共查询到20条相似文献,搜索用时 15 毫秒
1.
Laura M. Lilley Sarah Kamper Michael Caldwell Zer Keen Chia David Ballweg Luke Vistain Jeffrey Krimmel Teresa Anne Mills Keith MacRenaris Paul Lee Emily Alexandria Waters Thomas J. Meade 《Angewandte Chemie (International ed. in English)》2020,59(1):388-394
Our lab has developed a new series of self‐immolative MR agents for the rapid detection of enzyme activity in mouse models expressing β‐galactosidase (β‐gal). We investigated two molecular architectures to create agents that detect β‐gal activity by modulating the coordination of water to GdIII. The first is an intermolecular approach, wherein we designed several structural isomers to maximize coordination of endogenous carbonate ions. The second involves an intramolecular mechanism for q modulation. We incorporated a pendant coordinating carboxylate ligand with a 2, 4, 6, or 8 carbon linker to saturate ligand coordination to the GdIII ion. This renders the agent ineffective. We show that one agent in particular (6‐C pendant carboxylate) is an extremely effective MR reporter for the detection of enzyme activity in a mouse model expressing β‐gal. 相似文献
2.
Selective Ablation of β‐Galactosidase‐Expressing Cells with a Rationally Designed Activatable Photosensitizer
下载免费PDF全文
![点击此处可从《Angewandte Chemie (International ed. in English)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Yuki Ichikawa Dr. Mako Kamiya Dr. Fumiaki Obata Prof. Masayuki Miura Dr. Takuya Terai Dr. Toru Komatsu Dr. Tasuku Ueno Dr. Kenjiro Hanaoka Prof. Tetsuo Nagano Prof. Yasuteru Urano 《Angewandte Chemie (International ed. in English)》2014,53(26):6772-6775
We have developed an activatable photosensitizer capable of specifically inducing the death of β‐galactosidase‐expressing cells in response to photoirradiation. By using a selenium‐substituted rhodol scaffold bearing β‐galactoside as a targeting substituent, we designed and synthesized HMDESeR‐βGal, which has a non‐phototoxic spirocyclic structure owing to the presence of the galactoside moiety. However, β‐galactosidase efficiently converted HMDESeR‐βGal into phototoxic HMDESeR, which exists predominantly in the open xanthene form. This structural change resulted in drastic recovery of visible‐wavelength absorption and the ability to generate singlet oxygen (1O2). When HMDESeR‐βGal was applied to larval Drosophila melanogaster wing disks, which express β‐galactosidase only in the posterior region, photoirradiation induced cell death in the β‐galactosidase‐expressing region with high specificity. 相似文献
3.
β‐Galactosidase, a glycoside hydrolase enzyme, has been proved to be an important biomarker of cell senescence and primary ovarian cancer. Effective detection of β‐galactosidase has attracted wide attention. Herein, one ratiometric fluorescent probe has been successfully synthesized for detecting the β‐galactosidase in living cells. The as‐prepared probe exhibits two emission peaks at 490 nm and 530 nm, respectively, and the ratio of fluorescence intensities from the two emission peaks could be utilized to monitor the β‐galactosidase. This present ratiometric fluorescent probe is, therefore, very promising for effective, sensitive, and selective detection of the β‐galactosidase in living cells. 相似文献
4.
5.
Dr. Tomohiro Doura Dr. Mako Kamiya Dr. Fumiaki Obata Dr. Yoshifumi Yamaguchi Dr. Takeshi Y. Hiyama Takashi Matsuda Prof. Akiyoshi Fukamizu Prof. Masaharu Noda Prof. Masayuki Miura Prof. Yasuteru Urano 《Angewandte Chemie (International ed. in English)》2016,55(33):9620-9624
The LacZ gene, which encodes Escherichia coli β‐galactosidase, is widely used as a marker for cells with targeted gene expression or disruption. However, it has been difficult to detect lacZ‐positive cells in living organisms or tissues at single‐cell resolution, limiting the utility of existing lacZ reporters. Herein we present a newly developed fluorogenic β‐galactosidase substrate suitable for labeling live cells in culture, as well as in living tissues. This precisely functionalized fluorescent probe exhibited dramatic activation of fluorescence upon reaction with the enzyme, remained inside cells by anchoring itself to intracellular proteins, and provided single‐cell resolution. Neurons labeled with this probe preserved spontaneous firing, which was enhanced by application of ligands of receptors expressed in the cells, suggesting that this probe would be applicable to investigate functions of targeted cells in living tissues and organisms. 相似文献
6.
