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Absolute Configuration of (-)-Centratherin, a Sesquiterpenoid Lactone, Defined by Means of Chiroptical Spectroscopy.
Junior FM, Covington CL, de Albuquerque AC, Lobo JF, Borges RM, de Amorim MB, Polavarapu PL
(2015) J Nat Prod 78: 2617-23
MeSH Terms: Circular Dichroism, Lactones, Models, Chemical, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Optical Rotatory Dispersion, Sesquiterpenes, Stereoisomerism
Show Abstract · Added February 15, 2016
(-)-Centratherin is a bioactive sesquiterpenoid lactone, whose absolute configuration (AC) was not established, but has been proposed based on those of germacrane precursors. To verify this proposal, the experimental electronic circular dichroism (ECD), electronic dissymmetry factor (EDF), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD), and vibrational dissymmetry factor (VDF) spectra of (-)-centratherin have been analyzed with the corresponding density functional theoretical predictions. These analyses suggest the AC of naturally occurring (-)-centratherin to be (6R,7R,8S,10R,2'Z).
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8 MeSH Terms
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.
Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2015) Bioorg Med Chem Lett 25: 5107-10
MeSH Terms: Allosteric Regulation, Animals, Brain, Coumarins, Furans, Humans, Microsomes, Liver, Phthalimides, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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2 Members
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12 MeSH Terms
Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents.
Engers JL, Rodriguez AL, Konkol LC, Morrison RD, Thompson AD, Byers FW, Blobaum AL, Chang S, Venable DF, Loch MT, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2015) J Med Chem 58: 7485-500
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Antidepressive Agents, Brain, Calcium, Dogs, Heterocyclic Compounds, 2-Ring, Humans, Madin Darby Canine Kidney Cells, Mice, Microsomes, Liver, Permeability, Pyridines, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.
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3 Members
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18 MeSH Terms
Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility-Mass Spectrometry, Tandem Mass Spectrometry, and Computational Strategies. 2. Electrospray Spectra of 3-Ring and 4-Ring Isomers.
Stow SM, Onifer TM, Forsythe JG, Nefzger H, Kwiecien NW, May JC, McLean JA, Hercules DM
(2015) Anal Chem 87: 6288-96
MeSH Terms: Aniline Compounds, Computer Simulation, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Stereoisomerism, Tandem Mass Spectrometry
Show Abstract · Added December 17, 2018
Building on results from our previous study of 2-ring methylenedianiline (MDA), a combined mass spectrometry approach utilizing ion mobility-mass spectrometry (IM-MS) and tandem mass spectrometry (MS/MS) coupled with computational methods enables the structural characterization of purified 3-ring and 4-ring MDA regioisomers in this current study. The preferred site of protonation for the 3-ring and 4-ring MDA was determined to be on the amino groups. Additionally, the location of the protonated amine along the MDA multimer was found to influence the gas phase stability of these molecules. Fragmentation mechanisms similar to the 2-ring MDA species were observed for both the 3-ring and 4-ring MDA. The structural characterization of 3-ring and 4-ring MDA isomers using modern MS techniques may aid polyurethane synthesis by the characterization of industrial grade MDA, multimeric MDA species, and methylene diphenyl diisocyanate (MDI) mixtures.
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MeSH Terms
DNA Sequence Modulates Geometrical Isomerism of the trans-8,9- Dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)- 9-hydroxy Aflatoxin B1 Adduct.
Li L, Brown KL, Ma R, Stone MP
(2015) Chem Res Toxicol 28: 225-37
MeSH Terms: Aflatoxin B1, Base Sequence, Cytidine, DNA, Magnetic Resonance Spectroscopy, Stereoisomerism
Show Abstract · Added January 20, 2015
Aflatoxin B(1) (AFB(1)), a mycotoxin produced by Aspergillus flavus, is oxidized by cytochrome P450 enzymes to aflatoxin B(1)-8,9-epoxide, which alkylates DNA at N7-dG. Under basic conditions, this N7-dG adduct rearranges to yield the trans-8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy aflatoxin B(1) (AFB(1)−FAPY) adduct. The AFB(1)−FAPY adduct exhibits geometrical isomerism involving the formamide moiety. NMR analyses of duplex oligodeoxynucleotides containing the 5′-XA-3′, 5′-XC-3′, 5′-XT-3′, and 5′-XY-3′ sequences (X = AFB(1)−FAPY; Y = 7-deaza-dG)demonstrate that the equilibrium between E and Z isomers is controlled by major groove hydrogen bonding interactions.Structural analysis of the adduct in the 5′-XA-3′ sequence indicates the preference of the E isomer of the formamide group,attributed to formation of a hydrogen bond between the formyl oxygen and the N(6) exocyclic amino group of the 3′-neighboradenine. While the 5′-XA-3′ sequence exhibits the E isomer, the 5′-XC-3′ sequence exhibits a 7:3 E:Z ratio at equilibrium at 283K. The E isomer is favored by a hydrogen bond between the formyl oxygen and the N(4)-dC exocyclic amino group of the 3′-neighbor cytosine. The 5′-XT-3′ and 5′-XY-3′ sequences cannot form such a hydrogen bond between the formyl oxygen and the 3′-neighbor T or Y, respectively, and in these sequence contexts the Z isomer is favored. Additional equilibria between α and β anomers and the potential to exhibit atropisomers about the C5−N(5) bond do not depend upon sequence. In each of the four DNA sequences, the AFB(1)−FAPY adduct maintains the β deoxyribose configuration. Each of these four sequences feature the atropisomer of the AFB(1) moiety that is intercalated above the 5′-face of the damaged guanine. This enforces the Ra axialc onformation for the C5−N(5) bond.
