JOURNAL OF ORGANIC CHEMISTRY
·
2024
·
IF 3.3
Yan-Ling Liu,Xian-Chen He,Jie Gao,Ke-Rong Li,Kai Chen,Hao-Yue Xiang,Hua Yang
Herein, visible light-induced, nickel-catalyzed direct functionalization of the Hantzsch esters (HEs) with readily accessible alkyl bromides has been successfully achieved by taking advantage of HE as the reductant and substrate through an aromatization-dearomatization process. In this strategy, the single electron reduction of alkyl bromides by reactive Ni(I) species is essential for the success of this late-stage transformation. A wide range of 4-alkyl-1,4-dihydropyridines were rapidly assembled in moderate to good yields under mild conditions, rendering this photoinduced approach attractive for synthetic and medicinal chemistry.
研究领域:
有机化学
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光化学
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催化
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合成方法学
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药物化学
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DOI
高影响因子
ANALYST
·
2023
·
IF 4.2
Lihua Xu,Qiong Wang,Yan Liu,Songsen Fu,Yufen Zhao,Shaohua Huang,Biling Huang
Chiral amino-group compounds are of significance for human health, such as biogenic amino acids (AAs), dipeptides, and even various drugs. Enantiospecific discrimination of these chiral compounds is vital in diagnosing diseases, identifying pathological biomarkers and enhancing pharmaceutical chemistry research. Here, we report a simple and rapid 19F NMR-based strategy to differentiate chiral AAs, dipeptides, and amines, that were derivatized with (R)-2-(2-fluorophenyl)-2-hydroxyacetic acid ((R)-2FHA). As a result, 19 proteinogenic AAs (37 isomers) as well as Gly could be concurrently resolved. Moreover, various mirror-image dipeptides, such as Ser–His, Leu–Leu, and Ala–Ala, were commendably recognized. Intriguingly, we found that the absolute configuration of AAs in the N-terminus of dipeptides decided the relative 19F chemical shifts between two enantiomers. Besides, the ability of this method for enantiodiscrimination was further demonstrated by non-AA amines, including aromatic and aliphatic amines, and even amines having chiral centers several carbons away from the amino-group. The structurally similar antibiotics, amoxicillin and ampicillin, were well discriminated. Furthermore, this method accurately determines the de or dr values of non-racemic mixtures. Therefore, our strategy provides an effective approach for 19F NMR-based enantiodiscrimination and diastereomeric purity determination of amino-group compounds.
研究领域:
分析化学
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药物化学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOCHEMICAL ANALYSIS
·
2025
·
IF 2.6
Peng Yang,Hu-Dong Lv,Jie Wu,Fang Long,Jing Zhou,Cheng-Ying Wu,Jin-Di Xu,Shan-Shan Zhou,Qing-Ling Xiao,Song-Lin Li,Hong Shen
Introduction The role of macromolecular components in traditional Chinese medicines (TCMs) decoction remains poorly understood, primarily because of their structural complexity and limited systemic bioavailability. In the modernization of TCMs' decoctions, macromolecular components are often removed as “poor bioavailable impurities” by ethanol precipitation that might attenuate the efficacy thereof. Purpose A novel strategy integrating LC–MS-based serum pharmacochemistry, network pharmacology, and pharmacodynamics was developed to reveal the role of macromolecular components in TCMs' decoction, using Qi-Huo-Yi-Fei decoction (QH) treating chronic obstructive pulmonary disease (COPD) as a case study. Materials and Methods QH was separated into macromolecular components (QH-M) and small molecular components (QH-S) by ethanol precipitation. The absorbed components of QH and QH-S in serum were qualitatively and semiquantitatively analyzed by UPLC-QTOF-MS/MS. The differences in targets and pathways of the absorbed components were predicted by network pharmacology analysis. The therapeutic effects on pulmonary function, histopathology, and inflammation of QH, QH-S, and QH-M were comparatively investigated on a COPD rat model. Result A total of 103 components were identified in QH and QH-S, whereas 86 and 72 were detectable in QH- or QH-S-treated serum, respectively. The highest levels of absorbed components appeared from 15 to 60 min for QH-S and at 15 min for QH. The concentrations of most absorbed components of QH were twofold higher than those of QH-S. Their protein–protein interaction (PPI), herb–component–target networks, and GO/KEGG enrichment pathways were quite different, mainly in inflammatory, immunity, and cell apoptosis processes. QH-M improved pulmonary function, histopathology, and inflammatory infiltration, mainly on FVC ( p < 0.05), thickness/external diameter ( p < 0.01), Wac/Pbm ( p < 0.01), TNF-α ( p < 0.01), and IL-17 ( p < 0.05). Meanwhile, QH was more effective than QH-S, mainly on FEV0.3/FVC, MAN, GC/CC, TNF-α, and IL-17. Conclusion QH-M was not only effective independently on COPD but also showed integrative effects with the coexisting QH-S in improving their absorption, thus strengthening the component–target interactions, and consequently contributing to the COPD therapeutic effects of QH. Therefore, it was confirmed that QH-M was essential for QH's COPD therapy and should not be removed during the modern preparation development.