Matthew T. Richers Stefan Passlick Hitesh Agarwal Graham C. R. Ellis‐Davies 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(35):12214-12218
We have developed a caged neurotransmitter using an extended π‐electron chromophore for efficient multiphoton uncaging on living neurons. Widely studied in a chemical context, such chromophores are inherently bioincompatible due to their highly lipophilic character. Attachment of two polycarboxylate dendrimers, a method we call “cloaking”, to a bisstyrylthiophene (or BIST) core effectively transformed the chromophore into a water‐soluble optical probe, whilst maintaining the high two‐photon absorption of over 500 GM. Importantly, the cloaked caged compound was biologically inert at the high concentrations required for multiphoton chemical physiology. Thus, in contrast to non‐cloaked BIST compounds, the BIST‐caged neurotransmitter can be safely delivered onto neurons in acutely isolated brain slices, thereby enabling high‐resolution two‐photon uncaging without any side effects. We expect that our cloaking method will enable the development of new classes of cell‐compatible photolabile probes using a wide variety of extended π‐electron caging chromophores. 相似文献
7.
Qing Shao Yan Zheng Xueming Dong Prof. Kai Tang Prof. Xiaomei Yan Prof. Bengang Xing 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(33):10903-10910
Bacterial resistance to antibiotics poses a great clinical challenge in fighting serious infectious diseases due to complicated resistant mechanisms and time‐consuming testing methods. Chemical reaction‐directed covalent labeling of resistance‐associated bacterial proteins in the context of a complicated environment offers great opportunity for the in‐depth understanding of the biological basis conferring drug resistance, and for the development of effective diagnostic approaches. In the present study, three fluorogenic reagents LRBL1–3 for resistant bacteria labeling have been designed and prepared on the basis of fluorescence resonance energy transfer (FRET). The hydrolyzed probes could act as reactive electrophiles to attach the enzyme, β‐lactamase, and thus facilitated the covalent labeling of drug resistant bacterial strains. SDS electrophoresis and MALDI‐TOF mass spectrometry characterization confirmed that these probes were sensitive and specific to β‐lactamase and could therefore serve for covalent and localized fluorescence labeling of the enzyme structure. Moreover, this β‐lactamase‐induced covalent labeling provides quantitative analysis of the resistant bacterial population (down to 5 %) by high resolution flow cytometry, and allows single‐cell detection and direct observation of bacterial enzyme activity in resistant pathogenic species. This approach offers great promise for clinical investigations and microbiological research. 相似文献
8.
Synthesis of Site‐Specifically Phosphate‐Caged siRNAs and Evaluation of Their RNAi Activity and Stability
下载免费PDF全文
![点击此处可从《Chemistry (Weinheim an der Bergstrasse, Germany)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Li Wu Fen Pei Jinhao Zhang Junzhou Wu Mengke Feng Yuan Wang Dr. Hongwei Jin Prof. Liangren Zhang Prof. Xinjing Tang 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(38):12114-12122
A complete set of new photolabile nucleoside phosphoramidites were synthesized, then site‐specifically incorporated into sense or antisense strands of siRNA for phosphate caging. Single caging modification was made along siRNA strands and their photomodulation of gene silencing were examined by using the firefly luciferase reporter gene. Several key phosphate positions were then identified. Furthermore, multiple caging modifications at these key positions led to significantly enhanced photomodulation of gene silencing activity, suggesting a synergistic effect. The caging group on both the terminally phosphate‐caged siRNA and the single‐stranded caged RNA has comparatively high stability, whereas hydrolysis of the caged group from the internally caged siRNA was observed, irrespective of the presence of Mg2+. Molecular dynamic simulations demonstrated that enhanced hydrolysis of the caging group on internally phosphate‐caged siRNAs was due to easy fragmentation of the caging group upon formation of the pentavalent intermediate of the phosphotriester with attack by water. The caging group in the terminally phosphate‐caged siRNA or single‐stranded caged RNA prefers to form π–π stacks with nearby nucleobases. In addition to providing explanations for previous observations, this study sheds further light on the design of caged oligonucleotides and indicates the direction of future development of nucleic acid drugs with phosphate modifications. 相似文献
9.
