Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 34

Publication Record

Connections

To Avoid Chasing Incorrect Chemical Structures of Chiral Compounds: Raman Optical Activity and Vibrational Circular Dichroism Spectroscopies.
Polavarapu PL, Covington CL, Raghavan V
(2017) Chemphyschem 18: 2459-2465
MeSH Terms: Alcohols, Alkynes, Circular Dichroism, Furans, Ketones, Lactones, Molecular Structure, Quantum Theory, Sesquiterpenes, Spectrum Analysis, Raman
Show Abstract · Added April 10, 2018
A chemical structure (CS) identifies the connectivities between atoms, and the nature of those connections, for a given elemental composition. For chiral molecules, in addition to the identification of CS, the identification of the correct absolute configuration (AC) is also needed. Several chiral natural products are known whose CSs were initially misidentified and later corrected, and these errors were often discovered during the total synthesis of natural products. In this work, we present a new and convenient approach that can be used with Raman optical activity (ROA) and vibrational circular dichroism (VCD) spectroscopies, to distinguish between the correct and incorrect CSs of chiral compounds. This approach involves analyzing the spectral similarity overlap between experimental spectra and those predicted with advanced quantum chemical theories. Significant labor needed for establishing the correct CSs via chemical syntheses of chiral natural products can thus be avoided.
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
0 Resources
MeSH Terms
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.
Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 1869-72
MeSH Terms: Allosteric Regulation, Central Nervous System, Coumarins, Dose-Response Relationship, Drug, Drug Discovery, Drug Stability, Furans, Humans, Isoindoles, Molecular Structure, Phthalimides, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added April 6, 2017
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.
Garcia-Barrantes PM, Cho HP, Metts AM, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 751-756
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, Coumarins, Furans, Half-Life, Heterocyclic Compounds, Humans, Protein Binding, Rats, Receptors, Metabotropic Glutamate, Schizophrenia, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
13 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.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Association of plasma F2-isoprostanes and isofurans concentrations with erythropoiesis-stimulating agent resistance in maintenance hemodialysis patients.
Rivara MB, Ikizler TA, Ellis CD, Mehrotra R, Himmelfarb J
(2015) BMC Nephrol 16: 79
MeSH Terms: Adult, Aged, Anemia, C-Reactive Protein, Drug Resistance, F2-Isoprostanes, Female, Furans, Hematinics, Humans, Inflammation, Interleukin-6, Iron, Kidney Failure, Chronic, Linear Models, Male, Middle Aged, Oxidative Stress, Prospective Studies, Renal Dialysis
Show Abstract · Added August 5, 2015
BACKGROUND - In patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD.
METHODS - We analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed.
RESULTS - Patients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (β = 14.9 ng/ml; 95% CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (β = 10.8 mg/l; 95% CI 3.52, 18.1 for hsCRP; β = 10.2 pg/ml; 95% CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI.
CONCLUSIONS - In conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness.
0 Communities
2 Members
0 Resources
20 MeSH Terms
PET radiotracer [¹⁸F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: preliminary investigation.
Perrone MG, Malerba P, Uddin J, Vitale P, Panella A, Crews BC, Daniel CK, Ghebreselasie K, Nickels M, Tantawy MN, Manning HC, Marnett LJ, Scilimati A
(2014) Eur J Med Chem 80: 562-568
MeSH Terms: Animals, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Female, Fluorine Radioisotopes, Furans, Humans, Isoxazoles, Mice, Ovarian Neoplasms, Positron-Emission Tomography, Radioactive Tracers, Radiochemistry, Tomography, X-Ray Computed
Show Abstract · Added May 20, 2014
Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
0 Communities
3 Members
0 Resources
17 MeSH Terms
Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro.
Spinelli SL, Lannan KL, Casey AE, Croasdell A, Curran TM, Henrichs KF, Pollock SJ, Milne GA, Refaai MA, Francis CW, Phipps RP, Blumberg N
(2014) Transfusion 54: 1569-79
MeSH Terms: Blood Platelets, Dinoprost, Erythrocytes, F2-Isoprostanes, Furans, Humans, Immunoassay, Isoprostanes, Reactive Oxygen Species
Show Abstract · Added March 26, 2014
BACKGROUND - Stored red blood cells (RBCs) release hemoglobin (Hb) that leads to oxidative damage, which may contribute to thrombosis in susceptible transfusion recipients. Oxidative stress stimulates the generation of a new class of lipid mediators called F2 -isoprostanes (F2 -IsoPs) and isofurans (IsoFs) that influence cellular behavior. This study investigated RBC-derived F2 -IsoPs and IsoFs during storage and their influence on human platelets (PLTs).
