Copper Salt-Catalyzed Formation of a Novel Series of Triazole-Spirodienone Conjugates with Potent Anticancer Activity.

Copper salt-catalyzed oxidative amination resulted in the formation of a novel series of triazole-spirodienone conjugates, 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-3,8-diones and 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-8-ones. A single crystal of compound 1p among them was grown and analyzed by X-ray crystallography. These compounds were evaluated for their antiproliferative activities against MDA-MB-231, HeLa, A549 and MCF-7 cell lines. Most of them showed moderate to high anticancer potency in the four cancer cell lines. The discovery of the triazole-spirodienone conjugates as cytotoxic agents against cancer cells may open up a new field in which these novel small molecules could be further explored as promising anticancer agents

Charge redistribution, charge order and plasmon in La2−x_{2-x}Srx_{x}CuO4_{4}/La2_{2}CuO4_{4} superlattices

Interfacial superconductors have the potential to revolutionize electronics, quantum computing, and fundamental physics due to their enhanced superconducting properties and ability to create new types of superconductors. The emergence of superconductivity at the interface of La$_{2-x}$Sr$_{x}$CuO$_{4}$/La$_{2}$CuO$_{4}$ (LSCO/LCO), with a T$_c$ enhancement of $\sim$ 10 K compared to the La$_{2-x}$Sr$_{x}$CuO$_{4}$ bulk single crystals, provides an exciting opportunity to study quantum phenomena in reduced dimensions. To investigate the carrier distribution and excitations in interfacial superconductors, we combine O K-edge resonant inelastic X-ray scattering and atomic-resolved scanning transmission electron microscopy measurements to study La$_{2-x}$Sr$_{x}$CuO$_{4}$/La$_{2}$CuO$_{4}$ superlattices (x=0.15, 0.45) and bulk La$_{1.55}$Sr$_{0.45}$CuO$_{4}$ films. We find direct evidence of charge redistribution, charge order and plasmon in LSCO/LCO superlattices. Notably, the observed behaviors of charge order and plasmon deviate from the anticipated properties of individual constituents or the average doping level of the superlattice. Instead, they conform harmoniously to the effective doping, a critical parameter governed by the T$_c$ of interfacial superconductors.Comment: 8 pages, 5 figure

Synthesis and Antitumor Activity of a Series of Novel 1-Oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione Derivatives

A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (10a and 10b), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 11b and 11h were the most potent against A549 cell line with 0.18 and 0.19 µM of IC50, respectively; compounds 11d, 11h, and 11k showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC50, respectively, while the activities of 11h, 11k, and 12c against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC50, respectively. Compound 11h is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines

Coherent Random-Modulated Continuous-Wave LiDAR Based on Phase-Coded Subcarrier Modulation

A coherent random-modulated continuous-wave (RMCW) LiDAR transmits a lightwave modulated by a pseudo-random binary sequence (PRBS). The lightwave backscattered from targets is received and used to reconstruct the PRBS. Then, the time-of-flight is extracted by correlating the reconstructed PRBS and the original PRBS. We propose a coherent RMCW LiDAR based on phase-coded subcarrier modulation, in which the impacts of internal reflection and optical Doppler frequency shift (DFS) are mitigated. A continuous lightwave is amplitude-modulated by an RF signal which is phase-coded with a PRBS. Coherent detection is used in the receiver. A beat signal that consisted of a low-frequency signal and a high-frequency signal is obtained by a single balanced photodetector (BPD). The optical DFS can be directly extracted from the low-frequency signal. It is used to compensate for the frequency offset of PRBS, which is extracted from the high-frequency signal. In addition, the background noise caused by internal reflection is suppressed by averaging over successive measurement spots. In this paper, the performance of a coherent RMCW LiDAR is firstly analyzed by numeric simulations and demonstration experiments. Then, line-scanning measurements for moving targets are implemented to demonstrate the 3D imaging capability of the proposed coherent RMCW LiDAR

Boronic Prodrug of 4-hydroxytamoxifen is more Efficacious than Tamoxifen with Enhanced Bioavailability Independent of CYP2D*6 Status

Background: Poor initial response to tamoxifen due to CYP2D*6*4-OHT at therapeutically effective concentrations but at a fraction of the standard tamoxifen dose. Methods: A mouse xenograft tumor model was used to investigate the efficacy of ZB497 in comparison with tamoxifen. Pharmacokinetic studies were conducted to evaluate the metabolism and bioavailability of the drug in mice. Drug and metabolites distribution in xenograft tumor tissues was determined by high performance liquid chromatography-tandem mass spectrometry. Results: The boronic prodrug, ZB497, can not only be efficiently converted to 4-OHT in mice, but also afforded over 30 fold higher plasma concentrations of 4-OHT than in mice given either the same dose of 4-OHT or tamoxifen. Further, ZB497 was more effective than tamoxifen at lowered dosage in inhibiting the growth of xenograft tumors in mice. Consistent with these observations, ZB497 treated mice accumulated over 6 times higher total drug concentrations than tamoxifen treated mice. Conclusions: Our study demonstrates that ZB497 effectively delivers a markedly increased plasma concentration of 4-OHT in mice. The boronic prodrug was shown to have far superior bioavailability of 4-OHT compared to tamoxifen or 4-OHT administration as measured by the area under the plasma concentration time curve (AUC), plasma peak concentrations, and drug accumulation in tumor tissues. Further, ZB497 proves to be a more efficacious hormone therapy than tamoxifen administered at a reduced dose in mice