Lee‐Chiang Lo Chi‐Yuan Chu Fang‐An Lin Yen‐Ru Pan Yaw‐Kuen Li Jing‐Jer Lin 《中国化学会会志》2006,53(2):479-488
Due to their industrial interest and significance, developing a rapid method for screening β‐xylosidase activities would certainly facilitate the research and improve production in xylan‐related industries especially in the pulp and paper industries. Here we report the synthesis of two activity probes, LCL‐ 6X and ‐ 12X , for β‐xylosidase. They both carry a β‐xylopyranosyl recognition head, which is linked to a latent trapping device consisting of a 2‐fluoromethylphenoxyl group and a biotin reporter group. They differ only in the length of their hydrophobic linker. A model study using a β‐xylosidase from T. koningii demonstrates that both probes could successfully label the target hydrolase and give rise to biotinylated proteins. They could thus potentially become a powerful tool in screening β‐xylosidase from microbial sources. 相似文献
10.
He Li Joo Conde Ana Guerreiro Gonalo J. L. Bernardes 《Angewandte Chemie (International ed. in English)》2020,59(37):16023-16032
The bioorthogonal inverse‐electron‐demand Diels–Alder (IEDDA) cleavage reaction between tetrazine and trans‐cyclooctene (TCO) is a powerful way to control the release of bioactive agents and imaging probes. In this study, a pretargeted activation strategy using single‐walled carbon nanotubes (SWCNTs) that bear tetrazines (TZ@SWCNTs) and a TCO‐caged molecule was used to deliver active effector molecules. To optimize a turn‐on signal by using in vivo fluorescence imaging, we developed a new fluorogenic near‐infrared probe that can be activated by bioorthogonal chemistry and image tumours in mice by caging hemicyanine with TCO (tHCA). With our pretargeting strategy, we have shown selective doxorubicin prodrug activation and instantaneous fluorescence imaging in living cells. By combining a tHCA probe and a pretargeted bioorthogonal approach, real‐time, non‐invasive tumour visualization with a high target‐to‐background ratio was achieved in a xenograft mice tumour model. The combined advantages of enhanced stability, kinetics and biocompatibility, and the superior pharmacokinetics of tetrazine‐functionalised SWCNTs could allow application of targeted bioorthogonal decaging approaches with minimal off‐site activation of fluorophore/drug. 相似文献
11.
Comparing Cyclophellitol N‐Alkyl and N‐Acyl Cyclophellitol Aziridines as Activity‐Based Glycosidase Probes
下载免费PDF全文
![点击此处可从《Chemistry (Weinheim an der Bergstrasse, Germany)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jianbing Jiang Thomas J. M. Beenakker Dr. Wouter W. Kallemeijn Prof. Dr. Gijsbert A. van der Marel Hans van den Elst Dr. Jeroen D. C. Codée Prof. Dr. Johannes M. F. G. Aerts Prof. Dr. Herman S. Overkleeft 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(30):10861-10869
The synthesis and evaluation as activity‐based probes (ABPs) of three configurationally distinct, fluorescent N‐alkyl cyclophellitol aziridine isosteres for profiling GH1 β‐glucosidase (GBA), GH27 α‐galactosidase (GLA) and GH29 α‐fucosidase (FUCA) is described. In comparison with the corresponding acyl aziridine ABPs reported previously, the alkyl aziridine ABPs are synthesized easily and are more stable in mild acidic and basic media, and are thus easier to handle. The β‐glucose‐configured alkyl aziridine ABP proves equally effective in labeling GBA as its N‐acyl counterpart, whereas the N‐acyl aziridines targeting GLA and FUCA outperform their N‐alkyl counterparts. Alkyl aziridines can therefore be an attractive alternative in retaining glycosidase ABP design, but in targeting a new retaining glycosidase both N‐alkyl and N‐acyl aziridines are best considered at the onset of a new study. 相似文献
12.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2018,130(29):9171-9175
The majority of theranostic prodrugs reported so far relay information through a fluorogenic response generated upon release of the active chemotherapeutic agent. A chemiluminescence detection mode offers significant advantages over fluorescence, mainly due to the superior signal‐to‐noise ratio of chemiluminescence. Here we report the design and synthesis of the first theranostic prodrug monitored by a chemiluminescence diagnostic mode. As a representative model, we prepared a prodrug from the chemotherapeutic monomethyl auristatin E, which was modified for activation by β‐galactosidase. The activation of the prodrug in the presence of β‐galactosidase is accompanied by emission of a green photon. Light emission intensities, which increase with increasing concentration of the prodrug, were linearly correlated with a decrease in the viability of a human cell line that stably expresses β‐galactosidase. We obtained sharp intravital chemiluminescent images of endogenous enzymatic activity in β‐galactosidase‐overexpressing tumor‐bearing mice. The exceptional sensitivity achieved with the chemiluminescence diagnostic mode should allow the exploitation of theranostic prodrugs for personalized cancer treatment. 相似文献
13.
