Tunneling Interpenetrative Lithium Ion Conduction Channels in Polymer-in-Ceramic Composite Solid Electrolytes.

Polymer-in-ceramic composite solid electrolytes (PIC-CSEs) provide important advantages over individual organic or inorganic solid electrolytes. In conventional PIC-CSEs, the ion conduction pathway is primarily confined to the ceramics, while the faster routes associated with the ceramic-polymer interface remain blocked. This challenge is associated with two key factors: (i) the difficulty in establishing extensive and uninterrupted ceramic-polymer interfaces due to ceramic aggregation; (ii) the ceramic-polymer interfaces are unresponsive to conducting ions because of their inherent incompatibility. Here, we propose a strategy by introducing polymer-compatible ionic liquids (PCILs) to mediate between ceramics and the polymer matrix. This mediation involves the polar groups of PCILs interacting with Li+ ions on the ceramic surfaces as well as the interactions between the polar components of PCILs and the polymer chains. This strategy addresses the ceramic aggregation issue, resulting in uniform PIC-CSEs. Simultaneously, it activates the ceramic-polymer interfaces by establishing interpenetrating channels that promote the efficient transport of Li+ ions across the ceramic phase, the ceramic-polymer interfaces, and the intervening pathways. Consequently, the obtained PIC-CSEs exhibit high ionic conductivity, exceptional flexibility, and robust mechanical strength. A PIC-CSE comprising poly(vinylidene fluoride) (PVDF) and 60 wt % PCIL-coated Li3Zr2Si2PO12 (LZSP) fillers showcasing an ionic conductivity of 0.83 mS cm-1, a superior Li+ ion transference number of 0.81, and an elongation of ∼300% at 25 °C could be produced on meter-scale. Its lithium metal pouch cells show high energy densities of 424.9 Wh kg-1 (excluding packing films) and puncture safety. This work paves the way for designing PIC-CSEs with commercial viability.

Development of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation.

Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective CRBN-recruiting PROTACs for many other therapeutic targets.

Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment.

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 µM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90-HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (LBD) are an established mechanism of endocrine resistance and decrease the binding affinity of mainstay endocrine therapies targeting ER, reducing their ability to promote ER degradation or transcriptionally silence ER. Because dip G binds to HSP90 and does not bind to the LBD of ER, unlike endocrine therapies, it is insensitive to ER LBD mutations that drive endocrine resistance. Additionally, we determined that dip G promoted degradation of WT and mutant ER with similar efficacy, downregulated ER- and mutant ER-regulated gene expression, and inhibited WT and mutant cell proliferation. Our data suggest that dip G is not only a molecular probe to study HSP90 biology and the HSP90 conformation cycle, but also a new therapeutic avenue for various cancers, particularly endocrine-resistant breast cancer harboring ER LBD mutations.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.

Transition Metal-Catalyzed Selective Carbon-Carbon Bond Cleavage of Vinylcyclopropanes in Cycloaddition Reactions.

In this review, transition metal-catalyzed methodologies and applications that exploit C-C bond cleavage of vinylcyclopropanes (VCPs) are summarized with a focus on cycloaddition and related addition reactions. Transition metals, including palladium, nickel, iron, ruthenium, rhodium, cobalt, and iridium, can catalyze the cleavage of C-C bonds in activated or nonactivated VCPs. Additionally, these bond-breaking reactions can occur as intra- or intermolecular processes. The properties of activated and nonactivated VCPs are discussed in the Introduction. Various transition metal-catalyzed cycloaddition and addition reactions involving the cleavage of C-C bonds in activated VCPs are then discussed in the next chapter. The transition metal-catalyzed cycloadditions involving the cleavage of C-C in nonactivated VCPs are summarized in the following chapter. Finally, challenges and potential opportunities are outlined in the last chapter.

Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation.

Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin-proteasome system, have the potential to revolutionize the healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the in vivo performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the in vivo degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates.

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a RhII /chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2-OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

General Strategy for the Synthesis of Rare Sugars via Ru(II)-Catalyzed and Boron-Mediated Selective Epimerization of 1,2-trans-Diols to 1,2-cis-Diols.