研究领域:
药理学
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分析化学
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系统生物学
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中医药学
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呼吸医学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2025
·
IF 2.5
xiaoli wen,Fangyan Cai,Biting Cheng,Min Tan,Xiang Zhang,Ziheng Yao,Rumei Huang,Ge Zhang,Ling Liu,Hongning Liu
Qingzao Jiufei Decoction (QD) is a renowned prescription for nourishing lung Yin to treat lung related diseases in ancient and modern times. It has been reported that QD can effectively inhibit the growth of lung cancer, but the material basis and mechanism of its treatment of LC remain to be further studied. In this experiment, we combined serum pharmacochemistry and proteomics to study the pharmacodynamic material basis and mechanism of QD against lung cancer. The results showed that In vitro a total of 121 compounds were identified. A total of 33 prototype chemical components were identified in vivo, which may be effective active ingredients for QD treatment of LC. Proteomic experiments have shown that compared with the model group, 113 DEPs in LC tissues were significantly changed after QD treatment, among which 57 proteins were significantly up-regulated and 56 proteins were significantly down-regulated (p < 0.05), GO and KEGG enrichment analysis was performed on these DEPs. A total of 205 pathways were enriched, and the PI3K-Akt signaling pathway was experimentally verified. The results showed that QD can be used to treat lung cancer by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway.
研究领域:
药理学
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肿瘤学
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蛋白质组学
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中医药
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生物信息学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Xiao-yu Zhang,Kai-rou Xia,Ya-ni Wang,Pei Liu,Er-xin Shang,Cong-yan Liu,Yu-Ping Liu,Ding Qu,Wei-wen Li,Jin-ao Duan,Yan Chen,Huang-qin Zhang
Ethnopharmacological relevance Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. Aim of the study The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. Materials and methods The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H 2 O 2 -induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. Results The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1β, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1β, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H 2 O 2 -induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. Conclusion Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1β, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.
研究领域:
药理学
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心脏病学
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民族药理学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Nutrients
·
2024
·Vol. 16
·期 22
·3854
·
IF 4.8
Yannan Zhang,Sijuan Huang,Shuai Zhang,Zhihui Hao,Jianzhong Shen
Background: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic functional gastrointestinal disorder that causes diarrheal and intestinal barrier disruptions. Although pomegranate peel extract (PPE) has been reported for the treatment of diarrheal and intestinal inflammation, its effectiveness and mechanisms specifically for the treatment of IBS-D remain unknown. Objectives: This study aimed to explore the therapeutic effect of PPE on IBS-D and elucidate its underlying mechanisms. Methods: A high-fat diet, restraint stress, and senna gavage were combined to establish a rat model mimicking IBS-D, to evaluate the therapeutic effects of PPE. Network pharmacology analysis, serum medicinal chemistry, and transcriptomics were employed to investigate potential downstream signaling pathways. Findings were further validated through molecular docking and Western blot analysis. Results: The findings revealed that PPE significantly improved the symptoms of IBS-D, ameliorated intestinal inflammation, and promoted intestinal barrier function. The target genes in the MAPK and NF-κB signaling pathways were significantly enriched and down-regulated. Molecular docking and Western blot assays were performed to verify that PPE had a high affinity for the protein candidates in these pathways, and significantly down-regulated the expression of p-IκB, p-p65, p-JNK, p-p38, and p-ERK1/2. Conclusions: The present study is the first to demonstrate that PPE alleviates diarrheal and intestinal damage in IBS-D, potentially by inhibiting MAPK and NF-κB signaling pathways. These findings suggest that PPE may provide a novel therapeutic option for IBS-D.
CAS / MDL:
研究领域:
胃肠病学
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药理学
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分子生物学
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动物模型
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功能基因组学
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产品关联
DOI
PubMed
高影响因子
RUSSIAN JOURNAL OF GENERAL CHEMISTRY
·
2024
·Vol. 94
·期 1
·170-183
·
IF 0.9
Li T.,Fu X.,Wang Y.,Ouyang F.,Liu L.,Wen M.,Zha G.,Zhu L.
Abstract Celecoxib (CXB) is a nonsteroidal anti-inflammatory drug (NSAID). However, the application of CXB has been compromised by its poor aqueous solubility and low oral bioavailability. We developed a series of ternary solid dispersions (SDs) of CXB to increase its solubility. In this study, the polymers were screened to determine that they have the potential to increase the solubility of CXB in the solution. A hydrophilic polymer-hydroxypropyl methylcellulose (HPMC) and a surfactant Tween80 were employed as matrix respectively in the optimized formulations. Experimental data revealed that CXB was molecularly distributed within all dispersions in amorphous form by using Differential Scanning Calorimetry (DSC), Polarizing Light Microscopy (PLM), and X-ray powder diffraction (XRD). Fourier Transform Infrared Spectroscopy (FTIR) results showed that the characteristic peaks of CXB have shifted. Compared with pure CXB, the addition of excipients can reduce the contact angle, and improve the solubility of CXB. Ternary SDs were dissolved in PBS (pH 6.8) and formed drug-carrying nanoparticles. In vitro dissolution results indicated that the dissolution amount of HPMC-CXB 5 : 1 SD (32.08±1.56% for 120 min) was higher than pure CXB (3.09±0.29%). In particular, the greatest dissolution enhancement was obtained from the test of which the result was HPMC/Tween80-CXB 3 : 2 : 1 SD (44.12±2.01% for 120 min). This study showed that ternary SDs could be a promising strategy for improving CXB dissolution.
