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91.
Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library 下载免费PDF全文
Dr. Raphael M. Franzini Dr. Torun Ekblad Dr. Nan Zhong Moreno Wichert Willy Decurtins Angela Nauer Mauro Zimmermann Dr. Florent Samain Dr. Jörg Scheuermann Dr. Peter J. Brown Prof. Dr. Jonathan Hall Dr. Susanne Gräslund Prof. Dr. Herwig Schüler Prof. Dr. Dario Neri 《Angewandte Chemie (International ed. in English)》2015,54(13):3927-3931
Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA‐encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL‐100K, a DNA‐encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA‐sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate‐specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small‐molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding. 相似文献
92.
Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles 下载免费PDF全文
Dinesh Talwar Angela Gonzalez‐de‐Castro Dr. Ho Yin Li Prof. Jianliang Xiao 《Angewandte Chemie (International ed. in English)》2015,54(17):5223-5227
A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp3 C? H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles. 相似文献
93.
P. Ubbrìaco Angela Traini D. Manigrassi 《Journal of Thermal Analysis and Calorimetry》2008,92(1):301-305
The present research is concerning the characterization of FDR (fuel derived from residues) fly ash and mixtures with lime/brick
hydraulic binder by DTA/TG/DTG thermo-analysis, X-ray diffractometry and chemical analysis. The use of hydraulic binder obtained
from building brick rejects, which is less expensive than the usual solidifiers such as cementitious binder and silicates,
allows us to reutilize, in the meantime, this wreckage material, to the advantage of environmental sustainability. Fly ash
samples investigated in the present study were separated in a thermo-incineration plant. Mineralogical DTA/TG/DTG and XRD
investigations reveal the presence of different phases as well as chemical analysis shows a moderate concentration of heavy
metals and high content of chloride and sulphate. Results obtained from leaching tests with water carried out on hardened
pastes containing fly ash lead to interesting results, which highlight behaviour to the release of contaminants. The whole
of the results obtained in the present study make it possible to regard the objective of disposing such hardened materials
in inert waste landfill sites as achievable. 相似文献
94.
Zampella A Sepe V Luciano P Bellotta F Monti MC D'Auria MV Jepsen T Petek S Adeline MT Laprévôte O Aubertin AM Debitus C Poupat C Ahond A 《The Journal of organic chemistry》2008,73(14):5319-5327
A new anti-HIV cyclodepsipeptide, homophymine A, was isolated from a New Caledonian collection of the marine sponge Homophymia sp. The structure of homophymine A was determined by interpretation of spectroscopic data, acid hydrolysis, and LC-MS analysis. Homophymine A contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethyloctanoic acid moiety. Along with four D-, two L-, and one N-methyl amino acids, it also contains four unusual amino acid residues: (2S,3S,4R)-3,4-diMe-Gln, (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, L-ThrOMe, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid. In a cell-based XTT assay, homophymine A exhibited cytoprotective activity against HIV-1 infection with a IC50 of 75 nM. 相似文献
95.
The new inorganic-organic hybrid compound (dienH2)Cu2Sn2S6 (dien = diethylenetriamine) was synthesized under solvothermal conditions. It crystallizes in the tetragonal space group I4m2 with a = 7.8793(3) A, c = 24.9955(15) A, and V = 1551.80(13) A(3). The structure consists of anionic [Cu2Sn2S6](2-) layers extending in the (001) plane and protonated amine molecules as charge compensating ions sandwiched between the layers. The layered [Cu2Sn2S6](2-) anion is composed of a single layer of edge-sharing CuS4 tetrahedra which is joined above and below to straight chains constructed by corner-sharing SnS4 tetrahedra. The material is a semiconductor with an optical band gap of 1.51 eV. More interestingly, preliminary results demonstrate that the compound exhibits photoconductive properties with an increase of the conductivity by a factor of 3 when irradiated with UV light. Upon heating in an inert atmosphere the compound starts to decompose at about 256 degrees C. 相似文献
96.
Zhang C Occi J Masurekar P Barrett JF Zink DL Smith S Onishi R Ha S Salazar O Genilloud O Basilio A Vicente F Gill C Hickey EJ Dorso K Motyl M Singh SB 《Journal of the American Chemical Society》2008,130(36):12102-12110
Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 microg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro23, Pro22, and Pro26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described. 相似文献
97.
Angela Giorgia Potortì Alessia Tropea Vito Pellizzeri Asma Belfita Giacomo Dugo 《Natural product research》2020,34(1):167-171
AbstractSpices and aromatic herbs can be contaminated with mycotoxins, since of their preharvest, postharvest, and storage conditions. In this study, 112 samples of different spices and aromatic herbs were evaluated for their mycotoxins content by HPLC-MS/MS in order to highlight their possible risk linked with human use. The results showed that mycotoxins were occasionally detected only in samples of coriander, laurel, mint, rosemary, and verbena. In both geographical origins a different contamination was detected. Among the investigated mycotoxins, AFB2, AFG1, AFG2, T2 and HT2 were detected, whereas none of the samples contained AFB1 and FB1. The co-occurrence of two toxins were observed for some samples of rosemary and verbena. This study indicates that it is essential minimize the toxins in agriculture, industry, and food-product manufacturing for the consumer health protection. 相似文献
98.
Sen Ye Nir Hananya Ori Green Hansen Chen Angela Qian Zhao Jiangang Shen Doron Shabat Dan Yang 《Angewandte Chemie (International ed. in English)》2020,59(34):14326-14330
Selective and sensitive molecular probes for hydrogen peroxide (H2O2), which plays diverse roles in oxidative stress and redox signaling, are urgently needed to investigate the physiological and pathological effects of H2O2. A lack of reliable tools for in vivo imaging has hampered the development of H2O2 mediated therapeutics. By combining a specific tandem Payne/Dakin reaction with a chemiluminescent scaffold, H2O2‐CL‐510 was developed as a highly selective and sensitive probe for detection of H2O2 both in vitro and in vivo. A rapid 430‐fold enhancement of chemiluminescence was triggered directly by H2O2 without any laser excitation. Arsenic trioxide induced oxidative damage in leukemia was successfully detected. In particular, cerebral ischemia‐reperfusion injury‐induced H2O2 fluxes were visualized in rat brains using H2O2‐CL‐510 , providing a new chemical tool for real‐time monitoring of H2O2 dynamics in living animals. 相似文献
99.
100.
Isabel V. L. Wilkinson Kelly J. Perkins Hannah Dugdale Lee Moir Aini Vuorinen Maria Chatzopoulou Sarah E. Squire Sebastian Monecke Alexander Lomow Marcus Geese Philip D. Charles Peter Burch Jonathan M. Tinsley Graham M. Wynne Stephen G. Davies Francis X. Wilson Fraydoon Rastinejad Shabaz Mohammed Kay E. Davies Angela J. Russell 《Angewandte Chemie (International ed. in English)》2020,59(6):2420-2428
Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies. 相似文献