DataSheet1_Development of QSRR model for hydroxamic acids using PCA-GA-BP algorithm incorporated with molecular interaction-based features.pdf

As a potent zinc chelator, hydroxamic acid has been applied in the design of inhibitors of zinc metalloenzyme, such as histone deacetylases (HDACs). A series of hydroxamic acids with HDAC inhibitory activities were subjected to the QSRR (Quantitative Structure–Retention Relationships) study. Experimental data in combination with calculated molecular descriptors were used for the development of the QSRR model. Specially, we employed PCA (principal component analysis) to accomplish dimension reduction of descriptors and utilized the principal components of compounds (16 training compounds, 4 validation compounds and 7 test compounds) to execute GA (genetic algorithm)-BP (error backpropagation) algorithm. We performed double cross-validation approach for obtaining a more convincing model. Moreover, we introduced molecular interaction-based features (molecular docking scores) as a new type of molecular descriptor to represent the interactions between analytes and the mobile phase. Our results indicated that the incorporation of molecular interaction-based features significantly improved the accuracy of the QSRR model, (R2 value is 0.842, RMSEP value is 0.440, and MAE value is 0.573). Our study not only developed QSRR model for the prediction of the retention time of hydroxamic acid in HPLC but also proved the feasibility of using molecular interaction-based features as molecular descriptors.</p

Hybrid sp³/sp² Two-Dimensional Nanodiamonds for Electrochemical Ozone Production

Diamond electrodes have been receiving increased attention because of their favorable properties for wastewater treatment. However, the surface properties of the diamond anode have not been fully determined. Herein, an extensive study was conducted to explore hybrid two-dimension nanodiamonds (2D NDs) with variable sp3/sp2 ratios as metal-free electrochemical ozone production (EOP) electrocatalysts. The 2D ND-1100 electrocatalyst with interface heterojunction of sp3/sp2 exhibited outstanding EOP performance compared with the normal ND@G with sp3@sp2 core–shell structure. Theoretical calculations further revealed that a high sp3/sp2 ratio could effectively prohibit the O2*/O3* intermediate dissociation. O3* with five-ring configurations exhibited lower adsorption energies than O2* under the high sp3/sp2 ratio condition, indicating the high O3 selectivity. The optimal sp3/sp2 ratio was predicted to be 4:5 to 8:1 for O3 selective formation. In addition, the 2D ND-1100 electrocatalyst demonstrated remarkable performance in electrodegrading organic pollutants, indicating its broad potential for efficient and advanced oxidation applications. This work provides an effective strategy for the removal of organic pollutants in wastewater based on high-performance hybrid two-dimension nanodiamonds with appropriate sp3/sp2 rations

Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1

<div><p>Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage.</p> </div

DHA induced disturbance of iron homeostasis could not be reversed by NAC.

<p>(A) MCF7 cells were pretreated with 20 mM NAC or left untreated for 30 min and then DHA (25 µM) were added to further treatment. After 24 hours, cell lysates were prepared and immunoblotted. (B) HepG2 cells were pretreated with NAC or not and further incubated with 25 µM DHA for 24 hours. Quantitative RT-PCR was performed to detect the mRNA level. **, <i>P</i><0.01. Data are represented as mean ±SD of three different experiments.</p

Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases

We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound <b>15</b> possessing IC₅₀ values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model

DHA induced TfR1 internalization in a lipid rafts/caveolae mediated way.

<p>(A) After pretreatment with CPZ (20 µM) or nystatin (25 µg/ml) or left untreated for 30 min, HepG2 cells were incubated with 25 µM DHA for another 4 hours. Cells were harvested and the membrane-associated TfR1 was determined by flow cytometric analysis. *, <i>P</i><0.05 compared with DMSO-treated cells. Data are represented as mean ±SD of two different experiments. (B) HEK293 cells expressed GFP-TfR1 were treated with DMSO or 25 µM DHA for 24 hours and subjected to confocal microscope analysis. Scale bar, 5 µm. (C) HepG2 cells were treated with DMSO or 25 µM DHA for 24 hours and the endogenous TfR1 protein was immunoprecipitated to perform the palmitoylation assay as described in Materials and Methods.</p

The proposed mechanisms by which DHA disrupts iron homeostasis.

<p>The proposed mechanisms by which DHA disrupts iron homeostasis.</p

DHA decreased cell-surface TfR1 and inhibited Tf uptake.

<p>(A and B) After treated with DHA, HepG2 cells were harvested and incubated with PE-conjugated TfR1 antibody for 30 min and then subjected to flow cytometric analysis to determine membrane-associated TfR1 level. *, <i>P</i><0.05; **, <i>P</i><0.01 compared with control cells. Data are represented as mean ±SD of three different experiments. (C) HepG2 cells were treated with different concentrations of DHA for 24 hours and then incubated with Alexa fluor 633-conjugated transferrin for 2 hours. Harvested cells were subjected to flow cytometric analysis for internalized transferrin. *, <i>P</i><0.05; **, <i>P</i><0.01 compared with control cells. Data are represented as mean ±SD of three different experiments. (D) HepG2 treated with DMSO or 25 µM DHA for 24 hours were incubated with Alexa fluor 633-conjugated transferrin for the time indicated. Cells were harvested and subjected to flow cytometric analysis. *, <i>P</i><0.05; **, <i>P</i><0.01. Data are represented as mean ± SEM of three different experiments.</p

Discovery of 3‑(5′-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)‑1<i>H</i>‑indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation

Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this article, we describe the identification of the potent pan-FGFR inhibitor (<i>R</i>)-<b>21c</b> (FGFR1–4 IC₅₀ values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (<i>R</i>)-<b>21c</b> exhibited excellent <i>in vitro</i> inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analysis demonstrated that (<i>R</i>)-<b>21c</b> suppressed FGF/FGFR and downstream signaling pathways at nanomolar concentrations. Moreover, (<i>R</i>)-<b>21c</b> provided nearly complete inhibition of tumor growth (96.9% TGI) in NCI-H1581 (FGFR1-amplified) xenograft mice model at the dose of 10 mg/kg/qd via oral administration