Metal-Free Phosphination and Continued Functionalization of Pyridine: A Theoretical Study

This study investigates the mechanism of metal-free pyridine phosphination with P(OEt)₃, PPh₃, and PAr₂CF₃ using density functional theory calculations. The results show that the reaction mechanism and rate-determining step vary depending on the phosphine and additive used. For example, phosphination of pyridine with P(OEt)₃ occurs in five stages, and ethyl abstraction is the rate-determining step. Meanwhile, 2-Ph-pyridine phosphination with PPh₃ is a four-step reaction with proton abstraction as the rate-limiting step. Energy decomposition analysis of the transition states reveals that steric hindrance in the phosphine molecule plays a key role in the site-selective formation of the phosphonium salt. The mechanism of 2-Ph-pyridine phosphination with PAr₂CF₃ is similar to that with PPh₃, and analyses of the effects of substituents show that electron-withdrawing groups decreased the nucleophilicity of the phosphine, whereas aryl electron-donating groups increased it. Finally, TfO⁻ plays an important role in the C–H fluoroalkylation of pyridine, as it brings weak interactions.     

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor,Repurposing for Cancer Therapy

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual−target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N−ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug−resistant cell line MCF−7/ADR and the atypical drug−resistant tumor cell line HL−60/MX2. Our study identified quinacrine as a potential dual−target inhibitor of Topo II and Hsp90, depending on the ATP−binding domain, positioning it as a hit compound for further structural modification.     

Synthesis of N-Substituted Iminosugar C-Glycosides and Evaluation as Promising α-Glucosidase Inhibitors

A series of N-substituted iminosugar C-glycosides were synthesized and tested for α-glucosidase inhibition. The results suggested that 6e is a promising and potent α-glucosidase inhibitor. Enzymatic kinetic assays indicated that compound 6e may be classified as an uncompetitive inhibitor. The study of structure-activity relationships of those iminosugars provided a starting point for the discovery of new α-glucosidase inhibitors.     

Machine Learning for Evaluating the Cytotoxicity of Mixtures of Nano-TiO2 and Heavy Metals: QSAR Model Apply Random Forest Algorithm after Clustering Analysis

With the development and application of nanomaterials, their impact on the environment and organisms has attracted attention. As a common nanomaterial, nano-titanium dioxide (nano-TiO₂) has adsorption properties to heavy metals in the environment. Quantitative structure-activity relationship (QSAR) is often used to predict the cytotoxicity of a single substance. However, there is little research on the toxicity of interaction between nanomaterials and other substances. In this study, we exposed human renal cortex proximal tubule epithelial (HK-2) cells to mixtures of eight heavy metals with nano-TiO₂, measured absorbance values by CCK-8, and calculated cell viability. PLS and two ensemble learning algorithms are used to build multiple QSAR models for data sets, and the test set R² is increased from 0.38 to 0.78 and 0.85, and RMSE is decreased from 0.18 to 0.12 and 0.10. After selecting the better random forest algorithm, the K-means clustering algorithm is used to continue to optimize the model, increasing the test set R² to 0.95 and decreasing the RMSE to 0.08 and 0.06. As a reliable machine algorithm, random forest can be used to predict the toxicity of the mixture of nano-metal oxides and heavy metals. The cluster analysis can effectively improve the stability and predictability of the model, and provide a new idea for the prediction of cytotoxicity model in the future.     

A Collection of Molecular Fingerprints of Single Aerosol Particles in Air for Potential Identification and Detection Using Optical Trapping-Raman Spectroscopy

Characterization, identification, and detection of aerosol particles in their native atmospheric states remain a challenge. Recently, optical trapping-Raman spectroscopy (OT-RS) has been developed and demonstrated for characterization of single, airborne particles. Such particles in different chemical groups have been characterized by OT-RS in recent years and many more are being studied. In this work, we collected single-particle Raman spectra measured using the OT-RS technique and began construction of a library of OT-RS fingerprints that may be used as a reference for potential detection and identification of aerosol particles in the atmosphere. We collected OT-RS fingerprints of aerosol particles from eight different categories including carbons, bioaerosols (pollens, fungi, vitamins, spores), dusts, biological warfare agent surrogates, etc. Among the eight categories, spectral fingerprints of six groups of aerosol particles have been published previously and two other groups are new. We also discussed challenges, limitations, and advantages of using single-particle optical trapping-Raman spectroscopy for aerosol-particle characterization, identification, and detection.     

The Biosynthesis Related Enzyme,Structure Diversity and Bioactivity Abundance of Indole-Diterpenes: A Review

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure–activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure–activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.     

