6 research outputs found

    Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

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    Previously, we designed and synthesized a series of <i>o</i>-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound <b>11a</b> exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using <b>11a</b> as a lead. Representative compound <b>13b</b> showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound <b>13e</b> exhibited low nanomolar IC<sub>50</sub>s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC<sub>50</sub> of <b>13e</b> against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound <b>11a</b>. <i>In vitro</i> responses to <b>13e</b> vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, <b>13e</b> induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, <b>13e</b> caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis

    Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

    No full text
    Previously, we designed and synthesized a series of <i>o</i>-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound <b>11a</b> exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using <b>11a</b> as a lead. Representative compound <b>13b</b> showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound <b>13e</b> exhibited low nanomolar IC<sub>50</sub>s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC<sub>50</sub> of <b>13e</b> against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound <b>11a</b>. <i>In vitro</i> responses to <b>13e</b> vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, <b>13e</b> induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, <b>13e</b> caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis

    Mechanistic Insights into the Oxidation of Substituted Phenols via Hydrogen Atom Abstraction by a Cupric–Superoxo Complex

    No full text
    To obtain mechanistic insights into the inherent reactivity patterns for copper­(I)–O<sub>2</sub> adducts, a new cupric–superoxo complex [(DMM-tmpa)­Cu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>2</b>) [DMM-tmpa = tris­((4-methoxy-3,5-di­methyl­pyridin-2-yl)­methyl)­amine] has been synthesized and studied in phenol oxidation–oxygenation reactions. Compound <b>2</b> is characterized by UV–vis, resonance Raman, and EPR spectroscopies. Its reactions with a series of <i>para</i>-substituted 2,6-di-<i>tert</i>-butyl­phenols (<i>p</i>-X-DTBPs) afford 2,6-di-<i>tert</i>-butyl-1,4-benzo­quinone (DTBQ) in up to 50% yields. Significant deuterium kinetic isotope effects and a positive correlation of second-order rate constants (<i>k</i><sub>2</sub>) compared to rate constants for <i>p</i>-X-DTBPs plus cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak correlation of (<i>k</i><sub>B</sub><i>T</i>/<i>e</i>) ln <i>k</i><sub>2</sub> versus <i>E</i><sub>ox</sub> of <i>p</i>-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, <sup>18</sup>O-labeling experiments, and separate reactivity employing the 2,4,6-tri-<i>tert</i>-butyl­phenoxyl radical provide further mechanistic insights. After initial HAT, a second molar equiv of <b>2</b> couples to the phenoxyl radical initially formed, giving a Cu<sup>II</sup>–OO–(ArO′) intermediate, which proceeds in the case of <i>p</i>-OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which liberate H<sub>2</sub>O<sub>2</sub> and the corresponding alcohol. By contrast, four-electron oxygenation (O–O cleavage) mainly occurs for <i>p</i>-R-DTBP which gives <sup>18</sup>O-labeled DTBQ and elimination of the R group

    Mechanistic Insights into the Oxidation of Substituted Phenols via Hydrogen Atom Abstraction by a Cupric–Superoxo Complex

    No full text
    To obtain mechanistic insights into the inherent reactivity patterns for copper­(I)–O<sub>2</sub> adducts, a new cupric–superoxo complex [(DMM-tmpa)­Cu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>2</b>) [DMM-tmpa = tris­((4-methoxy-3,5-di­methyl­pyridin-2-yl)­methyl)­amine] has been synthesized and studied in phenol oxidation–oxygenation reactions. Compound <b>2</b> is characterized by UV–vis, resonance Raman, and EPR spectroscopies. Its reactions with a series of <i>para</i>-substituted 2,6-di-<i>tert</i>-butyl­phenols (<i>p</i>-X-DTBPs) afford 2,6-di-<i>tert</i>-butyl-1,4-benzo­quinone (DTBQ) in up to 50% yields. Significant deuterium kinetic isotope effects and a positive correlation of second-order rate constants (<i>k</i><sub>2</sub>) compared to rate constants for <i>p</i>-X-DTBPs plus cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak correlation of (<i>k</i><sub>B</sub><i>T</i>/<i>e</i>) ln <i>k</i><sub>2</sub> versus <i>E</i><sub>ox</sub> of <i>p</i>-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, <sup>18</sup>O-labeling experiments, and separate reactivity employing the 2,4,6-tri-<i>tert</i>-butyl­phenoxyl radical provide further mechanistic insights. After initial HAT, a second molar equiv of <b>2</b> couples to the phenoxyl radical initially formed, giving a Cu<sup>II</sup>–OO–(ArO′) intermediate, which proceeds in the case of <i>p</i>-OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which liberate H<sub>2</sub>O<sub>2</sub> and the corresponding alcohol. By contrast, four-electron oxygenation (O–O cleavage) mainly occurs for <i>p</i>-R-DTBP which gives <sup>18</sup>O-labeled DTBQ and elimination of the R group

    Stepwise Protonation and Electron-Transfer Reduction of a Primary Copper–Dioxygen Adduct

