- Inactivation of nitric oxide by uric acid
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The 1980 identification of nitric oxide (NO) as an endothelial cell-derived relaxing factor resulted in an unprecedented biomedical research of NO and established NO as one of the most important cardiovascular, nervous and immune system regulatory molecule. A reduction in endothelial cell NO levels leading to endothelial dysfunction has been identified as a key pathogenic event preceding the development of hypertension, metabolic syndrome, and cardiovascular disease. The reduction in endothelial NO in cardiovascular disease has been attributed to the action of oxidants that either directly react with NO or uncouple its substrate enzyme. In this report, we demonstrate that uric acid (UA), the most abundant antioxidant in plasma, reacts directly with NO in a rapid irreversible reaction resulting in the formation of 6-aminouracil and depletion of NO. We further show that this reaction occurs preferentially with NO even in the presence of oxidants peroxynitrite and hydrogen peroxide and that the reaction is at least partially blocked by glutathione. This study shows a potential mechanism by which UA may deplete NO and cause endothelial dysfunction, particularly under conditions of oxidative stress in which UA is elevated and intracellular glutathione is depleted. Copyright Taylor & Francis Group, LLC.
- Gersch, Christine,Palii, Sergiu P.,Kim, Kyung Mee,Angerhofer, Alexander,Johnson, Richard J.,Henderson, George N.
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- Synthesis and biological evaluation of novel pyrimido[4,5-b]quinoline-2,4- dione derivatives as MDM2 ubiquitin ligase inhibitors
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A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 μM to 9.0 μM.
- Dou, Xiaoxue,Li, Xin,Tao, Liu,Hu, Chunqi,Zhang, Lei,He, Qiaojun,Yang, Bo,Hu, Yongzhou
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p. 581 - 587
(2013/07/28)
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- Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II
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The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
- Raoof, Ali,Depledge, Paul,Hamilton, Niall M.,Hamilton, Nicola S.,Hitchin, James R.,Hopkins, Gemma V.,Jordan, Allan M.,Maguire, Laura A.,McGonagle, Alison E.,Mould, Daniel P.,Rushbrooke, Mathew,Small, Helen F.,Smith, Kate M.,Thomson, Graeme J.,Turlais, Fabrice,Waddell, Ian D.,Waszkowycz, Bohdan,Watson, Amanda J.,Ogilvie, Donald J.
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supporting information
p. 6352 - 6370
(2013/09/23)
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- 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
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Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.
- Dickens, Michael P.,Roxburgh, Patricia,Hock, Andreas,Mezna, Mokdad,Kellam, Barrie,Vousden, Karen H.,Fischer, Peter M.
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p. 6868 - 6877
(2013/11/06)
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- Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds
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Novel deazaflavin-cholestane hybrid compounds, 3′,8′-disubstituted-5′-deazacholest-2,4-dieno[2,3-g]pteridine-2′,4′(3′H,8′H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).
- Shrestha, Ajaya R.,Shindo, Takashi,Ashida, Noriyuki,Nagamatsu, Tomohisa
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body text
p. 8685 - 8696
(2009/04/11)
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- Chemical reactivity of lumazine derivatives. Acid-base and redox reactions of a number of lumazines, deazalumazines, and isoalloxazines. An unusual effect of methyl substitution
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Three lumazines, seven deazalumazines, and two isoalloxazines have been studied and the following chemical properties measured; equilibrium acidity (pKa), equilibrium basicity (pKSH+), polarographic reduction potential (E1/2), and, where applicable, the rates of the general acid and general base catalyzed dissociation of the protons in the C-5 and C-7 methyl groups (kSH+ + A- and kS + A- respectively).The latter quantities were determined by means of isotope exchange or iodination.Structural variations in the substrate produce compatible results in pKa and pKSH+ and, to lesser extents, in E1/2 and in the catalytic rate data.Anomalies in the rate constants appear when a methyl group is present at C-6; it facilitates ionization of the C-5 and C-7 methyl groups, reversing the quite large effect of more distant methyl.Buttressing effects appear to be absent.The effects of methyl substitution are attributed, in part, to (a) resonance stabilization by 5- and 7-methyl groups in the reactant molecules (neutral substrate and conjugate acid), and (b) relief of steric strain in going from essentially aromatic reactants to nonplanar intermediates.The significance of the 6-methyl group in the lumazine-flavin conversion is noted.
- Stewart, Ross,Srinivasan, R.,Gumbley, Stewart J.
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p. 2755 - 2765
(2007/10/02)
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