2936-08-5Relevant articles and documents
Incorporation of [3H]valproic acid into lipids in GT1-7 neurons
Siafaka-Kapadai, Athanassia,Patiris, Marinis,Bowden, Charles,Javors, Martin
, p. 207 - 212 (1998)
Valproic acid (2-propylpentanoic acid, valproate, VPA), an 8-carbon, branched chain fatty acid, is effectively used in the treatment of mania and epilepsy. The biochemical mechanisms by which this drug has its therapeutic effects are not yet established. The purpose of this study was to partially characterize the incorporation of [3H]VPA into phospholipids of GT1-7 neurons, an immortalized hypothalamic cell line. GT1-7 neurons were grown to confluence in culture dishes, and then were incubated with various concentrations of [3H]VPA between 10 and 400 μg/mL for various times up to 20 hr. Total lipids were extracted and phospholipids were separated from neutral lipids using TLC. Our results indicate that [3H]VPA (10 μg/mL) was incorporated into phospholipids of GT1-7 neurons in a time-dependent and saturable manner over 300 min. Subsequent separation of the lipid fraction by TLC indicated that 44.4% of the radioactivity taken up by the cells was incorporated into phospholipids and neutral lipids. One of the phospholipids migrated with a slightly lower R(f) value than authentic phosphatidylcholine. Our results show that the incorporation of VPA into phospholipids and glycerides was linear with VPA concentrations from 10 to 400 μg/mL. Finally, we synthesized 1-acyl-2-valproyl-sn-glycero-3-phosphocholine and validated its structure with nuclear magnetic resonance and electrospray mass spectrometry to verify the structure of this compound, confirming that this compound is structurally possible. We conclude that VPA is incorporated into lipids in GT1-7 neurons and discuss the possible effects of valproyl phospholipids on neuronal functional properties. Copyright (C) 1998 Elsevier Science, Inc.
Novel phosphinic and phosphonic acid analogues of the anticonvulsant valproic acid
Kehler, Jan,Hansen, Henrik I.,Sanchez, Connie
, p. 2547 - 2548 (2000)
1-Propylbutylphosphinic acid 2, (1-propylbutyl)methylphosphinic acid 3 and 1-propylbutylphosphonic acid 4 have been synthesized as bioisosteres of the corresponding carboxylic acid valproate 1, which is a potent anticonvulsant. The novel phosphinic and phosphonic acids were tested for their anticonvulsant activity and were found to be inactive. (C) 2000 Elsevier Science Ltd.
Practical aspects of cyclic voltammetry: How to estimate reduction potentials when irreversibility prevails
Espinoza, Eli M.,Clark, John A.,Soliman, Joey,Derr, James B.,Morales, Maryann,Vullev, Valentine I.
, p. H3175 - H3187 (2019)
What is the best approach for estimating standard electrochemical potentials, E(0), from voltammograms that exhibit chemical irreversibility? The lifetimes of the oxidized or reduced forms of the majority of known redox species are considerably shorter than the voltammetry acquisition times, resulting in irreversibility and making the answer to this question of outmost importance. Halfwave potentials, E(1/2), provide the best experimentally obtainable representation of E(0). Due to irreversible oxidation or reduction, however, the lack of cathodic or anodic peaks in cyclic voltammograms renders E(1/2) unattainable. Therefore, we evaluate how closely alternative potentials, readily obtainable from irreversible voltammograms, estimate E(0). Our analysis reveals that, when E(1/2) is not available, inflection-point potentials provide the best characterization of redox couples. While peak potentials are the most extensively used descriptor for irreversible systems, they deviate significantly from E(0), especially at high scan rates. Even for partially irreversible systems, when the cathodic peak is not as pronounced as the anodic one, the half-wave potentials still provide the best estimates for E(0). The importance of these findings extends beyond the realm of electrochemistry and impacts fields, such as materials engineering, photonics, cell biology, solar energy engineering and neuroscience, where cyclic voltammetry is a key tool.
Molecular modeling and LC–MS-based metabolomics of a glutamine-valproic acid (Gln-VPA) derivative on HeLa cells
Fragoso-Vázquez,Méndez-Luna,Rosales-Hernández,Luna-Palencia,Estrada-Pérez,Fromager, Benedicte,Vásquez-Moctezuma,Correa-Basurto
, p. 1077 - 1089 (2021)
Abstract: Glutaminase plays an important role in carcinogenesis and cancer cell growth. This biological target is interesting against cancer cells. Therefore, in this work, in silico [docking and molecular dynamics (MD) simulations] and in vitro methods (antiproliferative and LC–MS metabolomics) were employed to assay a hybrid compound derived from glutamine and valproic acid (Gln-VPA), which was compared with 6-diazo-5-oxo-l-norleucine (DON, a glutaminase inhibitor) and VPA (contained in Gln-VPA structure). Docking results from some snapshots retrieved from MD simulations show that glutaminase recognized Gln-VPA and DON. Additionally, Gln-VPA showed antiproliferative effects in HeLa cells and inhibited glutaminase activity. Finally, the LC–MS-based metabolomics studies on HeLa cells treated with either Gln-VPA (IC60 = 8?mM) or DON (IC50 = 3.5?mM) show different metabolomics behaviors, suggesting that they modulate different biological targets of the cell death mechanism. In conclusion, Gln-VPA is capable of interfering with more than one pharmacological target of cancer, making it an interesting drug that can be used to avoid multitherapy of classic anticancer drugs. Graphic abstract: [Figure not available: see fulltext.].
COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
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Paragraph 00135-00136, (2020/02/23)
The compositions and compounds of formula I and formula II which includes nucleic acid synthesis inhibitor conjugates or its polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These conjugates may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral administration, intravenous, solution, syrup, sachet, transdermal administration, or injection. Such compositions may be used to treatment of cancer or its associated complications.
Anti-epileptic activity, toxicity and teratogenicity in CD1 mice of a novel valproic acid arylamide derivative, N-(2-hydroxyphenyl)-2-propylpentanamide
Chamorro-Cevallos, Germán,Correa-Basurto, José,Cristóbal-Luna, José Melesio,Mendoza-Figueroa, Humberto L.
, (2020/05/25)
N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (～60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.
