Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.     

A highly regioselective synthesis of 2-aryl-6-chlorobenzothiazoles employing microwave-promoted Suzuki-Miyaura coupling reaction

Suzuki-Miyaura coupling reactions of 2,6-dichlorobenzothiazole with arylboronic acids, promoted by microwave heating, efficiently produce 2-aryl-6-chlorobenzothiazoles in a highly regioselective manner. This process serves as the foundation for a simple method to rapidly construct 2-aryl-6-chlorobenzothiazole libraries.     

Relative DNA binding affinity of helix 3 homeodomain analogues, major groove binders, can be rapidly screened by displacement of prebound ethidium bromide. A comparative study

The binding affinity for a 12-bp dsDNA of Antennapedia helix 3 analogues, major groove binders, has been measured by displacement of prebound ethidium bromide, a fluorescent displacement assay proposed for minor groove binders by Boger et al.(J. Am. Chem. Soc., 2000, 122, 6382-6394). Relative binding affinities determined by this method were compared to those obtained by gel mobility shift and footprinting assays for the 12-bp dsDNA and a 178-bp DNA fragment. The present work demonstrates that the fluorescence displacement assay is suitable for rapid screening of major groove binders, even though about 60 to 70% of the prebound ethidium bromide is displaced by these peptides. Total (100%) displacement of ethidium bromide was serendipitously achieved by addition in the peptide sequence, at the N-terminus, of a S-3-nitro-2-pyridinesulfenyl-N-acetyl-cysteine residue. S-3-nitro-2-pyridinesulfenylcysteine was shown to (i) bind to dsDNA with a micromolar affinity and (ii) direct within DNA grooves a peptide with no affinity for dsDNA.     

Transition metal ion directed supramolecular assembly of one- and two-dimensional polyrotaxanes incorporating cucurbituril

This paper reports a synthetic strategy to construct one- and two-dimensional (1D and 2D) polyrotaxanes, in which a number of rings are threaded onto a coordination polymer, by the combination of self-assembly and coordination chemistry. Our approach to construct polyrotaxanes with high structural regularity involves threading a cucurbituril (CB) "bead" with a short "string" to form a stable pseudorotaxane, followed by linking the pseudorotaxanes with metal ions as "linkers" to organize into a 1D or 2D polyrotaxane. A 4- or 3-pyridylmethyl group is attached to each end of 1,4-diaminobutane or 1,5-diaminopentane to produce the short "strings", which then react with the cucurbituril "bead" to form stable pseudorotaxanes. The reaction of the pseudorotaxanes with various transition metal ions including CuII, CoII, NiII, AgI, and CdII produces 1D or 2D polyrotaxanes, in which many molecular "beads" are threaded onto 1D or 2D coordination polymers as confirmed by X-ray crystallography. The overall structure of a polyrotaxane is the result of interplay among various factors that include the coordination preferences of the metal ion, spatial disposition of the donor atoms with respect to the CB beads in the pseudorotaxane, and the size and coordination ability of the counteranion.     

Free solution capillary electrophoresis of proteins using untreated fused-silica capillaries.

Numerous efforts have been made to separate proteins by capillary zone electrophoresis (CZE). The most common optimization techniques are changing the pH of the running buffer, coating the capillary surface with a hydrophilic polymer, or using additives in the sample solution. Surface coatings and solution additives can reduce the adsorption of the protein onto the capillary surface, but they diminish the separation efficiency and the resolution of CZE. This paper reports the successful separation of proteins in a untreated fused-silica capillary by raising the pH of the running buffer and washing between runs with 1.0 M sodium hydroxide. Under these conditions, model proteins and proteins in human serum have been determined by CZE. It is shown that the results from CZE are compatible with those of sodium dodecyl sulphate-polyacrylamide gel electrophoresis.     

