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1.
A Deadly Organometallic Luminescent Probe: Anticancer Activity of a ReI Bisquinoline Complex 下载免费PDF全文
Dr. Igor Kitanovic Suzan Can Dr. Hamed Alborzinia Dr. Ana Kitanovic Vanessa Pierroz Anna Leonidova Dr. Antonio Pinto Priv. Doz. Dr. Bernhard Spingler Priv. Doz. Dr. Stefano Ferrari Roberto Molteni Dr. Andreas Steffen Prof. Dr. Nils Metzler‐Nolte Prof. Dr. Stefan Wölfl Prof. Dr. Gilles Gasser 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(9):2496-2507
The photophysical properties of [Re(CO)3(L ‐N3)]Br (L ‐N3=2‐azido‐N,N‐bis[(quinolin‐2‐yl)methyl]ethanamine), which could not be localized in cancer cells by fluorescence microscopy, have been revisited in order to evaluate its use as a luminescent probe in a biological environment. The ReI complex displays concentration‐dependent residual fluorescence besides the expected phosphorescence, and the nature of the emitting excited states have been evaluated by DFT and time‐dependent (TD) DFT methods. The results show that fluorescence occurs from a 1LC/MLCT state, whereas phosphorescence mainly stems from a 3LC state, in contrast to previous assignments. We found that our luminescent probe, [Re(CO)3(L ‐N3)]Br, exhibits an interesting cytotoxic activity in the low micromolar range in various cancer cell lines. Several biochemical assays were performed to unveil the cytotoxic mechanism of the organometallic ReI bisquinoline complex. [Re(CO)3(L ‐N3)]Br was found to be stable in human plasma indicating that [Re(CO)3(L ‐N3)]Br itself and not a decomposition product is responsible for the observed cytotoxicity. Addition of [Re(CO)3(L ‐N3)]Br to MCF‐7 breast cancer cells grown on a biosensor chip micro‐bioreactor immediately led to reduced cellular respiration and increased glycolysis, indicating a large shift in cellular metabolism and inhibition of mitochondrial activity. Further analysis of respiration of isolated mitochondria clearly showed that mitochondrial respiratory activity was a direct target of [Re(CO)3(L ‐N3)]Br and involved two modes of action, namely increased respiration at lower concentrations, potentially through increased proton transport through the inner mitochondrial membrane, and efficient blocking of respiration at higher concentrations. Thus, we believe that the direct targeting of mitochondria in cells by [Re(CO)3(L ‐N3)]Br is responsible for the anticancer activity. 相似文献
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Anna Wieczorek Dr. Andrzej Błauż Aleksandra Żal Homayon John Arabshahi Dr. Jóhannes Reynisson Prof. Dr. Christian G. Hartinger Dr. Błażej Rychlik Dr. Damian Plażuk 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(32):11413-11421
A series of ferrocenyl analogues and derivatives of paclitaxel and docetaxel were synthesised and assayed for their antiproliferative/cytotoxic effects, impact on the cell cycle distribution and ability to induce tubulin polymerisation. The replacement of the 3′‐N‐benzoyl group of paclitaxel with a ferrocenoyl moiety, in particular, led to formation of an analogue that was at least one order of magnitude more potent in terms of antiproliferative activity than the parent compound (IC50 values of 0.11 versus 1.11 μm , respectively), but still preserved the classical taxane mode of action, that is, microtubule stabilisation leading to mitotic arrest. Molecular docking studies revealed an unexpected binding pocket in the tubulin structure for the ferrocenoyl group introduced in the paclitaxel backbone. 相似文献
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Dr. Prinessa Chellan Prof. Peter J. Sadler 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(40):8676-8688
Resistance to chemotherapy is a current clinical problem, especially in the treatment of microbial infections and cancer. One strategy to overcome this is to make new derivatives of existing drugs by conjugation to organometallic fragments, either by an appropriate linker, or by direct coordination of the drug to a metal. We illustrate this with examples of conjugated organometallic metallocene sandwich and half-sandwich complexes, RuII and OsII arene, and RhIII and IrIII cyclopentadienyl half-sandwich complexes. Ferrocene conjugates are particularly promising. The ferrocene–chloroquine conjugate ferroquine is in clinical trials for malaria treatment, and a ferrocene-tamoxifen derivative (a ferrocifen) seems likely to enter anticancer trails soon. Several other examples illustrate that organometallic conjugation can restore the activity of drugs to which resistance has developed. 相似文献
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Jeannine Hess Dr. Malay Patra Dr. Loganathan Rangasamy Sandro Konatschnig Dr. Olivier Blacque Dr. Abdul Jabbar Patrick Mac Dr. Erik M. Jorgensen Prof. Dr. Robin B. Gasser Prof. Dr. Gilles Gasser 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(46):16602-16612
