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排序方式: 共有1465条查询结果,搜索用时 234 毫秒
991.
Dr. Hajime Hirao Pratanphorn Chuanprasit Ying Yi Cheong Dr. Xiaoqing Wang 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(23):7361-7369
A precise understanding of the mechanism‐based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug–drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism‐based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1‐dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene‐type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C? H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N? H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene‐type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450‐catalyzed reaction. 相似文献
992.
Andrey V. Markov Kirill V. Odarenko Aleksandra V. Senkova Oksana V. Salomatina Nariman F. Salakhutdinov Marina A. Zenkova 《Molecules (Basel, Switzerland)》2020,25(24)
Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. Further study showed that SM effectively blocked transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-β-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate. 相似文献
993.
纳米材料在肿瘤治疗中有着广泛的应用,但其存在靶向效率低、肿瘤穿透性差以及副作用明显等缺点.细菌及其分泌物具有靶向肿瘤乏氧部位、肿瘤渗透能力强、刺激免疫应答的特点,但其安全性和单独使用疗效低的问题仍需解决.将纳米材料与细菌结合起来,可以补足彼此的缺陷,在肿瘤治疗中有很大的应用潜力.这篇综述中,我们根据细菌在治疗中起的作用,将细菌与纳米材料结合的作用方式分为三类:细菌与纳米材料形成复合物来增强肿瘤靶向、细菌的生物酶发生酶促反应以及细菌分泌物结合纳米材料用于抗肿瘤.通过典型示例重点介绍了近年来用纳米材料与细菌结合增强肿瘤治疗的研究,并讨论其增强机制,同时进行了前景展望. 相似文献
994.
Yang Cai Dongqi Ni Wenyu Cheng Chendong Ji Yaling Wang Klaus Müllen Zhiqiang Su Ying Liu Chunying Chen Meizhen Yin 《Angewandte Chemie (International ed. in English)》2020,59(33):14014-14018
Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide‐based nanocluster capable of enzyme‐triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)‐responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate‐decorated albumins into a nanocluster ( FHP ) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor‐specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP . Furthermore, such enzyme‐triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8‐fold) and elevated singlet oxygen generation ability (ca. 4‐fold), enabling in situ near‐infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging‐guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme‐triggered molecular disassembly is an effective strategy for precise cancer theranostics. 相似文献
995.
Ling‐Ling Wu Zhi‐Ling Zhang Man Tang Dong‐Liang Zhu Xiao‐Juan Dong Jiao Hu Chu‐Bo Qi Hong‐Wu Tang Dai‐Wen Pang 《Angewandte Chemie (International ed. in English)》2020,59(28):11240-11244
Comprehensive phenotypic profiling of heterogeneous circulating tumor cells (CTCs) at single‐cell resolution has great importance for cancer management. Herein, a novel spectrally combined encoding (SCE) strategy was proposed for multiplex biomarker profiling of single CTCs using a multifunctional nanosphere‐mediated microfluidic platform. Different cellular biomarkers uniquely labeled by multifunctional nanosphere barcodes, possessing identical magnetic tags and distinct optical signatures, enabled isolation of heterogeneous CTCs with over 91.6 % efficiency and in situ SCE of phenotypes. By further trapping individual CTCs in ordered microstructures on chip, composite single‐cell spectral signatures were conveniently and efficiently obtained, allowing reliable spectral‐readout for multiplex biomarker profiling. This SCE strategy exhibited great potential in multiplex profiling of heterogeneous CTC phenotypes, offering new avenues for cancer study and precise medicine. 相似文献
996.
Yang Cai Dongqi Ni Dr. Wenyu Cheng Dr. Chendong Ji Prof. Yaling Wang Prof. Klaus Müllen Prof. Zhiqiang Su Prof. Ying Liu Prof. Chunying Chen Prof. Meizhen Yin 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(33):14118-14122
Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide-based nanocluster capable of enzyme-triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)-responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate-decorated albumins into a nanocluster ( FHP ) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor-specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP . Furthermore, such enzyme-triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8-fold) and elevated singlet oxygen generation ability (ca. 4-fold), enabling in situ near-infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging-guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme-triggered molecular disassembly is an effective strategy for precise cancer theranostics. 相似文献
997.
