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学者姓名：胡利明
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Abstract ：
HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.
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| GB/T 7714 | Yang, Leifu , Li, Yaxin , Du, Yunling et al. Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases [J]. | JOURNAL OF MEDICINAL CHEMISTRY , 2024 , 67 (7) : 5662-5682 . |
| MLA | Yang, Leifu et al. "Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases" . | JOURNAL OF MEDICINAL CHEMISTRY 67 . 7 (2024) : 5662-5682 . |
| APA | Yang, Leifu , Li, Yaxin , Du, Yunling , Guo, Yan , Guo, Zhenke , Liu, Baoxiu et al. Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases . | JOURNAL OF MEDICINAL CHEMISTRY , 2024 , 67 (7) , 5662-5682 . |
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Abstract ：
Transforming growth factor beta type 1 receptor (TGF beta R1), a crucial serine-threonine kinase, is central to the TGF beta/Smad signaling pathway, governing cellular processes like growth, differentiation, apoptosis, and immune response. This pathway is closely linked to the epithelial-mesenchymal transition (EMT) process, which plays an important role in the metastasis of hepatocellular carcinoma (HCC). To date, only limited inhibitors targeting TGF beta R1 have entered clinical trials, yet they encounter challenges, notably high toxicity, in clinical applications. Herein, an efficient virtual screening pipeline was developed. Eighty compounds were screened from a pool of over 17 million molecules based on docking scores and binding free energy. Four compounds were manually selected with the assistance of enhanced sampling method BPMD (binding pose metadynamics). The binding stability of these four compounds complexed with TGF beta R1 was subsequently studied through long-timescale conventional molecular dynamics simulations. The three most promising compounds were subjected to in vitro bioactivity assays. Cpd272 demonstrated moderate inhibitory activity against TGF beta R1, with an IC50 value of 1.57 +/- 0.33 mu M. Moreover, it exhibited cytotoxic effects on human hepatocellular carcinoma cell line Bel-7402. By shedding light on the binding mode of the receptor-ligand complexes, Cpd272 was identified as a hit compound featuring a novel urea-based scaffold capable of effectively inhibiting TGF beta R1.
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| GB/T 7714 | Li, Yaxin , Liu, Sisi , Wang, Zhuoya et al. Discovery of a urea-based hit compound as a novel inhibitor of transforming growth factor-β type 1 receptor: in silico and in vitro studies [J]. | PHYSICAL CHEMISTRY CHEMICAL PHYSICS , 2024 , 26 (37) : 24564-24576 . |
| MLA | Li, Yaxin et al. "Discovery of a urea-based hit compound as a novel inhibitor of transforming growth factor-β type 1 receptor: in silico and in vitro studies" . | PHYSICAL CHEMISTRY CHEMICAL PHYSICS 26 . 37 (2024) : 24564-24576 . |
| APA | Li, Yaxin , Liu, Sisi , Wang, Zhuoya , Wang, Xiaoli , Xu, Jiamin , Yao, Keke et al. Discovery of a urea-based hit compound as a novel inhibitor of transforming growth factor-β type 1 receptor: in silico and in vitro studies . | PHYSICAL CHEMISTRY CHEMICAL PHYSICS , 2024 , 26 (37) , 24564-24576 . |
