Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors.

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.

Design, synthesis and biological evaluation of novel triazoloquinazolinone and imidazoquinazolinone derivatives as allosteric inhibitors of SHP2 phosphatase.

ABSTRCTA series of novel triazoloquinolinone and imidazoquinazolinone derivatives were designed and synthesised, and their biological activities against SHP2 protein and melanoma A357 cell line were evaluated in vitro. The results show that some target compounds have moderate to excellent inhibitory activity on SHP2 protein and melanoma A357 cell line. Structure-activity relationships (SARs) showed that both imidazoquinazolinone and triazoloquinazolinone derivatives have good SHP2 protein kinase and melanoma cell line A357 inhibitory activity. The results of molecular docking also showed that the cores of imidazoquinazolinone and triazoloquinazolinone have a certain affinity for SHP2 protein at the same time. Compared with SHP244, the target compounds have quite good liver microsomal stability and has more drug potential. The most promising compound B1 has a strong inhibitory effect on the melanoma cell line A357 at 100 µM (76.15% inhibition).

Design, synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors.

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.

Turbidity prediction of lake-type raw water using random forest model based on meteorological data: A case study of Tai lake, China.

Turbidity is an indication of water quality and enables the growth of pathogenic microorganisms. For drinking water treatment plants (DWTPs), violent fluctuations in turbidity are highly disruptive to operational performance due to the lag in process parameter adjustments. Such risks must be carefully managed to guarantee safe drinking water. Machine learning techniques have been proven to be effective for modeling complex nonlinear environmental systems, and this study adopted such a technique to develop a model for predicting source water turbidity for DWTPs to allow DWTPs to make proactive interventions in advance. A random forest (RF) model used preprocessed (empirical mode decomposition and quartile rejecting) meteorological factors (wind speed, wind direction, air temperature, and rainfall) as the input variables, to establish the turbidity prediction of a lake with significant turbidity in China's South Tai Lake. The modeling process included four main stages: (1) source data analysis, (2) raw data preprocessing, (3) modeling and tuning, and (4) model evaluation. The results of the RF model indicated that the correlation coefficient between the predicted and actual sequences is over 0.7, and more than 55% of the predicted values could control the errors within 20% compared to the actual measured values, suggesting that machine learning techniques are suitable for predicting the turbidity of raw source water. It was found that the RF model can provide a modest performance boost because of its stronger capacity to capture nonlinear interactions in the data. The findings of this study can inform the development of turbidity prediction models using readily available meteorological forecast data. The model can be applied to other DWTPs using similar shallow lakes as water sources.

Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment.

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

Synthesis, Crystal Structure, Absolute Configuration and Antitumor Activity of the Enantiomers of 5-Bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide.

Pyridinesulfonamide is an important fragment which has a wide range of applications in novel drugs. R- and S-isomers of 5-bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide have been synthesized, and the stereostructures have been researched. Single crystals of both compounds were obtained for X-ray analysis, and the absolute configurations (ACs) have been further confirmed by electronic circular dichroism (ECD), optical rotation (OR) and quantum chemical calculations. The crystal structures and calculated geometries were extremely similar, which permitted a comparison of the relative reliabilities of ACs obtained by ECD analyses and theoretical simulation. In addition, the effect of stereochemistry on the PI3Kα kinase and anticancer activity were investigated. Compounds 10a and 10b inhibit the activity of PI3Kα kinase with IC50 values of 1.08 and 2.69 µM, respectively. Furthermore, molecular docking was performed to analyze the binding modes of R- and S-isomers.

Quantitative prediction of enantioseparation using ß-cyclodextrin derivatives as chiral selectors in capillary electrophoresis.

ß-Cyclodextrin derivatives as chiral selectors are becoming increasingly important for enantioseparations in capillary electrophoresis (CE). Nevertheless, there are some enormous challenges in choosing effective selectors from a variety of compounds, and up to now no systematic quantitative studies for predicting the possibility of enantiomeric separation before CE experiments have been reported. In this paper, in order to resolve previous confusions, we investigated the enantioseparations of ten chiral drugs using a method of combining experiments with theoretical calculations. MMFF, PM3, DFT and ONIOM2 methods were simultaneously utilized during the course of our computer simulations. The results indicated that a specific value of greater than or approximately equal to 6 kJ mol(-1) for the interaction energy difference (ΔΔE) between a pair of enantiomers with a selector is required in order to achieve enantiomeric separation. This discovery offers a meaningful reference to predict enantiomeric separations, so as to design and synthesize some more efficient chiral selectors.