STUDY DESIGN AND METHODS - F2 -IsoP and IsoF levels in RBC supernatants were measured by mass spectrometry during storage and after washing. The effects of stored supernatants, cell-free Hb, or a key F2 -IsoP, 8-iso-prostaglandin F2α (PGF2α ), on PLT function were examined in vitro.
RESULTS - F2 -IsoPs, IsoFs, and Hb accumulated in stored RBC supernatants. Prestorage leukoreduction reduced supernatant F2 -IsoPs and IsoFs levels, which increased again over storage time. Stored RBC supernatants and 8-iso-PGF2α induced PLT activation marker CD62P (P-selectin) expression and prothrombotic thromboxane A2 release. Cell-free Hb did not alter PLT mediator release, but did inhibit PLT spreading. Poststorage RBC washing reduced F2 -IsoP and IsoF levels up to 24 hours.
CONCLUSIONS - F2 -IsoPs and IsoFs are produced by stored RBCs and induce adverse effects on PLT function in vitro, supporting a potential novel role for bioactive lipids in adverse transfusion outcomes. F2 -IsoP and IsoF levels could be useful biomarkers for determining the suitability of blood components for transfusion. A novel finding is that cell-free Hb inhibits PLT spreading and could adversely influence wound healing. Poststorage RBC washing minimizes harmful lipid mediators, and its use could potentially reduce transfusion complications.
© 2013 American Association of Blood Banks.
1 Communities
1 Members
0 Resources
9 MeSH Terms
New insights regarding tissue Se and Hg interactions on oxidative stress from plasma IsoP and IsoF measures in the Canadian Inuit population.
Alkazemi D, Egeland GM, Roberts LJ, Chan HM, Kubow S
(2013) J Lipid Res 54: 1972-9
MeSH Terms: Adolescent, Adult, Canada, F2-Isoprostanes, Female, Furans, Humans, Male, Mercury, Multivariate Analysis, Oxidative Stress, Selenium, Young Adult
Show Abstract · Added March 7, 2014
Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F2-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross-sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F2-IsoPs were inversely correlated with blood Se (r = -0.186, P = 0.005) and toenail Se (r = -0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r = -0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F2-IsoPs were not positively associated with Hg but with Hg:Se (β = 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F2-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Measurement of F2- isoprostanes and isofurans using gas chromatography-mass spectrometry.
Milne GL, Gao B, Terry ES, Zackert WE, Sanchez SC
(2013) Free Radic Biol Med 59: 36-44
MeSH Terms: F2-Isoprostanes, Furans, Gas Chromatography-Mass Spectrometry, Humans, Oxidative Stress
Show Abstract · Added December 5, 2013
F2-Isoprostanes (IsoPs) are isomers of prostaglandin F2α formed from the nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. Since discovery of these molecules by Morrow and Roberts in 1990, F2-IsoPs have been shown to be excellent biomarkers as well as potent mediators of oxidative stress in vivo in humans. Isofurans (IsoFs) are also oxidation products generated from the nonenzymatic oxidation of arachidonic acid. IsoFs are preferentially formed instead of F2-IsoPs in settings of increased oxygen tension. The protocol presented herein is the current methodology that our laboratory uses to quantify F2-IsoPs and IsoFs in biological tissues and fluids using gas chromatography/mass spectrometry (GC/MS). A variety of analytical procedures to measure F2-IsoPs, including other GC/MS methods and liquid chromatography/MS and immunological approaches, are reported in the literature. This method provides a very low limit of quantitation and is suitable for analysis of both F2-IsoPs and IsoFs from a variety of biological sources including urine, plasma, tissues, cerebral spinal fluid, exhaled breath condensate, and amniotic fluid, among others.
Copyright © 2012 Elsevier Inc. All rights reserved.
2 Communities
1 Members
0 Resources
5 MeSH Terms
Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress.
Bastarache JA, Sebag SC, Clune JK, Grove BS, Lawson WE, Janz DR, Roberts LJ, Dworski R, Mackman N, Ware LB
(2012) Thorax 67: 1032-9
MeSH Terms: Acute Lung Injury, Analysis of Variance, Animals, Blotting, Western, Bronchoalveolar Lavage, Cytokines, Electrophoresis, Polyacrylamide Gel, Furans, Hemoglobins, Hemorrhage, Inflammation, Isoprostanes, Lipopolysaccharides, Mice, Mice, Knockout, Oxidative Stress, Pulmonary Alveoli, Real-Time Polymerase Chain Reaction, Statistics, Nonparametric, Thromboplastin
Show Abstract · Added March 7, 2014
BACKGROUND - Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury.
METHODS - LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h.
RESULTS - Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4×10(5) wild-type (WT) LPS vs 3.3×10(5) LTF LPS, p=0.947) and protein (493 μg/ml WT LPS vs 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F(2) isoprostanes and isofurans).
CONCLUSIONS - These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI.
0 Communities
3 Members
0 Resources
20 MeSH Terms