UV-Blocking and Light-Responsive Poly (ϵ-Caprolactone)/ZIF-8 Multifunctional Composite Films for Efficient Antibacterial Activities.

Antibacterial photodynamic therapy (APDT) has received considerable attention owing to its superiority. ZIF-8 was used to address the poor stability of the photosensitizer Rose Bengal (RB) encapsulation to synthesize RB@ZIF-8 NPs, which were doped into a composite film with poly (ϵ-caprolactone) (PCL) and polyvinyl alcohol-quaternary ammonium chitosan (PVA-QCS) as substrates to form composite films (PQZ). The composite films exhibited excellent photodynamic sterilization and good resistance to bacterial adhesion. The tensile strength of the film increased to 43.4 MPa, which was approximately 1.8 times that of the PCL film. With the addition of SiO2 and RB@ZIF-8 NPs, the film exhibited water repellency and UV-blocking properties. RAW264.7 cells were selected using the MTT method to confirm that the composite films had excellent biocompatibility and had no significant inhibitory effect on cell growth and reproduction. PQZ multifunctional composite films show potential as novel APDT antimicrobial materials for food packaging.

Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.

Slope stability calculation method for highwall mining with open-cut mines.

Slope stability is a prominent problem for the efficient application and promotion of highwall mining technology, especially when mining residual coal under high and steep end-slope conditions. This study proposes the concept of target time pillar strength based on the required coal pillar service time. Creep tests were performed to measure the time-varying properties of coal shear strength parameters under different loads, and a time-varying function was established by regression. The highwall mining length is divided into three categories based on discontinuous structural plane theory, including goaf, yielding, and elastic zones, all of which are considered to have resistances against shear stress. The basal coal seam is prone to weakening owing to the weight of overlying strata, which may shift the slope failure mode from circular to sliding along the weak layer. Numerical modeling was used to study the influence of the bearing stress and target time strength on the development of the yielding zone at the coal pillar ribs. The coefficients of the three zones were determined, and the temporal and spatial evolution patterns of the shear strength parameters of the weak layer were acquired. A slope stability calculation method is proposed based on rigid body-limit equilibrium theory that can quantify the influence of highwall mining operations on slope stability, which is significant for popularizing highwall mining technology.

Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo.

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.

USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.

Zirconocene-Mediated Carbonylative Coupling of Grignard Reagents.

Organozirconocenes are versatile synthetic intermediates that can undergo carbonylation to yield acyl anion equivalents. Zirconocene hydrochloride ([Cp2 ZrHCl]) is often the reagent of choice for accessing these intermediates but generates organozirconocenes only from alkenes and alkynes. This requirement eliminates a broad range of substrates. For example, organozirconocenes in which the zirconium center is bonded to an aromatic ring, a benzylic group, or an alkyl group that possesses a tertiary or quaternary carbon atom α to the carbon-zirconium bond can not be formed in this way. To provide more generalized access to acyl zirconium reagents, we explored the transmetalation of Grignard reagents with zirconocene dichloride under a CO atmosphere. This protocol generates acyl zirconium(IV) complexes that are inaccessible with the Schwartz reagent, including those derived from secondary and tertiary alkyl and aryl Grignard reagents.

Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.

Rational assembly of small molecule libraries for purposes of drug discovery requires an efficient approach in which the synthesis of bioactive compounds is enabled so that numerous structurally related compounds of a similar basic formulation can be derived. Here, we describe (4 + 3) and (3 + 2) indole annulation strategies that quickly generate complex indole heterocycle libraries that contain novel cyclohepta- and cyclopenta[b]indoles, respectively. Screening of one such library comprised of these indoles identifies JWU-A021 to be an especially potent stimulator of glucagon-like peptide-1 (GLP-1) secretion in vitro. Surprisingly, JWU-A021 is also a potent stimulator of Ca(2+) influx through TRPA1 cation channels (EC50 ca. 200 nM), thereby explaining its ability to stimulate GLP-1 release. Of additional importance, the available evidence indicates that JWU-A021 is one of the most potent non-electrophilic TRPA-1 channel agonists yet to be reported in the literature.

Regioselective formal hydroamination of styrenes with 1-phenyl-1H-tetrazole-5-thiol.

1-Phenyl-1H-tetrazole-5-thiol 1 (PT-thiol) is employed in a unique Markovnikov-selective formal hydroamination of styrenyl compounds in the presence of catalytic amounts of Ga(OTf)3. This gives rise to the formation of tetrazolothione moieties in an atom-economical manner. Mechanistically, we have determined that this transformation may occur by kinetically favored hydrothiolation, followed by rearrangement to the observed hydroamination products.

Redox chain reaction-indole and pyrrole alkylation with unactivated secondary alcohols.

Secondary role: Indole and pyrrole derivatives are alkylated with unactivated secondary aliphatic alcohols by a Brønsted acid-catalyzed redox chain reaction mechanism. Broad functional-group tolerance has been demonstrated and preliminary studies suggest that 1,4-reduction of a putative indolyl carbocation is the dominant mechanistic pathway.

Sequence preference of α-helix N-terminal tetrapeptide.

The α-helix is the most abundant secondary structure in proteins. Due to the specific i, i+4 hydrogen bond pattern, the two termini have unsatisfied hydrogen bonds, and are less constrained; in order to compensate for this, specific residues are preferred for the terminal positions. However, a naive combination of the statistically-preferred residues for each position may not result in a stable N-terminal helical sequence. In order to provide a set of preferable N-terminal peptides for α-helix design, we have studied the N-terminal tetrapeptide sequence motifs that are favorable for helix formation using statistical analysis and atomistic simulations. A set of tetrapeptide sequences including TEEE and TPEE were found to be favorable motifs. In addition to forming more hydrogen bonds in the helical conformation, the favorable motifs also tended to form more capping boxes. To empirically test our predictions, we obtained 10 peptides with different N-terminal motifs and measured their α-helical content by circular dichroism spectroscopy. The experimental results agreed qualitatively with the statistical and simulation results. Furthermore, some of the suggested preferable tetrapeptide sequences have been successfully applied in de novo protein design.

Ga(OTf)3-catalyzed direct substitution of alcohols with sulfur nucleophiles.

It is reported that Ga(OTf)(3) catalyzes the direct displacement of alcohols with sulfur nucleophiles. The products are versatile intermediates that can be utilized in carbon-carbon, carbon-sulfur bond formation or used in modified Julia olefination reactions. The only byproduct generated is water.

Mild two-step process for the transition-metal-free synthesis of carbon-carbon bonds from allylic alcohols/ethers and grignard reagents.

A mild two-step process for the regioselective, transition-metal-free preparation of carbon-carbon bonds from allylic alcohols/ethers and Grignard reagents is described. This process obviates the need for the harsh deprotection conditions usually required for removal of methyl ethers. The synthesis is accomplished by photochemically promoted allylic substitution reactions of allylic alcohols and ethers with diethylphosphorothioic acid followed by sp(3)-sp(3) or sp(2)-sp(3) bond formation with various Grignard reagents under transition-metal-free conditions. Depending on the nature of the nucleophile, the regioselectivity of the carbon-carbon bond-forming event can be controlled to furnish either quaternary or tertiary carbon centers.