Biexciton Auger Recombination in CdSe/CdS Core/Shell Semiconductor Nanocrystals

A theoretical study of the positive and negative trion channels in the nonradiative Auger recombination of band-edge biexcitons (BXs) in CdSe/CdS core/shell nanocrystals (NCs) is presented. The theory takes into account the BX fine-structure produced by NC asymmetry and hole−hole exchange interaction. The calculations show that growth of CdS shell upon CdSe core suppresses the rate of the Auger recombination via negative trion channel, while the more efficient Auger recombination via positive trion channel shows much weaker dependence on the shell thickness. The demonstrated oscillatory dependence of the BX Auger rate on the core and shell sizes is explained qualitatively in terms of overlap of the ground and excited carrier wave functions. The calculations show that raise of temperature accelerates the Auger recombination in CdSe/CdS NCs due to reduction of the bulk energy gaps of CdSe and CdS

<i>Brugia</i> assay development.

<p>(<b>A–C</b>) Dose-response curve for the binding of 6 nM cy3B-GA to Hsp90 present in the adult <i>Brugia pahangi</i> worm extract (A), SKBr3 cell lysate (B) and <i>C. elegans</i> extract (-RNAi) or to a <i>C. elegans</i> extract in which <i>hsp90</i> had been depleted by RNAi by approximately 40% (+RNAi) (C) Various amounts of total lysate protein dissolved in binding buffer (0–20 µg/well) were incubated in triplicate wells with the ligand at 4°C, and the response was measured at the indicated time intervals. Fluorescence polarization was read with an Analyst GT instrument. Values obtained at several time intervals were plotted against the amount of added total protein. The assay window data were obtained by subtracting free tracer values from values recorded in the presence of specified protein concentrations. Data were analyzed and plotted in Prism 4.0. Points, mean; bars, s.d. (<b>D</b>) Overlay of GA-bound homology models (derived using Prime software of Schrodinger L.L.C, NY) of <i>B. pahangi</i> (orange, Accession number AJ005784) and <i>C. elegans</i> (green, Accession number Z75530) and the X-ray crystal structure of human Hsp90α (blue, PDB ID: 1YET).</p

<i>Brugia</i> assay identifies species selective Hsp90 inhibitors.

<p>(<b>A–C</b>) Increasing concentrations of indicated inhibitors were added in triplicate to the reaction buffer containing 6 nM of cy3B-GA and <i>Brugia</i> extracts (2 µg/well) (A) or SKBr3 cell lysates (3 µg/well) (B) in a final volume of 100 µL. Free (6 nM cy3B-GA) and bound (6 nM cy3B-GA with 2 µg/well <i>Brugia</i> or 3 µg/well SKBr3 extract) controls were included on each plate. The polarization values were measured after incubation at 4°C for 24 h with the indicated inhibitors to evaluate their <i>Brugia</i> and human tumor Hsp90 affinity. Points, mean; bars, s.d. EC₅₀ values were determined as shown in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000714#pntd-0000714-g003" target="_blank">Fig. 3</a>, and tabulated to indicate the selectivity ratio for the two Hsp90 species (C).</p

<i>Brugia</i> assay validation.

<p>(<b>A–C</b>) Increasing concentrations of indicated inhibitors were added in triplicate to the reaction buffer containing 6 nM of cy3B-GA and <i>Brugia</i> extracts (2 µg/well) in a final volume of 100 µL. Free (6 nM cy3B-GA) and bound (6 nM cy3B-GA with 2 µg/well <i>Brugia</i> extract) controls were included on each plate. The polarization values were measured after incubation at 4°C for the indicated times to evaluate assay stability (<b>A</b>) or for 24 h with the indicated inhibitors to evaluate their affinity for <i>Brugia</i> Hsp90 (<b>B, C</b>). The competitive effect was expressed as percentage of control and was calculated by dividing the millipolarization (mP; subtracting free cy3B-GA) value from inhibitor wells by the average mP (subtracting free cy3B-GA) from controls (cy3B-GA and cell lysate with vehicle DMSO) in each plate. Ligand binding was plotted against the log₁₀ inhibitor concentration, and EC₅₀ values were calculated using a nonlinear least-square curve-fitting program in Prism 4.0. Points, mean; bars, s.d. (<b>D</b>) Six adult female <i>B. pahangi</i> were incubated individually in 2.0 ml of tissue culture medium containing GA at 1.0 µM, PU-H71 at 10, 5 or 2.5 µM, PU-DZ8 at 10 or 5 µM, DMSO or medium alone. Graphs show mean and SD of Mf output over a three-day period from six female worms per group. Data combined from two separate experiments. *** P<0.005 for all drug concentrations vs DMSO except for PU-H71 at 2.5 µM where P = 0.0260 (**).</p

Analysis of <i>Brugia</i> assay performance.

<p>(<b>A–C</b>) Data collected at equilibrium in the binding experiment described in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000714#pntd-0000714-g001" target="_blank">Fig1A</a> were transformed and analyzed using a nonlinear regression method in Prism 4.0, and Hill plots were constructed. Specific binding represents the contribution of bound ligand to total recorded values. (<b>D</b>) Two 96-well plates each containing 48 free tracer control wells (6 nM cy3B-GA) and 48 bound tracer control wells (6 nM cy3B–GA with added lysate, 2 µg/well) were used to determine the suitability of the assay for high-throughput screening. The millipolarization value for each well was recorded, and average values corresponding to each plate were plotted. The signal-to-noise ratios and the Z' factors were calculated as indicated in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000714#s2" target="_blank">Methods</a>.</p

Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5‑(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure–activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5′-thiodipyrimidine and 5-(phenylthio)­pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives <b>17a</b> and <b>20a</b>, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics

Supplemental Figure 3 from Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma

BL cells but not normal GC B-cells are sensitive to inhibition by PU-H71.</p

Supplemental Figure Legends from Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma

Supplemental Figure Legends</p

Supplemental Figure 1 from Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma

Chemical Structure of PU-H71 and BEZ-235</p

Supplemental Table 2 from Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma

IPA analysis of Hps90 client protein networks</p