502-87-4Relevant academic research and scientific papers
Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor
Engel, Martin,Gee, Yi Sing,Cross, Dale,Maccarone, Alan,Heng, Benjamin,Hulme, Amy,Smith, Grady,Guillemin, Gilles J.,Stringer, Brett W.,Hyland, Christopher J. T.,Ooi, Lezanne
, p. 535 - 550 (2019)
Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. (Figure presented.).
Substituent effects on carbocation stability: The pKR for p-quinone methide
Toteva, Maria M.,Moran, Michael,Amyes, Tina L.,Richard, John P.
, p. 8814 - 8819 (2003)
A value of kH = 1.5 × 10-3 M-1 s-1 has been determined for the generation of simple p-quinone methide by the acid-catalyzed cleavage of 4-hydroxybenzyl alcohol in water at 25 °C and / = 1.0 (NaClO4). This was combined with ks = 5.8 × 106 s-1 for the reverse addition of solvent water to the 4-hydroxybenzyl carbocation [J. Am. Chem. Soc. 2002, 124, 6349-6356] to give pKR = -9.6 as the Lewis acidity constant of O-protonated p-quinone methide. Values of pKR = 2.3 for the Lewis acidity constant of neutral p-quinone methide and pKadd = -7.6 for the overall addition of solvent water to p-quinone methide to form 4-hydroxybenzyl alcohol are also reported. The thermodynamic driving force for transfer of the elements of water from formaldehyde hydrate to p-quinone methide to form formaldehyde and p-(hydroxymethyl)-phenol (4-hydroxybenzyl alcohol) is determined as 6 kcal/mol. This relatively small driving force represents the balance between the much stronger chemical bonds to oxygen at the reactant formaldehyde hydrate than at the product p-(hydroxymethyl) phenol and the large stabilization of product arising from the aromatization that accompanies solvent addition to p-quinone methide. The Marcus intrinsic barrier for nucleophilic addition of solvent water to the "extended" carbonyl group at p-quinone methide is estimated to be 4.5 kcal/mol larger than that for the addition of water to the simple carbonyl group of formaldehyde. O-Alkylation of p-quinone methide to give the 4-methoxybenzyl carbocation and of formaldehyde to give a simple oxocarbenium ion results in very little change in the relative Marcus intrinsic barriers for the addition of solvent water to these electrophiles.
Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: Relationship to toxicity
Thompson,Perera,London
, p. 55 - 60 (1995)
The oxidative metabolism and toxicity of the para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol were studied using male Sprague- Dawley rat liver microsomes and precision-cut liver slices. Reactive intermediates from each compound were trapped using radiolabeled glutathione and were detected and quantified by HPLC. Conjugates were collected and their structures determined by fast atom bombardment mass spectrometry and proton nuclear magnetic resonance. During microsomal incubations each test compound formed monoglutathione conjugates with structures which are consistent with the formation of quinone methide intermediates. In each case the glutathione moiety was attached to the benzylic carbon on the alkyl side chain of the phenol. With ethylphenol, which has a prochiral benzylic carbon, two isomeric conjugates were detected. The rate of formation of the glutathione conjugates in liver slice incubations was 4-isopropylphenol > 4-ethylphenol > 4- methylphenol. This correlated with the toxicity of the three compounds in liver slices. At equimolar concentrations 4-isopropylphenol was the most toxic while 4-methylphenol was the least toxic. Depletion of intracellular glutathione was observed in the presence of each test compound which preceded cell death. Enhancement of cellular thiol levels with N-acetylcysteine protected cells from the toxic effects of all three compounds as did inhibition of cytochrome P450 activity with metyrapone. These results suggest the formation of quinone methide intermediates from three alkylphenols during oxidative metabolism and demonstrate a correlation between the amount of reactive intermediate formed and toxicity observed in liver slices.
Endogenous peroxynitrite activated fluorescent probe for revealing anti‐tuberculosis drug induced hepatotoxicity
Ji, Xin,Liu, Jinying,Su, Huihui,Wang, Han,Wang, Jiamin,Wang, Nannan,Zhang, Jian,Zhao, Weili
supporting information, (2021/10/12)
Pyrazinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxynitrite (ONOO–) generated in liver has long been regarded as a biomarker for the prediction and measurement of drug-induced liver injury (DILI). In this article, we constructed a BODIPY-based fluorescent probe (BDP-Py+) that enabled quickly and sensitively detect and image ONOO– in vivo. Utilizing this probe, we demonstrated the change of ONOO– content in cells and mice model of DILI induced by acetaminophen (APAP), and for the first time revealed the mechanism of liver injury induced by antituberculosis drug PZA. Moreover, BDP-Py+ could be applied to screen out and evaluate the hepatotoxicity of different anti-tuberculosis drugs. Comparing with the existing serum enzymes detection and H&E staining, the probe could achieve early diagnosis of DILI before solid lesions in liver via monitoring the up-regulation of ONOO– levels. Collectively, this work will promote the understanding of the pathogenesis of anti-tuberculosis drug induced liver injury (ATB-DILI), and provide a powerful tool for the early diagnosis and treatment of DILI.
Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood
Degner, Amanda,Carlsson, Henrik,Karlsson, Isabella,Eriksson, Johan,Pujari, Suresh S.,Tretyakova, Natalia Y.,T?rnqvist, Margareta
, p. 1305 - 1314 (2018/12/11)
Humans are exposed to a wide range of electrophilic compounds present in our diet and environment or formed endogenously as part of normal physiological processes. These electrophiles can modify nucleophilic sites of proteins and DNA to form covalent addu
Visible-Light-Triggered Uncaging of Carbonyl Sulfide for Hydrogen Sulfide (H2S) Release
Sharma, Ajay Kumar,Nair, Mrutyunjay,Chauhan, Preeti,Gupta, Kavya,Saini, Deepak K.,Chakrapani, Harinath
supporting information, p. 4822 - 4825 (2017/09/22)
Generation of hydrogen sulfide (H2S) is challenging and few methods are capable of localized delivery of this gas. Here, a boron dipyrromethene-based carbamothioate (BDP-H2S) that is uncaged by visible light of 470 nm to generate carbonyl sulfide (COS), which is rapidly hydrolyzed to H2S in the presence of carbonic anhydrase, a widely prevalent enzyme, is reported.
Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H2S Donors
Steiger, Andrea K.,Marcatti, Michela,Szabo, Csaba,Szczesny, Bartosz,Pluth, Michael D.
, p. 2117 - 2123 (2017/08/23)
Hydrogen sulfide (H2S) is an important biological mediator, and synthetic H2S donating molecules provide an important class of investigative tools for H2S research. Here, we report esterase-activated H2S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2S or the common H2S donors GYY4137 and AP39. Using cellular bioenergetics measurements, we establish that the developed donors reduce cellular respiration and ATP synthesis in BEAS 2B human lung epithelial cells, which is consistent with COS/H2S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H2S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H2S in certain biological contexts or that the developed donors are more efficient at delivering H2S than other common H2S-releasing motifs.
COMPOUNDS AS STIMULI-RESPONSIVE PROBES, METHODS AND APPLICATIONS THEREOF
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Page/Page column 37; 38, (2017/03/14)
The present disclosure relates to the field of synthetic pharmaceutical chemistry and biology. The disclosure provides a compound of Formula I and a process of preparation thereof. The disclosure further relates to methods and use of Formula I compounds a
A switchable electrochemical redox ratiometric substrate based on ferrocene for highly selective and sensitive fluoride detection
Manibalan, Kesavan,Mani, Veerappan,Huang, Sheng-Tung
, p. 71727 - 71732 (2016/08/05)
A novel latent electrochemical probe based on a ferrocenyl carbamate derivate (FCCD) was synthesized for the highly selective ratiometric detection of fluoride (F-). FCCD was synthesized through an easy, one step reaction using ferrocenyl azide and silyl protected benzyl alcohol as precursors through a Curtius rearrangement. In presence of F-, FCCD undergoes a nucleophilic substitution reaction, which led to the removal of silyl protecting group through 1,6-quinone-methide rearrangement with concomitant release of ferrocenyl amine (FA). As the concentration of F- increases, the amount of FCCD is dissipated, while that of FA accumulated in the reaction medium were monitored through the linear changes in their redox couples. Compared with a conventional ion selective electrode, the use of a cheaper unmodified electrode as a transducer coupled with FCCD displayed higher stability, excellent selectivity and better sensitivity with LOD of 5.1 × 10-7 M (9.69 ppb). Moreover, FCCD is a selective and sensitive colorimetric visualization probe for F-. The proof-of-concept of the approach is demonstrated in direct toothpaste sample (non-transparent solutions), biological and water samples. The important advantages of this approach are high selectivity, the use of cheaper unmodified electrode, adoption of simple electrochemical methods, dual channel detection, low overpotential of the reporter, naked-eye detection, and ability to detect F- in non-transparent samples.
Improved synthesis of gastrodin, a bioactive component of a traditional chinese medicine
Li, Yu-Wen,Ma, Cui-Li
, p. 1205 - 1212 (2015/01/30)
Highly practical, four-step synthesis of gastrodin was developed using penta- O-acetyl-β-D-glucopyranose and p-cresol as glycosyl donor and glycosyl acceptor, respectively, in 58.1% overall yield. As the initial step, the penta-O-acetyl-β-D-glucopyranose was treated with p-cresol in the presence of BF3 ?Et2O as catalyst to generate 4-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D- -glucopyranoside in 76.3% yield. Further, this product was subjected to radical bromination with N-bromosuccinimide (NBS) to provide 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 91% yield. Subsequently, reaction of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside with a solution of acetone and saturated aqueous sodium bicarbonate led to 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 93% yield. Finally, global deprotection of 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O- -acetyl-β- D-glucopyranoside under Zemplen conditions furnished gastrodin in 90% yield. Compared to the previously reported methods, this protocol has the advantages of operational simplicity, chromatography-free separation, high overall yield, inexpensive and common reagents as well as less waste pollutants, rendering it an alternative suitable for industrial production.