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双靶标酪氨酸激酶抑制剂在克服药物抗性和减少药物毒副作用方面具有重要作用，本文设计并合成了含有吡唑酮基团的喹唑啉衍生物作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂。目标化合物由喹唑啉中间体和吡唑酮中间体通过亲核取代反应合成。喹唑啉中间体以2,3,4-三羟基苯甲酸为原料，通过酯化、硝化、还原、氯化和环化等反应合成；吡唑酮中间体以4-取代苯基肼盐酸盐为原料，通过甲基化和氧化等反应合成。目标化合物通过~1H NMR、~(13)C NMR和HR-MS进行结构鉴定。分别采用ADP-Glo激酶活性检测方法和CCK-8法测定了目标化合物对EGFR和VEGFR-2的抑制活性以及对Hela细胞、A549细胞、HUVEC细胞的抗增殖活性，其对EGFR和VEGFR-2抑制活性IC_(50)值为10～899 nM, 15～712 nM;对部分在分子水平测定表现出较高活性的化合物进行了抗增殖活性测定，所选定的化合物对人肺癌A549细胞的半抑制浓度IC_(50)值为10～267 nM,对人脐静脉内皮细胞HUVEC的半抑制浓度IC_(50)值为11～433 nM,对人宫颈癌细胞Hela细胞几乎没有表现出抑制活性。对在细胞和分子水平测试均表现出良好活性的化合物5l通过分子对接研究发现其能够很好地结合在EGFR激酶和VEGFR-2激酶的活性口袋中。本研究为发现EGFR和VEGFR-2双靶标小分子酪氨酸激酶抑制剂奠定了良好的基础。
Keyword ：
酪氨酸激酶 酪氨酸激酶 二噁烷并喹唑啉 二噁烷并喹唑啉 抗肿瘤活性 抗肿瘤活性 吡唑酮 吡唑酮 双靶标抑制剂 双靶标抑制剂
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| GB/T 7714 | 许佳敏 , 魏洪磊 , 李亚鑫 et al. 含吡唑酮基团的喹唑啉衍生物的合成及其作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂 [J]. | 合成化学 , 2024 , 32 (03) : 250-260,281 . |
| MLA | 许佳敏 et al. "含吡唑酮基团的喹唑啉衍生物的合成及其作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂" . | 合成化学 32 . 03 (2024) : 250-260,281 . |
| APA | 许佳敏 , 魏洪磊 , 李亚鑫 , 杨磊夫 , 莫善雁 , 胡利明 . 含吡唑酮基团的喹唑啉衍生物的合成及其作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂 . | 合成化学 , 2024 , 32 (03) , 250-260,281 . |
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Abstract ：
Peroxynitrite (ONOO-) is a crucial reactive oxygen species that plays a vital role in cellular signal transduction and homeostatic regulation. Determining and visualizing peroxynitrite accurately in biological systems is important for understanding its roles in physiological and pathological activity. Among the various detection methods, fluorescent probe-based spectroscopic detection offers real-time and minimally invasive detection, high sensitivity and selectivity, and easy structural and property modification. This review categorizes fluorescent probes by their fluorophore structures, highlighting their chemical structures, recognition mechanisms, and response behaviors in detail. We hope that this review could help trigger novel ideas for potential medical diagnostic applications of peroxynitrite-related molecular diseases.
Keyword ：
in vivo imaging in vivo imaging medical diagnostic medical diagnostic peroxynitrite peroxynitrite intracellular imaging intracellular imaging fluorescent probes fluorescent probes
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| GB/T 7714 | Liu, Zixin , Mo, Shanyan , Hao, Zhenming et al. Recent Progress of Spectroscopic Probes for Peroxynitrite and Their Potential Medical Diagnostic Applications [J]. | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES , 2023 , 24 (16) . |
| MLA | Liu, Zixin et al. "Recent Progress of Spectroscopic Probes for Peroxynitrite and Their Potential Medical Diagnostic Applications" . | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 24 . 16 (2023) . |
| APA | Liu, Zixin , Mo, Shanyan , Hao, Zhenming , Hu, Liming . Recent Progress of Spectroscopic Probes for Peroxynitrite and Their Potential Medical Diagnostic Applications . | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES , 2023 , 24 (16) . |