Human glycans are primarily composed of nine common sugar building blocks. On the other hand, several hundred monosaccharides have been discovered in bacteria and most of them are not readily available. The ability to access these rare sugars and the corresponding glycoconjugates can facilitate the studies of various fundamentally important biological processes in bacteria, including interactions between microbiota and the human host. Many rare sugars also exist in a variety of natural products and pharmaceutical reagents with significant biological activities. Although several methods have been developed for the synthesis of rare monosaccharides, most of them involve lengthy steps. Herein, we report an efficient and general strategy that can provide access to rare sugars from commercially available common monosaccharides via a one-step Ru(II)-catalyzed and boron-mediated selective epimerization of 1,2-trans-diols to 1,2-cis-diols. The formation of boronate esters drives the equilibrium toward 1,2-cis-diol products, which can be immediately used for further selective functionalization and glycosylation. The utility of this strategy was demonstrated by the efficient construction of glycoside skeletons in natural products or bioactive compounds.

Sertraline inhibits stress-induced tumor growth through regulating CD8 + T cell-mediated anti-tumor immunity.

Chronic stress has been reported to be associated with tumor initiation and progression. But the underlying mechanism and the specific role of tumor immunity in this process are still unknown. Herein, we applied the repeated restrain stress model in C57BL/6J mice and found that the tumor growth in stressed mice was accelerated compared with that in control mice. In addition, serotonin, also called 5-hydroxytryptamine (5-HT), in the serum of stressed mice was also elevated. Sertraline, a selective serotonin reuptake inhibitor used in the clinic, can restore the serum 5-HT level in stressed mice and restrain tumor growth. We further explored the distribution of major immune cells, including B lymphocytes cells, T lymphocytes, natural killer cells, dendritic cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg). We found that the infiltration of CD8 + T cells in the tumor microenvironment (TME) decreased significantly in stressed mice. And the extra 5-HT treatment could further decrease the infiltration of CD8 + T cells in the TME. The expression of IFN-γ and Granular enzyme B (GzmB) in CD8 + T cells were also dropped in the stressed mice group, whereas the expression of programmed cell death protein 1 (PD-1) on CD8 + T cells was increased. The T cell deficiency induced by stress can be reversed by sertraline, indicating its promising role in strengthening the efficacy of anti-PDL1/PD-1 immunotherapy. The present study provides new mechanistic insights into the impact of chronic stress on antitumor immunity and implicates a novel combined immunotherapy strategy for cancer patients with chronic stress.

Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform.

Proteolysis Targeting Chimera (PROTAC) has emerged as a novel therapeutic strategy. The major bottleneck for the development of PROTACs is the need to screen multiple parameters to create an effective degrader. It often involves the synthesis of dozens to hundreds of compounds one by one through a tedious process. We have developed a two-stage approach that allows for the rapid synthesis of PROTACs (Rapid-TAC) using preassembled building blocks to screen multiple parameters simultaneously. We herein report the application of this method to the development of PROTACs for FGFR, a challenging membrane protein target. In the first stage, we prepared 24 potential PROTACs quickly from a hydrazide-containing FGFR inhibitor and our previously reported VHL and CRBN ligand library bearing various linkers and an aldehyde functional group. These 24 PROTACs were then directly used for screening in cellular assay for protein degradation. Multiple hits were identified from the initial screening. We then prepared the corresponding stable analogues by replacing the hydrolytic labile acylhydrazone motif with an amide in the second stage. Among them, PROTAC LG1188 was identified as a potent and selective FGFR1 degrader.

Accurate prediction of microvascular invasion occurrence and effective prognostic estimation for patients with hepatocellular carcinoma after radical surgical treatment.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide, with an overall 5-year survival rate of less than 18%, which may be related to tumor microvascular invasion (MVI). This study aimed to compare the clinical prognosis of HCC patients with or without MVI after radical surgical treatment, and further analyze the preoperative risk factors related to MVI to promote the development of a new treatment strategy for HCC. METHODS: According to the postoperative pathological diagnosis of MVI, 160 study patients undergoing radical hepatectomy were divided into an MVI-negative group (n = 68) and an MVI-positive group (n = 92). The clinical outcomes and prognosis were compared between the two groups, and then the parameters were analyzed by multivariate logistic regression to construct an MVI prediction model. Then, the practicability and validity of the model were evaluated, and the clinical prognosis of different MVI risk groups was subsequently compared. RESULT: There were no significant differences between the MVI-negative and MVI-positive groups in clinical baseline, hematological, or imaging data. Additionally, the clinical outcome comparison between the two groups presented no significant differences except for the pathological grading (P = 0.002) and survival and recurrence rates after surgery (P < 0.001). The MVI prediction model, based on preoperative AFP, tumor diameter, and TNM stage, presented superior predictive efficacy (AUC = 0.7997) and good practicability (high H-L goodness of fit, P = 0.231). Compared with the MVI high-risk group, the patients in the MVI low-risk group had a higher survival rate (P = 0.002) and a lower recurrence rate (P = 0.004). CONCLUSION: MVI is an independent risk factor for a poor prognosis after radical resection of HCC. The MVI prediction model, consisting of AFP, tumor diameter, and TNM stage, exhibits superior predictive efficacy and strong clinical practicability for MVI prediction and prognostication, which provides a new therapeutic strategy for the standardized treatment of HCC patients.