The discovery of novel drugs against animal parasites is in high demand due to drug‐resistance problems encountered around the world. Herein, the synthesis and characterization of 27 organic and organometallic derivatives of the recently launched nematocidal drug monepantel (Zolvix®) are described. The compounds were isolated as racemates and were characterized by 1H, 13C, and 19F NMR spectroscopy, mass spectrometry, and IR spectroscopy, and their purity was verified by microanalysis. The molecular structures of nine compounds were confirmed by X‐ray crystallography. The anthelmintic activity of the newly designed analogues was evaluated in vitro against the economically important parasites Haemonchus contortus and Trichostrongylus colubriformis. Moderate nematocidal activity was observed for nine of the 27 compounds. Three compounds were confirmed as potentiators of a known monepantel target, the ACR‐23 ion channel. Production of reactive oxygen species may confer secondary activity to the organometallic analogues. Two compounds, namely, an organic precursor ( 3 a ) and a cymantrene analogue ( 9 a ), showed activities against microfilariae of Dirofilaria immitis in the low microgram per milliliter range. 相似文献
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Dr. Martin Strack Prof. Dr. Andrea Bedini Dr. King T. Yip Sara Lombardi Daniel Siegmund Prof. Dr. Raphael Stoll Prof. Dr. Santi M. Spampinato Prof. Dr. Nils Metzler‐Nolte 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(41):14605-14610
Herein, the selective enforcement of one particular receptor‐ligand interaction between specific domains of the μ‐selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N‐terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C‐terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C‐terminal binding mode shows potent dose‐dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand‐protein interactions are similar for both binding modes, which is in line with previous protein mutation studies. 相似文献
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Dr. Matthieu Fonvielle Dénia Mellal Delphine Patin Maxime Lecerf Dr. Didier Blanot Dr. Ahmed Bouhss Dr. Marco Santarem Dr. Dominique Mengin‐Lecreulx Dr. Matthieu Sollogoub Dr. Michel Arthur Dr. Mélanie Ethève‐Quelquejeu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(4):1357-1363
Peptidyl–RNA conjugates have various applications in studying the ribosome and enzymes participating in tRNA‐dependent pathways such as Fem transferases in peptidoglycan synthesis. Herein a convergent synthesis of peptidyl–RNAs based on Huisgen–Sharpless cycloaddition for the final ligation step is developed. Azides and alkynes are introduced into tRNA and UDP‐MurNAc‐pentapeptide, respectively. Synthesis of 2′‐azido RNA helix starts from 2′‐azido‐2′‐deoxyadenosine that is coupled to deoxycytidine by phosphoramidite chemistry. The resulting dinucleotide is deprotected and ligated to a 22‐nt RNA helix mimicking the acceptor arm of Ala‐tRNAAla by T4 RNA ligase. For alkyne UDP‐MurNAc‐pentapeptide, meso‐cystine is enzymatically incorporated into the peptidoglycan precursor and reduced, and L ‐Cys is converted to dehydroalanine with O‐(mesitylenesulfonyl)hydroxylamine. Reaction of but‐3‐yne‐1‐thiol with dehydroalanine affords the alkyne‐containing UDP‐MurNAc‐pentapeptide. The CuI‐catalyzed azide alkyne cycloaddition reaction in the presence of tris[(1‐hydroxypropyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amine provided the peptidyl‐RNA conjugate, which was tested as an inhibitor of non‐ribosomal FemXWv aminoacyl transferase. The bi‐substrate analogue was found to inhibit FemXWv with an IC50 of (89±9) pM , as both moieties of the peptidyl–RNA conjugate contribute to high‐affinity binding. 相似文献
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Dr. Daniel J. Foley M. Sc. Sarah Zinken Dr. Dale Corkery Assist. Prof. Luca Laraia Dr. Axel Pahl Prof. Dr. Yao-Wen Wu Prof. Dr. Herbert Waldmann 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(30):12570-12576
Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34. 相似文献
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Daniel J. Foley Sarah Zinken Dale Corkery Luca Laraia Axel Pahl Yao‐Wen Wu Herbert Waldmann 《Angewandte Chemie (International ed. in English)》2020,59(30):12470-12476
Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34. 相似文献
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Substrate Profiling of Glutathione S‐transferase with Engineered Enzymes and Matched Glutathione Analogues 下载免费PDF全文
Dr. Shan Feng Lei Zhang Gulishana Adilijiang Jieyuan Liu Prof. Minkui Luo Prof. Haiteng Deng 《Angewandte Chemie (International ed. in English)》2014,53(28):7149-7153
The identification of specific substrates of glutathione S‐transferases (GSTs) is important for understanding drug metabolism. A method termed bioorthogonal identification of GST substrates (BIGS) was developed, in which a reduced glutathione (GSH) analogue was developed for recognition by a rationally engineered GST to label the substrates of the corresponding native GST. A K44G‐W40A‐R41A mutant (GST‐KWR) of the mu‐class glutathione S‐transferases GSTM1 was shown to be active with a clickable GSH analogue (GSH‐R1) as the cosubstrate. The GSH‐R1 conjugation products can react with an azido‐based biotin probe for ready enrichment and MS identification. Proof‐of‐principle studies were carried to detect the products of GSH‐R1 conjugation to 1‐chloro‐2,4‐dinitrobenzene (CDNB) and dopamine quinone. The BIGS technology was then used to identify GSTM1 substrates in the Chinese herbal medicine Ganmaocongji. 相似文献
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Dr. Suzanne G. Rzuczek Dr. HaJeung Park Prof. Dr. Matthew D. Disney 《Angewandte Chemie (International ed. in English)》2014,53(41):10956-10959
Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease‐causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable whereas higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands by a reaction that is catalyzed by binding to a target in cells expressing a genetic defect. It was shown that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)exp, the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction by a Huisgen 1,3‐dipolar cycloaddition reaction, a variant of click chemistry. 相似文献
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Maksimoska J Williams DS Atilla-Gokcumen GE Smalley KS Carroll PJ Webster RD Filippakopoulos P Knapp S Herlyn M Meggers E 《Chemistry (Weinheim an der Bergstrasse, Germany)》2008,14(16):4816-4822
In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC(50) values against the protein kinases GSK-3beta and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity. 相似文献
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Flavio M. Gall Deborah Hohl David Frasson Tobias Wermelinger Peer R. E. Mittl Martin Sievers Rainer Riedl 《Angewandte Chemie (International ed. in English)》2019,58(12):4051-4055
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X‐ray crystallography, which was auto‐tailored by the therapeutic target MMP‐13 through partial self‐degradation and subsequent structure‐based optimization to a highly potent and selective β‐sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non‐proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP‐13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP‐2 (IC50: 170 nm ) and MMP‐9 (IC50: 140 nm ). 相似文献
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In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria. 相似文献
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Meggers E 《Angewandte Chemie (International ed. in English)》2011,50(11):2442-2448
The tremendous challenge presented by the specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This Minireview discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the underlying chemical scaffolds. These include complicated natural-product-like organic molecules, stable octahedral metal complexes, fullerenes, carboranes, polymetallic clusters, and even polymers. Thus the whole repertoire of organic, inorganic, and macromolecular chemistry can be applied to tackle the problem of target-specific enzyme inhibition. 相似文献
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Johannes C. B. Dietschreit Annika Wagner T. Anh Le Philipp Klein Hermann Schindelin Till Opatz Bernd Engels Ute A. Hellmich Christian Ochsenfeld 《Angewandte Chemie (International ed. in English)》2020,59(31):12669-12673
The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of 19F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area. 相似文献
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Xiaoman Liu Louis A. Silks Prof. Dr. Cuiping Liu Dr. Morgane Ollivault‐Shiflett Xin Huang Jing Li Dr. Guimin Luo Prof. Dr. Ya‐Ming Hou Prof. Dr. Junqiu Liu Prof. Dr. Jiacong Shen Prof. 《Angewandte Chemie (International ed. in English)》2009,48(11):2020-2023
A rival to native peroxidase! An existing binding site for glutathione was combined with the catalytic residue tellurocysteine by using an auxotrophic expression system to create an engineered enzyme that functions as a glutathione peroxidase from the scaffold of a glutathione transferase (see picture). The catalytic activity of the telluroenzyme in the reduction of hydroperoxides by glutathione is comparable to that of native glutathione peroxidase.