Analysis of Components and Properties of Extractives from Alnus cremastogyne Pods from Different Provenances

Chemical components with anti-oxidant, anti-inflammatory, and anti-cancer properties extracted from Alnus bark and leaves have been extensively studied. However, less attention has been paid to extractives from Alnus pods, which are mostly treated as waste. Here, extractives of Alnus cremastogyne pods from 12 provenances in Sichuan Province were studied for high value-added utilization of Alnus waste. The extractives were analyzed by Gas Chromatography-Mass Spectrometer (GC-MS), Ultraviolet-visible spectroscopy (UV-Vis spectra), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity. A total of 58, 49, and 51 chemical components were found when the organic solvents of ethanol, petroleum ether, and ethyl acetate were used to collect extractives, respectively. These chemical components including Phytol, CIS-5,8,11,14,17-eicosapentaenoic acid, Germacrene D, Lupeol, and β-sitosterol, etc., have wide applications in the fields of pharmacy and cosmetics. Moreover, it was also found that extractives in ethanol and ethyl acetate had impressive UV resistance, especially for UV-C and UV-B blocking. The results showed that the maximum block ratio towards UV-C and UV-B could reach 99%. In addition, the ethanol extract showed good anti-oxidant activity with a maximum free radical scavenging rate of 96.19%. This comprehensive and systematic study on extractives from Alnus cremastogyne pods promotes the development of high-value utilization of Alnus components.     

Ultrasensitive Simultaneous Detection of Multiple Rare Modified Nucleosides as Promising Biomarkers in Low-Put Breast Cancer DNA Samples for Clinical Multi-Dimensional Diagnosis

Early cancer diagnosis is essential for successful treatment and prognosis, and modified nucleosides have attracted widespread attention as a promising group of cancer biomarkers. However, analyzing these modified nucleosides with an extremely low abundance is a great challenge, especially analyzing multiple modified nucleosides with a different abundance simultaneously. In this work, an ultrasensitive quantification method based on chemical labeling, coupled with LC-MS/MS analysis, was established for the simultaneous quantification of 5hmdC, 5fdC, 5hmdU and 5fdU. Additionally, the contents of 5mdC and canonical nucleosides could be obtained at the same time. Upon derivatization, the detection sensitivities of 5hmdC, 5fdC, 5hmdU and 5fdU were dramatically enhanced by several hundred times. The established method was further applied to the simultaneous detection of nine nucleosides with different abundances in about 2 μg genomic DNA of breast tissues from 20 breast cancer patients. The DNA consumption was less than other overall reported quantification methods, thereby providing an opportunity to monitor rare, modified nucleosides in precious samples and biology processes that could not be investigated before. The contents of 5hmdC, 5hmdU and 5fdU in tumor tissues and normal tissues adjacent to the tumor were significantly changed, indicating that these three modified nucleosides may play certain roles in the formation and development of tumors and be potential cancer biomarkers. While the detection rates of 5hmdC, 5hmdU and 5fdU alone as a biomarker for breast cancer samples were 95%, 75% and 85%, respectively, by detecting these three cancer biomarkers simultaneously, two of the three were 100% consistent with the overall trend. Therefore, simultaneous detection of multiple cancer biomarkers in clinical samples greatly improved the accuracy of cancer diagnosis, indicating that our method has great application potential in clinical multidimensional diagnosis.     

Recent Progress in Biosensors for Detection of Tumor Biomarkers

Cancer is a leading cause of death worldwide, with an increasing mortality rate over the past years. The early detection of cancer contributes to early diagnosis and subsequent treatment. How to detect early cancer has become one of the hot research directions of cancer. Tumor biomarkers, biochemical parameters for reflecting cancer occurrence and progression have caused much attention in cancer early detection. Due to high sensitivity, convenience and low cost, biosensors have been largely developed to detect tumor biomarkers. This review describes the application of various biosensors in detecting tumor markers. Firstly, several typical tumor makers, such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), squamous cell carcinoma antigen (SCCA), carbohydrate, antigen19-9 (CA19-9) and tumor suppressor p53 (TP53), which may be helpful for early cancer detection in the clinic, are briefly described. Then, various biosensors, mainly focusing on electrochemical biosensors, optical biosensors, photoelectrochemical biosensors, piezoelectric biosensors and aptamer sensors, are discussed. Specifically, the operation principles of biosensors, nanomaterials used in biosensors and the application of biosensors in tumor marker detection have been comprehensively reviewed and provided. Lastly, the challenges and prospects for developing effective biosensors for early cancer diagnosis are discussed.     

O2 Carrier Myoglobin Also Exhibits β-Lactamase Activity That Is Regulated by the Heme Coordination State

Heme proteins perform a variety of biological functions and also play significant roles in the field of bio-catalysis. The β-lactamase activity of heme proteins has rarely been reported. Herein, we found, for the first time, that myoglobin (Mb), an O₂ carrier, also exhibits novel β-lactamase activity by catalyzing the hydrolysis of ampicillin. The catalytic proficiency ((k_cat/K_M)/k_uncat) was determined to be 6.25 × 10¹⁰, which is much higher than the proficiency reported for designed metalloenzymes, although it is lower than that of natural β-lactamases. Moreover, we found that this activity could be regulated by an engineered disulfide bond, such as Cys46-Cys61 in F46C/L61C Mb or by the addition of imidazole to directly coordinate to the heme center. These results indicate that the heme active site is responsible for the β-lactamase activity of Mb. Therefore, the study suggests the potential of heme proteins acting as β-lactamases, which broadens the diversity of their catalytic functions.