The Design and Experimentation of a Corn Moisture Detection Device Based on Double Capacitors

Detecting the moisture content of grain accurately and rapidly has important significance for harvesting, transport, storage, processing, and precision agriculture. There are some problems with the slow detection speeds, unstable detection, and low detection accuracy of moisture contents in corn harvesters. In that case, an online moisture detection device was designed, which is based on double capacitors. A new method of capacitance complementation and integration was proposed to eliminate the limitation of single data. The device is composed of a sampling mechanism and a double-capacitor sensor consisting of a flatbed capacitor and a cylindrical capacitor. The optimum structure size of the capacitor plates was determined by simulation optimization. In addition to this, the detection system with software and hardware was developed to estimate the moisture content. Indoor dynamic measurement tests were carried out to analyze the influence of temperature and porosity. Based on the influencing factors and capacitance, a model was established to estimate the moisture content. Finally, the support vector machine (SVM) regressions between the capacitance and moisture content were built up so that the R2 values were more than 0.91. In the stability test, the standard deviation of the stability test was 1.09%, and the maximum relative error of the measurement accuracy test was 1.22%. In the dynamic verification test, the maximum error of the measurement was 4.62%, less than 5%. It provides a measurement method for the accurate, rapid, and stable detection of the moisture content of corn and other grains

Metabolism, Pharmacokinetics, and Bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

ZB716 is a selective estrogen receptor downregulator (SERD) with excellent oral bioavailability and superior efficacy. In this study, we investigate the in vitro and in vivo metabolism and the pharmacokinetics of ZB716 by incubation with liver microsomes, liver cytosol, and by orally dosing rodents. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem +mass spectrometry. The metabolic profile of ZB716 showed fulvestrant and ZB716- sulfone as the two major oxidative metabolites. ZB716 also underwent some degree of sulfation and glucuronidation in vitro. The major oxidative metabolites of ZB716 were found in rat plasma, feces, and urine samples. No sulfation and glucuronidation metabolites from ZB716 were found in plasma. Limited amounts of sulfate conjugates and glucuronides of ZB716 were detected in feces. The glucuronidation on 3-OH position of fulvestrant was the main metabolite found in urine, suggesting that this specific site of phase 2 metabolism is blocked in ZB716 and formation of glucuronide 3-fulvestrant must be preceded by metabolic transformation of ZB716 to fulvestrant. The pharmacokinetic study of ZB716 showed a half-life (t1/2) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (Cmax) at 158.12 ng/mL reached at 2 h after a single dose of 10 mg/kg by oral gavage. Overall this study elucidated important metabolic characteristics of ZB716, an oral SERD that has demonstrated superior bioavailability and efficacy in preclinical studies conducted so far

Fermented Feed Modulates Meat Quality and Promotes the Growth of Longissimus Thoracis of Late-Finishing Pigs

This study investigated the effect of fermented diet on growth performance, carcass traits, meat quality and growth of longissimus thoracis (LT) of finishing pigs. A total of 48 finishing pigs [Duroc × (Landrace × Large White), male, 126 ± 5-d-old] weighing 98.76 ± 1.27 kg were randomly assigned to two treatments (eight pens per treatment and three pigs per pen) for a 28-d feeding trial, including control diet and fermented diet. Fermented diet significantly increased the loin eye area and lean mass percentage, decreased backfat thickness and improved meat quality of LT by decreasing the shear force and drip loss at 48 h post slaughter and improving meat sensory characteristics compared with control diet. A fermented diet also significantly increased the abundance of insulin, insulin receptor (IR), myoblast determination protein (MyoD) and myosin heavy chain-I (MyHC-I) transcripts, and the phosphorylation levels of AKT, mTORC1, 4EBP1 and S6K1 in LT, while decreasing the expression of muscle atrophy F-box (MAFbx) and forkhead Box O1 (Foxo1) mRNA transcripts. Moreover, proteomic analysis revealed that differentially expressed proteins predominantly involved in protein synthesis and muscle development were modulated by fermented diet. Our results indicated that a fermented diet improved meat quality and enhanced LT growth of finishing pigs by increasing insulin/AKT/mTORC1 protein synthesis cascade and activating the Foxo1/MAFbx pathway, along with the regulation of ribosomal protein and proteins involved in muscle contraction and muscle hypertrophy

Development of covalent inhibitors: Principle, design, and application in cancer

Abstract Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages in cancer therapy. As opposed to noncovalent inhibitory drugs, covalent inhibitors reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming to selectively recognize and bind to protein targets and addressing some of the challenges faced by noncovalent drugs. Most successful targeted covalent inhibitors depend primarily on binding‐site cysteine residues, but this has limitations for certain protein targets that lack targetable cysteine residues. Recently, the rational design of covalent inhibitors or covalent probes targeting other nucleophilic residues, such as lysine, tyrosine, serine, has turned out to be another promising strategy for cancer therapy. Thus, the development of novel strategies to extend the scope of covalent binding and improve the binding properties is required. This review gives a summary of the development of covalent inhibitors targeting noncysteine from different aspects, including target identification, structure–activity relationships, drug discovery strategies, and binding properties, in the hope of providing a scientific reference for future covalent drug discovery as a means of expanding research in cancer therapy