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The high structural homology of histone deacetylases 6 and 8 (HDAC6/8) poses a challenge in achieving isoform selectivity and has resulted in adverse side effects due to pan-inhibition in clinical applications. Additionally, the rational design of dual-target inhibitors, centered on HDAC6/8, demands a profound understanding of their selectivity mechanisms. Addressing the urgent need for enhanced specificity in the development of inhibitors targeting specific isoforms, we elucidate the mechanism underpinning the selective inhibition of HDAC6/8 inhibitors through in-silico strategies. The hydrogen bonding interaction with Asp101 and Tyr306 is a key factor that enables compound 12b to selectively inhibit HDAC8. Its favorable spatial orientation places the Cap group of 12b between Tyr306 and Tyr100, resulting in an overall L-shaped conformation. These two factors significantly contribute to the selective inhibitory activity of 12b against HDAC8. The zinc binding group (ZBG) of compound NN-390 forms a hydrogen bond with His610, a key residue of HDAC6, facilitating stable chelation with zinc ions. In addition, the Cap group of NN-390 interacts with Phe620 and Phe680 via van der Waals forces, leading to an overall Y-shaped conformation. The aforementioned factors are the main reasons for the selective inhibition of HDAC6 by NN-390. Furthermore, whether the Cap group is in the para or meta-position will influence the selective inhibition of either HDAC6 or HDAC8. We believe these clues can offer valuable insights for the rational design of selective inhibitors targeting HDAC6/8 and pave the way for rational design of dual-target HDAC6/8-based inhibitors.Communicated by Ramaswamy H. Sarma
Keyword ：
isoform selectivity isoform selectivity molecular dynamics simulation molecular dynamics simulation Histone deacetylases Histone deacetylases binding pose metadynamics binding pose metadynamics drug design drug design
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| GB/T 7714 | Li, Yaxin , Liu, Sisi , Xu, Ximing et al. Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8 [J]. | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS , 2023 . |
| MLA | Li, Yaxin et al. "Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8" . | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023) . |
| APA | Li, Yaxin , Liu, Sisi , Xu, Ximing , Xu, Jiamin , Yang, Leifu , Hu, Liming . Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8 . | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS , 2023 . |
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Abstract ：
为阐明模拟失重条件下免疫功能变化在过敏性哮喘发生中的作用,在正常条件下和尾吊模拟失重条件下利用卵清蛋白(OVA)刺激诱导小鼠过敏性哮喘,通过小鼠外观、精神、呼吸、擦鼻情况以及肺组织切片、支气管肺泡灌洗液细胞计数评估过敏性哮喘的程度,通过脾细胞计数和淋巴细胞亚群测定小鼠免疫状态.结果表明:小鼠尾吊模拟失重可以改善OVA诱导过敏性哮喘小鼠的外观、精神、呼吸、擦鼻情况,减少OVA诱导小鼠支气管肺组织中炎性细胞浸润,减轻肺泡壁的增厚,降低细胞间质的渗出;与单纯的OVA组相比,尾吊减少了支气管肺泡灌洗液细胞的数目(P<0.001),降低脾细胞的总数(P<0.01),T辅助细胞(Th)1、Th2和Th17亚群占比降低,调节T细胞(Treg)亚群占比显著升高(P<0.05).尾吊模拟失重下,OVA诱导条件下,机体免疫功能发生改变,与过敏性哮喘的病情有一定相关性.