Mechanism of activation for the sirtuin 6 protein deacylase.

The histone deacetylase sirtuin 6 (SIRT6) regulates numerous biological functions, including transcriptional repression, DNA repair, and telomere maintenance. Recombinant SIRT6 displays catalytic efficiencies 2 orders of magnitude greater for long-chain deacylation than deacetylation against peptide substrates; however, deacetylation can be enhanced by allosteric small-molecule activators. Here, we investigated the mechanisms of activated lysine deacetylation and enhanced long-chain acyl-group removal by SIRT6. Activity-based screening identified compounds that activated histone peptide deacetylation 18-48-fold. Chemical optimization based on structure-activity relationships yielded an activator with improved potency and selectivity for SIRT6. Using this novel activator, we conducted biochemical and kinetic analyses revealing that SIRT6 is activated via acceleration of a catalytic step occurring after substrate binding but before NAD+ cleavage. We identified a SIRT6 variant, R65A, that maintains basal deacetylase activity but cannot be activated and failed to enhance long-chain deacylation. Additional biochemical studies revealed that Arg-65 is critical for activation by facilitating a conformational step that initiates chemical catalysis. This work suggests that SIRT6 activation of deacetylation involves a similar mechanism to improved catalysis as that of long-chain deacylation. The identification of novel SIRT6 activators and the molecular insights into activation and catalysis presented here provide a foundational understanding for physiological SIRT6 activation and for rational design of activating molecules.

Rhodium-Catalyzed (5 + 2) and (5 + 1) Cycloadditions Using 1,4-Enynes as Five-Carbon Building Blocks.

Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in natural products and pharmaceutical agents. Most cycloadditions occur under thermal or photochemical conditions, but transition-metal complexes can promote reactions that occur beyond these circumstances. Transition-metal complexation with alkynes, alkenes, allenes, or dienes often alters the reactivity of those π-systems and facilitates access to diverse cycloaddition products. This Account describes our efforts toward the design of novel five-carbon synthons for use in rhodium-catalyzed (5 + n) cycloadditions, which include 3-acyloxy-1,4-enynes (ACEs) for (5 + 1) and (5 + 2) cycloadditions and 3-hydroxy-1,4-enynes (HYEs) for (5 + 1) cycloadditions. Furthermore, this Account includes relevant computational information, mechanistic insights, and applications of these cycloadditions in the synthesis of various highly substituted carbo- and heterocycles. The (5 + n) cycloaddition reactions presented herein share the following common mechanistic features: the 1,2-migration of an acyloxy group in propargyl esters or the ionization of a hydroxyl group in propargylic alcohols, oxidative cyclization to form a metallacycle, insertion of the one- or two-carbon component, and reductive elimination to yield the final product. In conjunction with a cationic rhodium catalyst, we used ACEs for the intramolecular (5 + 2) cycloaddition with tethered alkynes, alkenes, and allenes. In some cases, an electron-deficient phosphine ligand improved the reaction yields, especially when the ACE featured an internal alkyne. We also demonstrated that chirality could be efficiently transferred from a relatively simple starting material to a more complex bicyclic product. Products derived from ACEs with tethered alkenes and allenes contained one or more stereocenters, and high diastereoselectivity was achieved in most of these cases. For ACEs tethered to an allene, the reaction preferentially occurred at the internal alkene. We also switched the positions of the alkene and the alkyne in the 1,4-enyne of our original ACE to provide an inverted ACE variant, which produced products with complementary functionalities. After we successfully developed the Rh-catalyzed intramolecular (5 + 2) cycloaddition, we optimized conditions for the intermolecular version, which required a neutral rhodium catalyst and phosphine ligand. When a terminal alkyne was used as the two-carbon component, high regioselectivity was observed. While investigating the effect of esters on the rate of the intermolecular (5 + 2) cycloadditions, we determined that an electron-rich ester significantly accelerated the reaction. Subsequently, we demonstrated that (5 + 1) cycloadditions undergo this rate enhancement as well in the presence of an ester. Aside from ACEs, we synthesized HYEs in four steps from commercially available 2-aminobenzoic acid for use in the (5 + 1) cycloaddition. Mechanistically, HYEs were designed so that the aniline nitrogen could serve as the nucleophile and the -OH could serve as the leaving group. Using HYEs, we developed a novel method to make substituted carbazoles, dibenzofurans, and tricyclic compounds with a cyclohexadienone moiety. Although the occurrence of transition-metal-catalyzed acyloxy migrations has been known for decades, only recently has their synthetic value been realized. We hope our studies that employ readily available 1,4-enynes as the five-carbon components in (5 + n) cycloadditions can inspire the design of new two-component and multicomponent cycloadditions.