Kinetic Resolution of β‐Sulfonyl Ketones through Enantioselective β‐Elimination using a Cation‐Binding Polyether Catalyst
下载免费PDF全文
![点击此处可从《Angewandte Chemie (International ed. in English)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Liang Li Yidong Liu Yang Peng Lei Yu Xiaoyan Wu Prof. Hailong Yan 《Angewandte Chemie (International ed. in English)》2016,55(1):331-335
Reported herein is the first enantioselective β‐elimination reaction catalyzed by a chiral cation‐binding polyether. By using this catalytic protocol, a wide range of β‐sulfonyl ketones could be effectively resolved with high stereoselectivity (S up to >300). Key to the success of this process is the favorable secondary interactions of the catalyst with the Lewis basic groups on the sulfone substrate. The enone product of this process can be easily converted into the racemic starting material, and allows an effective recycling and overall synthesis of chiral β‐sulfonyl ketones in high yield and excellent enantioselectivity. 相似文献
14.
The photochemistry of caged compounds of the o‐nitrobenzyl type has been investigated thoroughly in the past. However, even recently new side reactions have been discovered. Earlier, we reported [Bley, F., K. Schaper, and H. Görner (2008), Photochem. Photobiol. 84 162–171] that we found long‐lived triplet states which do not lead to product formation for the bathochromic absorbing compounds with 4,5‐methylendioxy‐2‐nitrobenzyl caging group. Here, we report on theoretical studies which explain the special behavior of these compounds. These studies reveal that the bathochromic shift of absorption for these compounds compared with o ‐nitrobenzyl compounds themselves is not due to a shift in energy of the involved states, but due to a substantial change of oscillator strength of the respective transitions. The lack of reactivity of the triplet state of 4,5‐methylendioxy‐2‐nitrobenzyl compounds can be attributed to state switching. In the triplet manifold the lowest state is a nonreactive charge transfer state, while the lowest state in the singlet manifold is a reactive local excitation in the nitro‐group. From these results we conclude that it will be most likely not possible to create derivatives of caged compounds based on the o ‐nitrobenzyl caging group which have absorption which is shifted even more strongly to longer wavelengths. 相似文献
15.
Novel caged intramolecular ketals of β‐C‐glycosidic ketones were prepared from pyranoses. The structures of the new compounds were elucidated by NMR and HRMS spectral analysis. Preliminary studies revealed that the intramolecular ketal could be used to protect 3‐ and 6‐hydroxyl groups of β‐C‐glycosidic ketones. 相似文献
16.
Prof. Dr. Konstantin V. Kudryavtsev Chia‐Chun Yu Polina M. Ivantcova Prof. Dr. Vladimir I. Polshakov Dr. Andrei V. Churakov Prof. Dr. Stefan Bräse Prof. Dr. Nikolay S. Zefirov Prof. Dr. Jih‐Hwa Guh 《化学:亚洲杂志》2015,10(2):383-389
Functionalized oligomeric organic compounds with well‐defined β‐proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β‐peptides was investigated by NMR spectroscopic and X‐ray methods determining the conformational shapes of the β‐proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β‐peptide bonds between 5‐arylpyrrolidine‐2‐carboxylic acid units existing in Z/E configurations. The whole library of short β‐peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone‐refractory prostate cancer cell line PC‐3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine‐substituted dimeric and trimeric acrylamides induced caspase‐dependent apoptosis of PC‐3 cells through cell‐cycle arrest and mitochondrial damage. 相似文献
17.