Keyword ：
尾吊模拟失重 尾吊模拟失重 过敏性哮喘 过敏性哮喘 免疫功能 免疫功能
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| GB/T 7714 | 甄珍 , 宋锦苹 , 李悠悠 et al. 尾吊模拟失重对小鼠过敏性哮喘的影响及其机制研究 [J]. | 载人航天 , 2023 , 29 (2) : 164-169 . |
| MLA | 甄珍 et al. "尾吊模拟失重对小鼠过敏性哮喘的影响及其机制研究" . | 载人航天 29 . 2 (2023) : 164-169 . |
| APA | 甄珍 , 宋锦苹 , 李悠悠 , 杜锐凯 , 凌树宽 , 胡利明 et al. 尾吊模拟失重对小鼠过敏性哮喘的影响及其机制研究 . | 载人航天 , 2023 , 29 (2) , 164-169 . |
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Abstract ：
Due to the lack of confirmation technology for rapid identification of rice origin, 186 rice samples from Wuchang, Northeast and South of China, were identified by near-infrared mid-infrared, and Raman combined with chemometric analysis in this study. Firstly, the recognition effects of three algorithms of k-nearest neighbor method (KNN) linear discriminant analysis (LDA) and least squares-support vector machine LS-SVM), combined with five preprocessing methods on three single spectrum rice origin identification models are compared. The results show that the Raman spectrum model of the LS-SVM algorithm combined with the SNV+2nd preprocessing method is the best, and the accuracy of the calibration set and validation set are 100% and 93. 48% respectively. In order to further improve the accuracy of the identification model, the rice-origin identification models of data layer fusion, feature layer fusion and decision-layer fusion based on near-infrared spectroscopy, midinfrared spectroscopy and Raman spectroscopy are established innovatively. The results show that the recognition accuracy of the three spectral information fusion model levels is greatly improved compared with the single spectral model. In the data layer fusion rice origin identification model, the LS-SVM algorithm combined with SNV+2nd preprocessing method is the best model. The accuracy of the calibration set and validation set are 100% and 95. 65% respectively, which is 2.17% higher than that of a single spectral optimal model. In the decision-level fusion identification model, the LS-SVM algorithm combined with the SNV+ 1st preprocessing method is the best model. The accuracy of the calibration set and validation set are 100% and 97. 83% respectively, which is 4. 35% higher than that of a single spectral optimal model. In the feature layerfusion origin identification model, the LS-SVM algorithm combined with SNV+2nd preprocessing method is the best identification model. The recognition accuracy of the calibration set and validation set are both 100%, which is 6. 52% higher than that of the single spectral optimal model. The results show that it is feasible to use near-infrared spectroscopy, mid-infrared spectroscopy and Raman spectroscopy combined with chemometrics to identify rice origin, and the rice origin identification model based on Raman spectroscopy combined with LS-SVM algorithm is the best. The recognition accuracy of the three spectral information fusion model levels is greatly improved compared with the single spectral model. Among them, the feature level fusion method is more suitable for the data type of this fusion and can quickly and accurately identify the origin of Wuchang rice, Southern rice and Northeast rice. This study provides a new method for rapidly and accurately identifying rice-producing areas.
Keyword ：
Rice origin Rice origin Spectral information fusion Spectral information fusion Identification analysis Identification analysis
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| GB/T 7714 | Luan Xin-xin , Zhai Chen , An Huan-jiong et al. Applications of Molecular Spectral Information Fusion to Distinguish the Rice From Different Growing Regions [J]. | SPECTROSCOPY AND SPECTRAL ANALYSIS , 2023 , 43 (9) : 2818-2824 . |
| MLA | Luan Xin-xin et al. "Applications of Molecular Spectral Information Fusion to Distinguish the Rice From Different Growing Regions" . | SPECTROSCOPY AND SPECTRAL ANALYSIS 43 . 9 (2023) : 2818-2824 . |
| APA | Luan Xin-xin , Zhai Chen , An Huan-jiong , Qian Cheng-jing , Shi Xiao-mei , Wang Wen-xiu et al. Applications of Molecular Spectral Information Fusion to Distinguish the Rice From Different Growing Regions . | SPECTROSCOPY AND SPECTRAL ANALYSIS , 2023 , 43 (9) , 2818-2824 . |
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Abstract ：
Spaceflight presents a series of physiological and pathological challenges to astronauts resulting from ionizing radiation, microgravity, isolation, and other spaceflight hazards. These risks cause a series of aging-related diseases associated with increased oxidative stress and mitochondria dysfunction. The skin contains many autofluorescent substances, such as nicotinamide adenine dinucleotide phosphate (NAD(P)H), keratin, melanin, elastin, and collagen, which reflect physiological and pathological changes in vivo. In this study, we used a portable handheld two-photon microscope to conduct high-resolution in vivo skin imaging on volunteers during 15 days of head-down bed rest. The two-photon microscope, equipped with a flexible handheld scanning head, was used to measure two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) images of the left forearm, left front chest, and forehead of volunteers. Changes in TPEF, SHG, and the extended SHG-to-AF(TPEF) aging index of the dermis (SAAID) were measured. It was found that TPEF intensity increased during bed rest and was restored to normal levels after recovery. Meanwhile, SHG increased slightly during bed rest, and the skin aging index increased. Moreover, we found the skin TPEF signals of the left forearm were significantly negatively associated with the oxidative stress marker malondialdehyde (MDA) and DNA damage marker 8-hydroxy-2 '-desoxyguanosine (8-OHdG) values of subjects during head-down bed rest. Meanwhile, the SHG signals were also significantly negatively correlated with MDA and 8-OHDG. A significant negative correlation between the extended SAAID of the left chest and serum antioxidant superoxide dismutase (SOD) levels was also found. These results demonstrate that skin autofluorescence signals can reflect changes in human oxidant status. This study provides evidence for in-orbit monitoring of changes in human stress using a portable handheld two-photon microscope for skin imaging.