The influence of wind-induced sediment resuspension and migration on raw water turbidity in Lake Taihu, China.

Lake Taihu is an important drinking water source for cities in the Yangtze River Delta region, while the dramatic fluctuation in turbidity has caused severe problems for local waterwork management. The effects of sediment resuspension and migration on turbidity of water intake in a waterworks located in the south of Lake Taihu are studied. Because the sediment behavior induced by wind disturbance was believed to be the main factor for the matter, the effect of wind field on the hydrodynamics and sediment distribution of Lake Taihu was conducted based on a wind-driven numerical model. The obtained results indicate that wind direction was more influential on the structure of flow and wave fields, while wind speed contributed more to the field intensity. The suspended sediment concentration (SSC) of water intake area was most sensitive to onshore winds, which led to significant increase in suspended sediment concentration at 3 m/s, while for alongshore winds, the incipient speed was 4 m/s, and offshore winds were less influential. In addition, the suspended sediment of the water intake area was primarily migrated from other erosion regions rather than local suspended particles. A 7-h lag was found between SSC and the measured turbidity confirmed the lag effect of wind disturbance on turbidity change. The high consistency between the 2 series demonstrated the potential of this method to turbidity prediction when combined with the weather forecast technique.

Characterization of Single Nucleotide Variants of OPN3 Gene in Melanocytic Nevi and Melanoma.

In this study, we examined single nucleotide variants (SNVs) of the OPN3 gene in malignant melanoma and melanocytic nevi. A total of 20 variants of SNVs were detected. Of these variants, five nonsynonymous mutations of OPN3 were identified, including c.T152C, c.T401C, c.G547A, c.G768A, and c.G992A. Three prediction tools, MutationTaster2, Polymorphism Phenotyping version 2, and PROVEAN (Protein Variation Effect Analyzer), which predict possible impact of an amino acid substitution, suggested that the mutations could be deleterious. Nine SNVs occurred in 3' untranslated regions, whereas two were observed in 5' untranslated regions. In all cases, four intronic variants were identified. In addition, we identified nine 3' untranslated region SNVs in OPN3; one of them (OPN3[NM_014322:c.∗83C>T]) is predicted to disrupt a conserved microRNA (has-miR-376c-3p) target site, located in position 86-93 of OPN3 3' untranslated region. Our findings suggest that there is a strong possibility that OPN3 SNVs play a role in the pathogenesis of melanocytic tumors via prediction of functional phenotype.

Study on molecular structure, spectroscopic investigation (IR, Raman and NMR), vibrational assignments and HOMO-LUMO analysis of L-sodium folinate using DFT: a combined experimental and quantum chemical approach.

In the present work, an exhaustive conformational search of N-[4-[[(2-amino-5-formyl-(6S)-3,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid disodium salt (L-SF) has been preformed. The optimized structure of the molecule, vibrational frequencies and NMR spectra studies have been calculated by density functional theory (DFT) using B3LYP method with the 6-311++G (d, p) basis set. IR and FT-Raman spectra for L-SF have been recorded in the region of 400-4000 cm(-1) and 100-3500 cm(-1), respectively. 13C and 1H NMR spectra were recorded and 13C and 1H nuclear magnetic resonance chemical shifts of the molecule were calculated based on the gauge-independent atomic orbital (GIAO) method. Finally all of the calculation results were applied to simulate IR, Raman, 1H NMR and 13C NMR spectrum of the title compound which showed excellent agreement with observed spectrum. Furthermore, reliable vibrational assignments which have been made on the basis of potential energy distribution (PED) and characteristic vibratinonal absorption bands of the title compound in IR and Raman have been figured out. HOMO-LUMO energy and Mulliken atomic charges have been evaluated, either.