Pyxinol skeleton is a promising framework of anti-inflammatory agents formed in the human liver from 20S-protopanaxadiol, the main active aglycone of ginsenosides. In the present study, a new series of amino acid-containing derivatives were produced from 12-dehydropyxinol, a pyxinol oxidation metabolite, and its anti-inflammatory activity was assessed using an NO inhibition assay. Interestingly, the dehydrogenation at C-12 of pyxinol derivatives improved their potency greatly. Furthermore, half of the derivatives exhibited better NO inhibitory activity than hydrocortisone sodium succinate, a glucocorticoid drug. The structure–activity relationship analysis indicated that the kinds of amino acid residues and their hydrophilicity influenced the activity to a great extent, as did R/S stereochemistry at C-24. Of the various derivatives, 5c with an N-Boc-protected phenylalanine residue showed the highest NO inhibitory activity and relatively low cytotoxicity. Moreover, derivative 5c could dose-dependently suppress iNOS, IL-1β, and TNF-α via the MAPK and NF-κB pathways, but not the GR pathway. Overall, pyxinol derivatives hold potential for application as anti-inflammatory agents.

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Design, Synthesis, and Anti-Inflammatory Activities of 12-Dehydropyxinol Derivatives

Event-driven bifunctional molecules, typified by proteolysis targeting chimera (PROTAC) technology, have been successfully applied in degrading many proteins of interest (POI). Due to the unique catalytic mechanism, PROTACs will induce multiple cycles of degradation until the elimination of the target protein. Here, we propose a versatile "Ligation to scavenging" approach to terminate event-driven degradation for the first time. Ligation to the scavenging system consists of a TCO-modified dendrimer (PAMAM-G5-TCO) and tetrazine-modified PROTACs (Tz-PROTACs). PAMAM-G5-TCO can rapidly scavenge intracellular free PROTACs via an inverse electron demand Diels-Alder reaction and terminate the degradation of certain proteins in living cells. Thus, this work proposes a flexible chemical knockdown approach to adjust the levels of POI on-demand in living cells, which paves the way for controlled target protein degradation.

Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation.

Sound waves are sensitive to environmental perturbation effects and therefore offer great potential for non-invasive sensing of background temperature, pressure or bio-chemical materials. This paper presents a robust design of electromechanical cavity that can supports high Q resonance for the incident sound waves. The electromechanical cavity consists of subwavelength sized tube residing on a piezoelectric substrate. The cavity utilizes piezoelectric base to absorb and convert incident sound waves to resonant electric currents. At the same time the residue resonant acoustic energy is also back reflected in the form of scattered acoustic fields. The resonator is specially designed to enhance the sound matter interactions towards the base of the cavity and therefore increase the sound energy harvesting many folds. The proposed design of electromechanical resonator cavity system offers potential for low cost and ultrasensitive environmental sensing applications.

High Q-factor Electro-Acoustic Cavity Resonator for Sensing Applications

Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.

Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-κB pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis. 

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.

Because of the limited sound insulation provided by a single material, it is common to use multiple layers of materials to improve the effects of sound insulation, but multiple materials increase the size of the model. In some cases, there are limits to the size of the model, or, if subwavelength sizes are required, it is necessary to investigate wideband sound insulation of subwavelength size. We designed a coded topological spherical model on the subwavelength scale, with two materials arranged periodically according to the coding idea. The results showed that at the subwavelength scale, the sound insulation effect of the coded topological spherical model was very significant; the sound pressure after using sound insulation was near 0.3 Pa, but the incident sound pressure was 100 Pa. These results overcome the excessive thickness problem of traditional materials used in sound insulation, which has long puzzled researchers, and expands the application of new sound insulation materials in the energy collection field.

Sound insulation properties of a spherical structure of subwavelength size

The continuous trend to integrate more multi-functions in a package often involves, Heterogeneous Integration of multi-functional blocks in some kind of 3D stacking. The conventional flip chip for die-on-substrate technology applies solder for integration. However, solder joint integration has the disadvantages of restricting height, reflow issues and re-melting at high operating temperatures. Nanometallic particle sintering offers a potential solution for these solder related issues. Nanometallic particle sintering occurs at low temperature and does not reflow and melt at higher temperatures. Hence, it can be applied for quite precise alignment and integration technologies, such as photonic components on silicon for harsh environment applications. In order to test this concept, we use sapphire and Si wafers with different mechanical properties, which can lead to the coefficient of thermal expansion mismatch. The sapphire chip can operate at a higher temperature applied for ultraviolet photonics application. This report describes a novel approach using copper nanoparticles paste patterned through photolithographic stencil printing. The photoresist acts as the stencil mask, and a photoresist lift-off process is applied to strip the photoresist stencil. This process has the advantages of lithographic form factor and precision and provides a chip to chip interconnect with a standard height of 20 µm.

Low Temperature Sapphire to Silicon Flip Chip Interconnects by Copper Nanoparticle Sintering

Janus tyrosine kinase (JAK) inhibitors have been on the market for several years, but their use is limited by drug resistance and intolerable side effects. Herein, we propose a novel strategy of JAK tyrosine kinase (TK) and pseudokinase (PK) domain co-inhibition system to consolidate robust JAK inhibition and on-demand activation. A photoexcited prodrug PAT-SIL-TG-1&AT exhibits the synergy effects of TK-PK co-inhibition and enable the spatiotemporal control of JAK2 signaling. The hypoxia-activated prodrug HAT-SIL-TG-1&AT significantly inhibited HEL cells proliferation and downregulated phosphorylated STAT3/5 under hypoxic conditions. Importantly, HAT-SIL-TG-1&AT showed synergistic antitumor effects and selectively inhibited the JAK-STAT signaling in tumor tissues in vivo. This work demonstrates a viable solution to achieve superior JAK2 inhibition, and provides an inspiration for other kinases containing PK domain. 

Xinrui Ji

Papers

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.

Sound insulation properties of a spherical structure of subwavelength size

Low Temperature Sapphire to Silicon Flip Chip Interconnects by Copper Nanoparticle Sintering

A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation.