray data or when the ACs of two of the chiral centers are constrained to be those derived from the synthetic scheme. In the absence of this outside information, the QC predicted ORD, ECD, and VCD for incorrect diastereomers are also found to satisfactorily reproduce the corresponding experimental spectra. Nevertheless, incorrect diastereomers could be eliminated when combined electronic dissymmetry factor (EDF) and vibrational dissymmetry factor (VDF) spectral analyses are included, leaving the correct diastereomer as the sole choice. Thus, the combined EDF and VDF spectral analysis is seen to be a helpful diastereomer discrimination tool.
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    Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy
    (Cell Reports, 2020-02-11) Waterson, Alex G.
    The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.
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    Interlaced crystals having a perfect Bravais lattice and complex chemical order revealed by real-space crystallography
    (2014-11-14) Shen, Xiao; Herna´ndez-Pagan, Emil A; Zhou, Wu; Puzyrev, Yevgeniy S.; Idrobo, Juan-Carlos; Macdonald, Janet E.; Pennycook, Stephen J.; Pantelides, Sokrates T.
    The search for optimal thermoelectric materials aims for structures in which the crystalline order is disrupted to lower the thermal conductivity without degradation of the electron conductivity. Here we report the synthesis and characterisation of ternary nanoparticles (two cations and one anion) that exhibit a new form of crystalline order: an uninterrupted, perfect, global Bravais lattice, in which the two cations exhibit a wide array of distinct ordering patterns within the cation sublattice, forming interlaced domains and phases. Partitioning into domains and phases is not unique; the corresponding boundaries have no structural defects or strain and entail no energy cost. We call this form of crystalline order ‘interlaced crystals’ and present the example of hexagonal CuInS2. Interlacing is possible in multi-cation tetrahedrally bonded compound with an average of two electrons per bond. Interlacing has minimal effect on electronic properties, but should strongly reduce phonon transport, making interlaced crystals attractive for thermoelectric applications.