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6 MeSH Terms
Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction.
Teder T, Boeglin WE, Brash AR
(2014) J Lipid Res 55: 2587-96
MeSH Terms: 8,11,14-Eicosatrienoic Acid, Animals, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Biocatalysis, Blood Platelets, Chromatography, High Pressure Liquid, Eicosanoids, Epoxy Compounds, Gas Chromatography-Mass Spectrometry, Humans, Hydroxylation, Linolenic Acids, Lipid Peroxides, Lipoxygenase, Mice, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Recombinant Proteins, Soybean Proteins, Spectrometry, Mass, Electrospray Ionization, Stereoisomerism
Show Abstract · Added January 21, 2015
Herein, we characterize a generally applicable transformation of fatty acid epoxides by lipoxygenase (LOX) enzymes that results in the formation of a five-membered endoperoxide ring in the end product. We demonstrated this transformation using soybean LOX-1 in the metabolism of 15,16-epoxy-α-linolenic acid, and murine platelet-type 12-LOX and human 15-LOX-1 in the metabolism of 14,15-epoxyeicosatrienoic acid (14,15-EET). A detailed examination of the transformation of the two enantiomers of 15,16-epoxy-α-linolenic acid by soybean LOX-1 revealed that the expected primary product, a 13S-hydroperoxy-15,16-epoxide, underwent a nonenzymatic transformation in buffer into a new derivative that was purified by HPLC and identified by UV, LC-MS, and ¹H-NMR as a 13,15-endoperoxy-16-hydroxy-octadeca-9,11-dienoic acid. The configuration of the endoperoxide (cis or trans side chains) depended on the steric relationship of the new hydroperoxy moiety to the enantiomeric configuration of the fatty acid epoxide. The reaction mechanism involves intramolecular nucleophilic substitution (SNi) between the hydroperoxy (nucleophile) and epoxy group (electrophile). Equivalent transformations were documented in metabolism of the enantiomers of 14,15-EET by the two mammalian LOX enzymes, 15-LOX-1 and platelet-type 12-LOX. We conclude that this type of transformation could occur naturally with the co-occurrence of LOX and cytochrome P450 or peroxygenase enzymes, and it could also contribute to the complexity of products formed in the autoxidation reactions of polyunsaturated fatty acids.
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
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23 MeSH Terms
Major groove orientation of the (2S)-N(6)-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine DNA adduct induced by 1,2-epoxy-3-butene.
