3 research outputs found

    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

    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

    Optimization of N‑Substituted Oseltamivir Derivatives as Potent Inhibitors of Group‑1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

    No full text
    On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, <b>15b</b> and <b>15c</b> were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80–12.47 and 1.20–3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. <b>15b</b> demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of <b>15b</b> in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents
    corecore