Keyword ：
SHG SHG portable handheld two-photon microscope portable handheld two-photon microscope head-down bed rest head-down bed rest skin skin TPEF TPEF
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| GB/T 7714 | Wang, Junjie , Zhen, Zhen , Wang, Yanqing et al. Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope [J]. | FRONTIERS IN PHYSIOLOGY , 2022 , 13 . |
| MLA | Wang, Junjie et al. "Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope" . | FRONTIERS IN PHYSIOLOGY 13 (2022) . |
| APA | Wang, Junjie , Zhen, Zhen , Wang, Yanqing , Wu, Runlong , Hu, Yanhui , Fu, Qiang et al. Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope . | FRONTIERS IN PHYSIOLOGY , 2022 , 13 . |
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Abstract ：
We successfully designed and synthesized a photolabile protecting group (PLPG) for thiol that can be rapidly photolyzed by irradiation at 365 nm to release thiol groups within 100 s. The photolytic reaction has mild conditions and avoids acid cleavage, leading to good yields with no side reactions as validated by HPLC. The PLPG has good acid/alkali tolerance
Keyword ：
Photolysis yield Photolysis yield alkali tolerance alkali tolerance Photolabile Protecting Group (PLPG) Photolabile Protecting Group (PLPG) Thiol groups Thiol groups Acid Acid
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| GB/T 7714 | Yang, Hongpeng , Chen, Lei , Zhang, Shouguo et al. Synthesis and Application of a Thiol Photolabile Protecting Group [J]. | CHEMISTRYSELECT , 2022 , 7 (16) . |
| MLA | Yang, Hongpeng et al. "Synthesis and Application of a Thiol Photolabile Protecting Group" . | CHEMISTRYSELECT 7 . 16 (2022) . |
| APA | Yang, Hongpeng , Chen, Lei , Zhang, Shouguo , Wang, Gang , Chen, Tingting , Xu, Jing et al. Synthesis and Application of a Thiol Photolabile Protecting Group . | CHEMISTRYSELECT , 2022 , 7 (16) . |
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Abstract ：
合成了一种反应型近红外荧光探针N-Rh-GSH,该探针以罗丹明衍生物为荧光母体，通过与谷胱甘肽(GSH)作用触发螺环的开关来实现信号的响应，其开环释放的荧光产物具有760 nm的近红外发射波长。细胞实验表明，该探针可实现对活细胞中GSH的成像。
Keyword ：
谷胱甘肽 谷胱甘肽 近红外 近红外 反应型 反应型 荧光探针 荧光探针
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| GB/T 7714 | 林一凡 , 王鹏 , 郝振铭 et al. 用于谷胱甘肽检测的新型罗丹明衍生物荧光探针 [J]. | 分析试验室 , 2022 , 41 (03) : 296-301 . |
| MLA | 林一凡 et al. "用于谷胱甘肽检测的新型罗丹明衍生物荧光探针" . | 分析试验室 41 . 03 (2022) : 296-301 . |
| APA | 林一凡 , 王鹏 , 郝振铭 , 莫善雁 , 曾程初 , 胡利明 . 用于谷胱甘肽检测的新型罗丹明衍生物荧光探针 . | 分析试验室 , 2022 , 41 (03) , 296-301 . |
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