Kowal EA, Wickramaratne S, Kotapati S, Turo M, Tretyakova N, Stone MP
(2014) Chem Res Toxicol 27: 1675-86
MeSH Terms: Alkylation, Butadienes, DNA, DNA Adducts, Deoxyadenosines, Epoxy Compounds, Humans, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Nucleic Acid Conformation, Nucleic Acid Denaturation, Oligodeoxyribonucleotides, Stereoisomerism, Transition Temperature, ras Proteins
Show Abstract · Added January 20, 2015
1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. It is oxidized by cytochrome P450 monooxygenases to 1,2-epoxy-3-butene (EB), which alkylates DNA. BD exposures lead to large numbers of mutations at A:T base pairs even though alkylation of guanines is more prevalent, suggesting that one or more adenine adducts of BD play a role in BD-mediated genotoxicity. However, the etiology of BD-mediated genotoxicity at adenine remains poorly understood. EB alkylates the N(6) exocyclic nitrogen of adenine to form N(6)-(hydroxy-3-buten-1-yl)-2'-dA ((2S)-N(6)-HB-dA) adducts ( Tretyakova , N. , Lin , Y. , Sangaiah , R. , Upton , P. B. , and Swenberg , J. A. ( 1997 ) Carcinogenesis 18 , 137 - 147 ). The structure of the (2S)-N(6)-HB-dA adduct has been determined in the 5'-d(C(1)G(2)G(3)A(4)C(5)Y(6)A(7)G(8)A(9)A(10)G(11))-3':5'-d(C(12)T(13)T(14)C(15)T(16)T(17)G(18)T(19) C(20)C(21)G(22))-3' duplex [Y = (2S)-N(6)-HB-dA] containing codon 61 (underlined) of the human N-ras protooncogene, from NMR spectroscopy. The (2S)-N(6)-HB-dA adduct was positioned in the major groove, such that the butadiene moiety was oriented in the 3' direction. At the Cα carbon, the methylene protons of the modified nucleobase Y(6) faced the 5' direction, which placed the Cβ carbon in the 3' direction. The Cβ hydroxyl group faced toward the solvent, as did carbons Cγ and Cδ. The Cβ hydroxyl group did not form hydrogen bonds with either T(16) O(4) or T(17) O(4). The (2S)-N(6)-HB-dA nucleoside maintained the anti conformation about the glycosyl bond, and the modified base retained Watson-Crick base pairing with the complementary base (T(17)). The adduct perturbed stacking interactions at base pairs C(5):G(18), Y(6):T(17), and A(7):T(16) such that the Y(6) base did not stack with its 5' neighbor C(5), but it did with its 3' neighbor A(7). The complementary thymine T(17) stacked well with both 5' and 3' neighbors T(16) and G(18). The presence of the (2S)-N(6)-HB-dA resulted in a 5 °C reduction in the Tm of the duplex, which is attributed to less favorable stacking interactions and adduct accommodation in the major groove.
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15 MeSH Terms
Absolute Configuration of a Rare Sesquiterpene: (+)-3-Ishwarone.
Junior FM, Covington CL, de Amorim MB, Velozo LS, Kaplan MA, Polavarapu PL
(2014) J Nat Prod 77: 1881-6
MeSH Terms: Algorithms, Brazil, Circular Dichroism, Molecular Structure, Optical Rotatory Dispersion, Peperomia, Plant Components, Aerial, Sesquiterpenes, Stereoisomerism
Show Abstract · Added February 12, 2015
To determine the absolute configuration of 3-ishwarone, the experimental electronic circular dichroism (ECD), electronic dissymmetry factor (EDF), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD), and vibrational dissymmetry factor (VDF) spectra of (+)-3-ishwarone are analyzed with the corresponding density functional theoretical predictions for different diastereomers. ECD and ORD spectra by themselves could not facilitate the determination of the absolute configuration of this molecule. However, the magnitude of the experimental EDF of (+)-3-ishwarone is found to match better with that predicted for the (1R,2S,4S,5R,9R,11R) diastereomer. The analyses of similarity measures between experimental and predicted spectra for VCD and VDF clearly suggested that the absolute configuration of (+)-3-ishwarone is (1R,2S,4S,5R,9R,11R).
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9 MeSH Terms
Structure and Stereochemical Determination of Hypogeamicins from a Cave-Derived Actinomycete.
Derewacz DK, McNees CR, Scalmani G, Covington CL, Shanmugam G, Marnett LJ, Polavarapu PL, Bachmann BO
(2014) J Nat Prod 77: 1759-63
MeSH Terms: Actinobacteria, Caves, Circular Dichroism, Humans, Models, Molecular, Molecular Conformation, Molecular Structure, Naphthoquinones, Nuclear Magnetic Resonance, Biomolecular, Optical Rotatory Dispersion, Stereoisomerism
Show Abstract · Added February 12, 2015
Culture extracts from the cave-derived actinomycete Nonomuraea specus were investigated, resulting in the discovery of a new S-bridged pyronaphthoquinone dimer and its monomeric progenitors designated hypogeamicins A-D (1-4). The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds. Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners. Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.
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11 MeSH Terms
Structural basis for rational design of inhibitors targeting Trypanosoma cruzi sterol 14α-demethylase: two regions of the enzyme molecule potentiate its inhibition.
Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI
(2014) J Med Chem 57: 6704-17
MeSH Terms: 14-alpha Demethylase Inhibitors, Carbamates, Crystallography, X-Ray, Drug Design, Imidazoles, Models, Molecular, Protein Binding, Protein Conformation, Stereoisomerism, Sterol 14-Demethylase, Trypanocidal Agents, Trypanosoma cruzi
Show Abstract · Added February 12, 2015
Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.
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12 MeSH Terms