Silver-Catalyzed Direct Thiolation of Quinones by Activation of Aryl Disulfides to Synthesize Quinonyl Aryl Thioethers

A silver-catalyzed coupling reaction of quinones with aryl disulfides for the synthesis of quinonyl aryl thioethers is described. In the presence of AgOAc (0.2 equiv)/dppp (0.24 equiv) as the catalyst, (NH₄)₂S₂O₈ (3.0 equiv) as the oxidant, and Bu₄NBF₄ (1.0 equiv) as the additive, the reaction is simple, provides high yield (up to 88% yield), and possesses a broad substrate scope. The reaction is believed to proceed via direct activation of disulfides evidenced by observation of a metathesis reaction between two different disulfides placed together under the reaction conditions and ¹³C NMR spectroscopy analysis

Structure–Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents

Historically known for its role in blood coagulation and bone formation, vitamin K (VK) has begun to emerge as an important nutrient for brain function. While VK involvement in the brain has not been fully explored, it is well-known that oxidative stress plays a critical role in neurodegenerative diseases. It was recently reported that VK protects neurons and oligodendrocytes from oxidative injury and rescues Drosophila from mitochondrial defects associated with Parkinson’s disease. In this study, we take a chemical approach to define the optimal and minimum pharmacophore responsible for the neuroprotective effects of VK. In doing so, we have developed a series of potent VK analogues with favorable drug characteristics that provide full protection at nanomolar concentrations in a well-defined model of neuronal oxidative stress. Additionally, we have characterized key cellular responses and biomarkers consistent with the compounds’ ability to rescue cells from oxidative stress induced cell death

A Novel Class of Small Molecule Inhibitors of HDAC6

Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor’s selective toxicity against leukemia

A Novel Class of Small Molecule Inhibitors of HDAC6

Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor’s selective toxicity against leukemia

Development of <i>N</i>‑Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap Group

A novel series of histone deacetylase inhibitors combining <i>N</i>-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (<b>17c</b>, <b>17g</b>, <b>17h</b>, <b>17j</b>, and <b>17k</b>) exhibited comparable, even superior, total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound <b>17a</b> with moderate HDACs inhibition was progressed to isoform selectivity profile, Western blot analysis, and in vivo antitumor assay. Although HDACs isoform selectivity of <b>17a</b> was similar to that of SAHA, our Western blot results indicated that intracellular effects of <b>17a</b> at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time, while the effect on histone H4 acetylation of <b>17a</b> was maintained and even increased. Most importantly, compound <b>17a</b> exhibited promising in vivo antitumor activity in a U937 xenograft model

Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia

One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The <i>N</i>-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogues’ efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells

Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously

Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one <i>ortho</i>-aminoanilide <b>6d</b> and one hydroxamic acid <b>13f</b> exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed <b>6d</b> and <b>13f</b> with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds <b>6d</b> and <b>13f</b> possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively. <b>6d</b> and <b>13f</b> also exhibited uncompromised multiple tyrosine kinases inhibitory activities relative to pazopanib. The intracellular dual inhibition to HDAC and VEGFR of <b>6d</b> and <b>13f</b> was validated by Western blot analysis. In both HUVECs tube formation assay and rat thoracic aorta rings assay, <b>6d</b> and <b>13f</b> showed comparable antiangiogenic potencies to pazopanib. What’s more, <b>6d</b> possessed desirable pharmacokinetic profiles with the oral bioavailability of 72% in SD rats and considerable in vivo antitumor efficacy in a human colorectal adenocarcinoma (HT-29) xenograft model

Cytotoxicity (MTS) assays on resting murine BM cells and human MNCs.

<p>(A) Ficoll-Hypaque-separated murine BM cells were plated in triplicate with 1R-Chl (10, 100, 500, and 1000 nM) without any growth factors or mitogens. After 72 and 96 hours, 20 µL of Celltiter 96 Aqueous One solution (Promega, WI) was added. The absorbances of the MTS metabolites were read corresponding to the numbers of metabolically active cells. (B) Ficoll-Hypaque-separated human MNCs were treated as above, and the viabilities of the cells were assessed after 72 and 96 hours.</p

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

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 IC₅₀s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC₅₀ 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

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 IC₅₀s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC₅₀ 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