Systemically Injectable Enzyme‐Loaded Polyion Complex Vesicles as In Vivo Nanoreactors Functioning in Tumors
下载免费PDF全文
![点击此处可从《Angewandte Chemie (International ed. in English)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Yasutaka Anraku Dr. Akihiro Kishimura Dr. Mako Kamiya Dr. Sayaka Tanaka Dr. Takahiro Nomoto Dr. Kazuko Toh Dr. Yu Matsumoto Shigeto Fukushima Daiki Sueyoshi Prof. Mitsunobu R. Kano Prof. Yasuteru Urano Prof. Nobuhiro Nishiyama Prof. Kazunori Kataoka 《Angewandte Chemie (International ed. in English)》2016,55(2):560-565
The design and construction of nanoreactors are important for biomedical applications of enzymes, but lipid‐ and polymeric‐vesicle‐based nanoreactors have some practical limitations. We have succeeded in preparing enzyme‐loaded polyion complex vesicles (PICsomes) through a facile protein‐loading method. The preservation of enzyme activity was confirmed even after cross‐linking of the PICsomes. The cross‐linked β‐galactosidase‐loaded PICsomes (β‐gal@PICsomes) selectively accumulated in the tumor tissue of mice. Moreover, a model prodrug, HMDER‐βGal, was successfully converted into a highly fluorescent product, HMDER, at the tumor site, even 4 days after administration of the β‐gal@PICsomes. Intravital confocal microscopy showed continuous production of HMDER and its distribution throughout the tumor tissues. Thus, enzyme‐loaded PICsomes are useful for prodrug activation at the tumor site and could be a versatile platform for enzyme delivery in enzyme prodrug therapy. 相似文献
18.
Ren‐Qi Xu Ping Yang Hang‐Fei Tu Shou‐Guo Wang Prof. Dr. Shu‐Li You 《Angewandte Chemie (International ed. in English)》2016,55(48):15137-15141
The first Pd0‐catalyzed intermolecular arylative dearomatization of β‐naphthols with aryl halides is described. It was found that Q‐Phos could facilitate the palladium‐catalyzed cross‐coupling‐type dearomatization of β‐naphthols, while avoiding O‐arylation, to construct 2‐naphthalenones in excellent yields and with high chemoselectivity. 相似文献
19.
New glycosyl donors have been developed that contained several para‐substituted O‐aryl protecting groups and their stereoselectivity for the glycosylation reaction was evaluated. A highly β‐selective glycosylation reaction was achieved by using thioglycosides that were protected by 4‐nitrophenyl (NP) groups, which were introduced by using the corresponding diaryliodonium triflate. Analysis of the stereoselectivities of several glycosyl donors indicated that the β‐glycosides were obtained through an SN2‐type displacement from the corresponding α‐glycosyl triflate. The NP group could be removed by reduction of the nitro group and acylation, followed by oxidation with ceric ammonium nitrate (CAN). 相似文献
20.
Dr. Graeme J. Stasiuk Dr. Florencia Minuzzi Dr. Myra Sae‐Heng Charlotte Rivas Dr. Hans‐Paul Juretschke Dr. Lorenzo Piemonti Dr. Peter R. Allegrini Dr. Didier Laurent Andrew R. Duckworth Prof. Andrew Beeby Prof. Guy A. Rutter Prof. Nicholas J. Long 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(13):5023-5033
Despite the contribution of changes in pancreatic β‐cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic‐resonance imaging (MRI) provides a potentially useful technique, targeting MRI‐active probes to the β cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual‐modal probes based on transition‐metal chelates capable of binding zinc. The first of these, Gd ?1 , binds ZnII directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from λem=410 to 500 nm with an increase in relaxivity from r1=4.2 up to 4.9 mM ?1 s?1. The probe is efficiently accumulated into secretory granules in β‐cell‐derived lines and isolated islets, but more poorly by non‐endocrine cells, and leads to a reduction in T1 in human islets. In vivo murine studies of Gd ?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes. 相似文献