Sterically induced shape and crystalline phase control of GaP nanocrystals

We demonstrate a novel synthetic scheme that can be used to control the crystalline phase and shape of GaP semiconductor nanocrystals. Our study shows that steric effects of surfactant ligands can modulate the crystalline phases and control the shapes of nanocrystals. The shape of the nanocrystals obtained varies from zero-dimensional spheres to one-dimensional rods via controlling the ratio between primary and tertiary alkylamines. III-V semiconductors (in our case: GaP) under 10 nm in width are first reported, and unique optical properties due to shape anisotropy are also observed.     

A compact finite difference method for solving Burgers' equation

In this paper, a high‐order accurate compact finite difference method using the Hopf–Cole transformation is introduced for solving one‐dimensional Burgers' equation numerically. The stability and convergence analyses for the proposed method are given, and this method is shown to be unconditionally stable. To demonstrate efficiency, numerical results obtained by the proposed scheme are compared with the exact solutions and the results obtained by some other methods. The proposed method is second‐ and fourth‐order accurate in time and space, respectively. Copyright © 2009 John Wiley & Sons, Ltd.     

CH3NH3PbI3/poly‐3‐hexylthiophen perovskite mesoscopic solar cells: Performance enhancement by Li‐assisted hole conduction

To address if the non‐triphenylamine derivative hole transporting materials such as P3HT (poly‐3‐hexylthiophene) could also exhibit high device efficiency in mesoscopic MAPbI₃ perovskite solar cells, we examined the effect of Li‐TFSI (Li‐bis(trifluoromethanesulfonyl) imide) and t‐BP (4‐tert‐butylpyridine) additives added in P3HT on device performance. Unlike the triphenylamine HTMs, the P3HT thiophene HTM without amine moiety was not doped by the additives but its conductivity was significantly improved by the Li‐TFSI/t‐BP mediated additional hole conduction. By inclusion of Li‐TFSI/t‐BP additive, we could fabricate more efficient mesoscopic MAPbI₃ perovskite solar cells with smaller hysteresis with respect to scan direction due to Li mediated additional hole conduction. (© 2014 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim)     

The improved photosensitivity of photosensitive polyimides containing o-nitrobenzyl ether groups induced by the addition of photoacid generator

In this article, photosensitive polyimides (PSPIs) with photosensitive groups, o-nitrobenzyl ether groups (Nb), were successfully synthesized based on 2,2′-dihydroxy benzophenone-3,3′,4,4′-tetracarboxylic dianhydride and on diamine containing ethylene glycol chains (ODA). Also, a series of polyimide (PI), ODA-1-PI, ODA-3-PI, and ODA-5-PI with a number of ethylene glycol chains of 1, 3, and 5 were prepared to investigate the relationship between structure and solubility. Interestingly, ODA-5-PI, which possesses a large number of ethylene glycols, exhibited the most excellent solubility. Therefore, due to the good solubility of ODA-5-PI in organic solvents and alkaline solutions, a PSPI, poly(1,4-phenyleneoxy-3,6,9,12,15-pentaoxaoctane-1,4-phenylene-2,2′-di[2-nitrobenzyloxy]benzophenone-3,3′,4,4′-tetracarboxdiimide), named ODA-5-PSPI, was synthesized by linking Nb, which is a photosensitive group. Aiming at producing positive tone patterns, the synthesized ODA-5-PSPI was exposed to UV irradiation and then to a post-exposure bake. Afterward, it was developed using a 2.38 wt% tetramethylammonium hydroxide solution. Furthermore, a photoacid generator (PAG) was additionally incorporated for a micropatterning process. Notably, in the presence of the PAG, the photocleavage of ODA-5-PSPI occurred not only by the intramolecular rearrangement of Nb but also by its hydrolysis reaction. As a result, due to the synergistic effect of photocleavage, the micropatterning of ODA-5-PSPI with PAG could be clearly obtained with less energy (2.0 J/cm²) compared with that without PAG (3.6 J/cm²). Therefore, through the addition of PAG, the photosensitivity was improved by 45%.