研究领域:
药剂学
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药物化学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yang Zhao,Xinyue Zhao,Lewei Duan,Ruxue Hou,Yuxin Gu,Zhen Liu,Jianbin Chen,Feizhen Wu,Limin Yang,X. Chris Le,Qiuquan Wang,Xiaowen Yan
The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton’s tyrosine kinase (BTK). The effects of As warheads’ valency, thiol protection, methylation, spacer length, and size on inhibitors’ activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against BTK. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL cancer treatment.
研究领域:
癌症研究
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药理学
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分子生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yinghui Ding,Xinzhong Ruan,Kun Shu,Weiyuan Xu,Yao Liu,Gengshen Mo,Jiao Xu,Yong Jian,Jilai Zhang,Lingfeng Zhang,Keren Wang,Ji-Ting Hou,Jianliang Shen,Zhihan Yan,Fangfu Ye,Jiang Zhu,Lixiong Dai
Hepatobiliary-specific magnetic resonance imaging contrast agents (MRI CAs) play a crucial role in the early diagnosis of hepatocellular carcinoma (HCC). However, only two acyclic CAs, Gd-BOPTA and Gd-EOB-DTPA, exhibit unfavorable kinetic inertness. Our study focused on the development of superior stable innovative macrocyclic CAs. By introducing a lipophilic benzyloxy group (OBn) into the H4DOTA ring (Gd-L1), we achieved significant enhancement in kinetic inertness. In vivo experiments in mice demonstrated that 40% of the dosage was distributed to the liver at 5 min, providing sustained hepatic enhancement for over 35 min. We also developed an MPO-responsive MRI CA (Gd-L3), which can participate in the “peroxidase cycle” as the substrate, generating oligomers with a 3.8-fold increase in relaxivity, and selectively enhance the lesion in an acute gout mouse model. Overall, our work represents a significant advancement in the field of hepatic and inflammatory MRI, offering promising avenues for early diagnosis and improved imaging outcomes.
研究领域:
医学成像
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Ting Wang,Xiufeng Liao,Xiaodi Zhao,Kai Chen,Yangzhonghui Chen,Hui Wen,Dali Yin,Yuchen Wang,Bin Lin,Sen Zhang,Huaqing Cui
Mimicking the transition state of tryptophan (Trp) and O 2 in the enzymatic reaction is an effective approach to design indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC 50 of 82–91 nM, and exhibited selectivity between IDO1 and tryptophan 2, 3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.
研究领域:
药理学
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免疫学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Ping Sun,Na Xu,Xue Zhang,Yun-Fei Gao,Jia-Yin Zhang,Qi-Ming Zhang,Chen Liang,Ri-Lei Yu,Ya-Mu Xia,Wei-Wei Gao
In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[ de ]isoquinoline-1,3(2H)-dione ( D-11 ) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[ de ]isoquinoline-1,3(2H)-dione ( D-12 ) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 ( D-12 ) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ct DNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12 , the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 ( D-12 ) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV–vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 ( D-12 ) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.
研究领域:
药物化学
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生物化学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Future Medicinal Chemistry
·
2024
·
IF 3.2
Haili Yang,Xiaoyang Zhang,Letian Xu,Yuting Zhou,Rui Ma,Hao Chen,Siqin Zhao,Munkhtsetseg Baatar,Lvyi Chen,Xukun Deng,Hongwei Gu,Xiaoming Wang
Aim: Lysosomal pH changes are associated with drug resistance, cell growth and invasion of tumors, but effective and specific real-time monitoring of lysosomal pH compounds for cancer therapy is lacking. Materials & methods: Here, based on the covalent linkage of the anticancer drug palbociclib and fluorescent dye fluorescein isothiocyanate (FITC), we designed and developed a novel palbociclib-derived multifunctional molecule (Pal-FITC) for lysosomal targeting and diagnostic therapeutic integration. Results & discussion: Pal-FITC fluoresces is 20-fold stronger than that of FITC and shows a linear response in the pH range of 4.0–8.2 (R2 = 0.9901). Pal-FITC blocks cells in G1 phase via Cyclin D-CDK4/6-Rb. Conclusion: Our study provides new strategies for tumor-targeted imaging and personalized therapy.
研究领域:
肿瘤学
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药物化学
·
分子生物学
·
诊疗一体化
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）