    No full text
    The protonation–reduction of a dioxygen adduct with [LCu<sup>I</sup>]­[B­(C<sub>6</sub>F<sub>5</sub>)<sub>4</sub>], cupric superoxo complex [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>1</b>) (L = TMG<sub>3</sub>tren (1,1,1-tris­[2-[<i>N</i><sup>2</sup>-(1,1,3,3-tetramethylguanidino)]­ethyl]­amine)) has been investigated. Trifluoroacetic acid (HOAc<sub>F</sub>) reversibly associates with the superoxo ligand in ([LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup>) in a 1:1 adduct [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)­(HOAc<sub>F</sub>)]<sup>+</sup> (<b>2</b>), as characterized by UV–visible, resonance Raman (rR), nuclear magnetic resonance (NMR), and X-ray absorption (XAS) spectroscopies, along with density functional theory (DFT) calculations. Chemical studies reveal that for the binding of HOAc<sub>F</sub> with <b>1</b> to give <b>2</b>, <i>K</i><sub>eq</sub> = 1.2 × 10<sup>5</sup> M<sup>–1</sup> (−130 °C) and Δ<i>H</i><sup>o</sup> = −6.9(7) kcal/mol, Δ<i>S</i><sup>o</sup> = −26(4) cal mol<sup>–1</sup> K<sup>–1</sup>). Vibrational (rR) data reveal a significant increase (29 cm<sup>–1</sup>) in <i>v</i><sub>O–O</sub> (= 1149 cm<sup>–1</sup>) compared to that known for [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>1</b>). Along with results obtained from XAS and DFT calculations, hydrogen bonding of HOAc<sub>F</sub> to a superoxo O-atom in <b>2</b> is established. Results from NMR spectroscopy of <b>2</b> at −120 °C in 2-methyltetrahydrofuran are also consistent with <b>1</b>/HOAc<sub>F</sub> = 1:1 formulation of <b>2</b> and with this complex possessing a triplet (<i>S</i> = 1) ground state electronic configuration, as previously determined for <b>1</b>. The pre-equilibrium acid association to <b>1</b> is followed by outer-sphere electron-transfer reduction of <b>2</b> by decamethylferrocene (Me<sub>10</sub>Fc) or octamethylferrocene (Me<sub>8</sub>Fc), leading to the products H<sub>2</sub>O<sub>2</sub>, the corresponding ferrocenium salt, and [LCu<sup>II</sup>(OAc<sub>F</sub>)]<sup>+</sup>. Second-order rate constants for electron transfer (<i>k</i><sub>et</sub>) were determined to be 1365 M<sup>–1</sup> s<sup>–1</sup> (Me<sub>10</sub>Fc) and 225 M<sup>–1</sup> s<sup>–1</sup> (Me<sub>8</sub>Fc) at −80 °C. The (bio)­chemical relevance of the proton-triggered reduction of the metal-bound dioxygen-derived fragment is discussed

    Stepwise Protonation and Electron-Transfer Reduction of a Primary Copper–Dioxygen Adduct

    No full text
    The protonation–reduction of a dioxygen adduct with [LCu<sup>I</sup>]­[B­(C<sub>6</sub>F<sub>5</sub>)<sub>4</sub>], cupric superoxo complex [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>1</b>) (L = TMG<sub>3</sub>tren (1,1,1-tris­[2-[<i>N</i><sup>2</sup>-(1,1,3,3-tetramethylguanidino)]­ethyl]­amine)) has been investigated. Trifluoroacetic acid (HOAc<sub>F</sub>) reversibly associates with the superoxo ligand in ([LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup>) in a 1:1 adduct [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)­(HOAc<sub>F</sub>)]<sup>+</sup> (<b>2</b>), as characterized by UV–visible, resonance Raman (rR), nuclear magnetic resonance (NMR), and X-ray absorption (XAS) spectroscopies, along with density functional theory (DFT) calculations. Chemical studies reveal that for the binding of HOAc<sub>F</sub> with <b>1</b> to give <b>2</b>, <i>K</i><sub>eq</sub> = 1.2 × 10<sup>5</sup> M<sup>–1</sup> (−130 °C) and Δ<i>H</i><sup>o</sup> = −6.9(7) kcal/mol, Δ<i>S</i><sup>o</sup> = −26(4) cal mol<sup>–1</sup> K<sup>–1</sup>). Vibrational (rR) data reveal a significant increase (29 cm<sup>–1</sup>) in <i>v</i><sub>O–O</sub> (= 1149 cm<sup>–1</sup>) compared to that known for [LCu<sup>II</sup>(O<sub>2</sub><sup>•–</sup>)]<sup>+</sup> (<b>1</b>). Along with results obtained from XAS and DFT calculations, hydrogen bonding of HOAc<sub>F</sub> to a superoxo O-atom in <b>2</b> is established. Results from NMR spectroscopy of <b>2</b> at −120 °C in 2-methyltetrahydrofuran are also consistent with <b>1</b>/HOAc<sub>F</sub> = 1:1 formulation of <b>2</b> and with this complex possessing a triplet (<i>S</i> = 1) ground state electronic configuration, as previously determined for <b>1</b>. The pre-equilibrium acid association to <b>1</b> is followed by outer-sphere electron-transfer reduction of <b>2</b> by decamethylferrocene (Me<sub>10</sub>Fc) or octamethylferrocene (Me<sub>8</sub>Fc), leading to the products H<sub>2</sub>O<sub>2</sub>, the corresponding ferrocenium salt, and [LCu<sup>II</sup>(OAc<sub>F</sub>)]<sup>+</sup>. Second-order rate constants for electron transfer (<i>k</i><sub>et</sub>) were determined to be 1365 M<sup>–1</sup> s<sup>–1</sup> (Me<sub>10</sub>Fc) and 225 M<sup>–1</sup> s<sup>–1</sup> (Me<sub>8</sub>Fc) at −80 °C. The (bio)­chemical relevance of the proton-triggered reduction of the metal-bound dioxygen-derived fragment is discussed
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