Single-detecting-path high-resolution displacement sensor based onself-interference effect of a single submicrometer grating.

On the basis of the self-interference effect between ±1 st-order diffraction beams from a single optical submicrometer grating, we demonstrate a single-detecting-path optical displacement sensor with high resolution. Using a quadrant optoelectronic detector, a single-detecting-path system without any wave plates is realized experimentally. Combined with an interpolation circuit, we demonstrate the system for displacement measurement within a range of 200 µm. The results indicate a detecting sensitivity of 905.4°/µm and an accuracy of ±1.9µm. It is worth mentioning that, considering a maximum subdividing factor of 9674 used in experiment, the resolution goes down to 41.1 pm in principle. We demonstrate a compact optical sensor with high resolution, which is promising in developing miniaturized displacement systems.

Chemical Synthesis and Biological Application of Modified Oligonucleotides.

RNA plays a myriad of roles in the body including the coding, decoding, regulation, and expression of genes. RNA oligonucleotides have garnered significant interest as therapeutics via antisense oligonucleotides or small interfering RNA strategies for the treatment of diseases ranging from hyperlipidemia, HCV, and others. Additionally, the recently developed CRISPR-Cas9 mediated gene editing strategy also relies on Cas9-associated RNA strands. However, RNA presents numerous challenges as both a synthetic target and a potential therapeutic. RNA is inherently unstable, difficult to deliver into cells, and potentially immunogenic by itself or upon modification. Despite these challenges, with the help of chemically modified oligonucleotides, multiple RNA-based drugs have been approved by the FDA. The progress is made possible due to the nature of chemically modified oligonucleotides bearing advantages of nuclease stability, stronger binding affinity, and some other unique properties. This review will focus on the chemical synthesis of RNA and its modified versions. How chemical modifications of the ribose units and of the phosphatediester backbone address the inherent issues with using native RNA for biological applications will be discussed along the way.

Mild Cu(OTf)2-Mediated C-Glycosylation with Chelation-Assisted Picolinate as a Leaving Group.

C-Glycosylation reactions of glycosyl picolinates with allyltrimethylsilane or silyl enol ethers were developed. Picolinate as a chelation-assisted leaving group could be activated by Cu(OTf)2 and avoided the use of harsh Lewis acids. The glycosylations were operated under mild neutral conditions and gave the corresponding C-glycosides in up to 95% yield with moderate to excellent stereoselectivities.

Synthesis of Lactams via Ir-Catalyzed C-H Amidation Involving Ir-Nitrene Intermediates.

x-membered lactams were synthesized via either an amidation of sp3 C-H bonds or an electrophilic substitution of arenes via Ir-nitrene intermediates. With the employment of a readily available iridium catalyst in dichloromethane or hexafluoro-2-propanol, a wide range of lactams were synthesized in good to excellent yields with high selectivity.

Synthesis and biological evaluation of FICZ analogues as agonists of aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor involved in multiple biological processes including immune cell differentiation, intestinal function and inflammation. Based on the scaffold of naturally occurring AhR ligand 6-formylindolo (3,2-b) carbazole (FICZ, 2), a series of analogues has been designed, synthesized and evaluated by cell-based assays. The structure-activity relationships study has successfully led to the discovery of compound 11e with extremely potent activity.

Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR).

Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100-1000-fold by incubation or long-term storage and relies on the hydrophobic ligand-binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace-extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist.

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion.

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans-1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O-alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.