Catalytic Asymmetric Synthesis of Esomeprazole by a Titanium Complex with a Hexa-aza-triphenolic Macrocycle Ligand

<div><p></p><p>An efficient synthesis of esomeprazole via catalytic asymmetric oxidation of 1<i>H</i>-benzimidazolyl pyridinylmethyl sulfide by a titanium complex with a hexa-aza-triphenolic macrocycle ligand is described. Esomeprazole was prepared with 99.6% <i>ee</i>, which meets the high requirement of the European Pharmacopeia on enantiomeric purity.</p> </div

Development of Synthetic Aminopeptidase N/CD13 Inhibitors to Overcome Cancer Metastasis and Angiogenesis

Cancer metastasis is a major barrier to its treatment and an important cause of patient death. Antimetastatic agents hold promise for patients with advanced metastatic tumors. Aminopeptidase N/CD13 (APN) is being pursued by many as an important target against cancer metastasis and angiogenesis, but there are few reports on the <i>in vivo</i> evaluation of synthetic APN inhibitors. Herein, a series of compounds targeting APN were synthesized and evaluated for their antimetastasis and antiangiogenesis potency both <i>in vitro</i> and <i>in vivo</i>. Excitingly, compounds <b>4m</b>, <b>4t</b>, and <b>4cc</b>, with the most potent APN inhibitory activities, displayed significant antimetastasis and antiangiogenesis effects <i>in vitro</i> and <i>in vivo</i>, suggesting that those synthetic APN inhibitors have the potential to overcome cancer metastasis and angiogenesis

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

Design, Synthesis, and Antitumor Evaluation of 4‑Amino-(1<i>H</i>)‑pyrazole Derivatives as JAKs Inhibitors

Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>–<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC₅₀ values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC₅₀: 0.35 μM) and K562 (IC₅₀: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib

Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC₅₀ values (1.8–1.9 μM). Further studies demonstrated that compound <b>H8-A5</b> was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for <b>H8-A5</b>, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment

Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC₅₀ values (1.8–1.9 μM). Further studies demonstrated that compound <b>H8-A5</b> was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for <b>H8-A5</b>, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment

Discovery of N‑Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase

To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound <b>20l</b> was the most potent N1-selective inhibitor, with IC₅₀ values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound <b>32</b> was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus

Seasonal and Spatial Variations of Bulk Nitrogen Deposition and the Impacts on the Carbon Cycle in the Arid/Semiarid Grassland of Inner Mongolia, China

<div><p>Atmospheric nitrogen (N) deposition is an important component that affects the structure and function of different terrestrial ecosystem worldwide. However, much uncertainty still remains concerning the magnitude of N deposition on grassland ecosystem in China. To study the spatial and temporal patterns of bulk N deposition, the levels of N (NH₄⁺-N and NO₃^--N) concentration in rainfall were measured at 12 sites across a 1200 km grassland transect in Inner Mongolia, China, and the respective N deposition rates were estimated. The inorganic N deposition rates ranged from 4.53 kg N ha^-1 to 12.21 kg N ha^-1 with a mean value of 8.07 kg N ha^-1 during the entire growing season, decreasing steadily from the eastern to the western regions. Inorganic N deposition occurred mainly in July and August across meadow steppe, typical steppe, and desert steppe, which corresponded to the seasonal distribution of mean annual precipitation. A positive relationship was found between inorganic N deposition and mean annual precipitation (R² = 0.54 ~ 0.72, <i>P</i> < 0.0001) across the grassland transect. Annual estimation of inorganic N deposition was 0.67 Pg yr^-1 in Inner Mongolia, China based on the correlation between N deposition rates and precipitation. N deposition was an important factor controlling aboveground biomass and ecosystem respiration, but has no effect on root biomass and soil respiration. We must clarify that we used the bulk deposition samplers during the entire sampling process and estimated the dissolved NH₄⁺-N and NO₃^--N deposition rates during the entire growing season. Long-term N deposition monitoring networks should be constructed to study the patterns of N deposition and its potential effect on grassland ecosystem, considering various N species, i.e., gaseous N, particle N, and wet N deposition.</p></div

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

Dissolved inorganic N deposition and the ratio of NH₄⁺-N/NO₃^--N during the entire growing season at the 12 experimental sites.

<p>Dissolved inorganic N deposition and the ratio of NH₄⁺-N/NO₃^--N during the entire growing season at the 12 experimental sites.</p