Dr. Weili Wang Dr. Yifei Kong Jun Jiang Qianqian Xie Yang Huang Guanna Li Di Wu Huizhen Zheng Meng Gao Shujuan Xu Yanxia Pan Wei Li Ronglin Ma Mei X. Wu Xuehua Li Han Zuilhof Xiaoming Cai Prof. Ruibin Li 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(50):22617-22621
The application of NIR-II emitters for gastrointestinal (GI) tract imaging remains challenging due to fluorescence quenching in the digestive microenvironment. Herein, we report that red-shifting of the fluorescence emission of Au nanoclusters (AuNCs) into NIR-II region with improved quantum yields (QY) could be achieved by engineering a protein corona structure consisting of a ribonuclease-A (RNase-A) on the particle surfaces. RNase-A-encapsulated AuNCs (RNase-A@AuNCs) displayed emissions at 1050 nm with a 1.9 % QY. Compared to rare earth and silver-based NIR-II emitters, RNase-A@AuNCs had excellent biocompatibility, showing >50-fold higher sensitivity in GI tract, and migrated homogenously during gastrointestinal peristalsis to allow visualization of the detailed structures of the GI tract. RNase-A@AuNCs could successfully examine intestinal tumor mice from healthy mice, indicating a potential utility for early diagnosis of intestinal tumors. 相似文献
998.
In this work, we demonstrate a single-view field filter (SVFF) device for the efficient filtration and enumeration of rare tumor cells in the blood. In our device, the track-etched membrane is integrated within a low-cost polymer-film microfluidic chip, and multiplex microfiltration chambers are designed. Our device permits the performing of multiple sample tests on a single membrane and the dynamical observation of the entire filtration process in a single field of view. To characterize the device performance, our device is first tested using tumor cells, and three different cell behaviors are observed during the filtration process. Finally, we successfully apply our device for the separation of rare tumor cells from the lysed blood samples at various flow rates. The recovery rates of 93.3, 87.6, and 84.1% can be respectively achieved at the throughputs of 50, 100, and 150 μL/min. Our single-view field filter (SVFF) device offers the advantages of label-free filtration, efficient enumeration, easy integration, and low cost, and holds the potential to be used as an efficient tool for the filtration and enumeration of rare cells. 相似文献
999.
Xiaochun Wang Jingguo Hou Michael Jann Yuen Yi Hon Shahab A. Shamsi 《Journal of chromatography. A》2013,1271(1):207-216
The enantioseparation of warfarin (WAR) along with the five positional and optical isomers is challenging because of the difficulty to simultaneously separate and quantitate these chiral compounds. Currently, no effective chiral CE–MS methods exist for the simultaneous enantioseparation of WAR and all its hydroxylated metabolites in a single run. Polymeric surfactants (aka. molecular micelles) are particularly compatible with micellar electrokinetic chromatography–mass spectrometry (MEKC–MS) because they have a wider elution window for enantioseparation and do not interfere with the MS detection of chiral drugs. Using polysodium N-undecenoyl-l,l-leucylvalinate (poly-l,l-SULV) as a chiral pseudophase in MEKC–MS baseline separation of WAR, its five metabolites along with the internal standard was obtained in 45 min. This is in comparison to 100 min required for separation of the same mixture with packed column CEC–MS using a vancomycin chiral stationary phase. Serum samples were extracted with mixed-mode anion-exchange (MAX) cartridge with recoveries of greater than 85.2% for all WAR and hydroxywarfarin (OH-WAR) metabolites. Utilizing the tandem MS and multiple reaction monitoring mode, the MEKC–MS/MS method was used to simultaneously generate calibration curves over a concentration range from 2 to 5000 ng/mL for R- and S-warfarin, 5 to 1000 ng/mL for R- and S-6-, 7-, 8- and 10-OH-WAR and 10 to 1000 ng/mL for R and S-4′-OH-WAR. For the first time, the limits of detection and quantitation for most WAR metabolites by MEKC–MS/MS were found to be at levels of 2 and 5 ng/mL, respectively. The method was successfully applied for the first time to analyze WAR and its metabolites in plasma samples of 55 patients undergoing WAR therapy, demonstrating the potential of chiral MEKC–MS/MS method to accurately quantitate with high sensitivity. 相似文献
1000.
Lovro Kramer Catherine Germanier Dr. K. Ulrich Wendt Prof. Markus Rudin Prof. Boris Turk Dr. Oliver Plettenburg Priv.‐Doz. Dr. Carsten Schultz 《Angewandte Chemie (International ed. in English)》2014,53(29):7669-7673
The synthesis and evaluation of two cathepsin S‐specific probes is described. For long‐term retention of the probe at the target site and a high signal‐to‐noise ratio, we introduced a lipidation approach via the simple attachment of palmitoic acid to the reporter. After cathepsin S‐specific cleavage in cultured cells and in a grafted tumor mouse model, fluorescence increased owing to dequenching and we observed an intracellular accumulation of the fluorescence in the target tissue. The lipidated probe provided a prolonged and strongly fluorescent signal in tumors when compared to the very similar non‐lipidated probe, demonstrating that non‐invasive tumor identification is feasable. The homing principle by probe lipidation might also work for selective administration of cytotoxic compounds to specifically reduce tumor mass. 相似文献