- Anti-dormant mycobacterial activity and target analysis of nybomycin produced by a marine-derived Streptomyces sp.
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Abstract In the course of our search for anti-dormant Mycobacterial substances, nybomycin (1) was re-discovered from the culture broth of a marine-derived Streptomyces sp. on the bioassay-guided separation. Compound 1 showed anti-microbial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG with the MIC of 1.0 μg/mL under both actively growing aerobic conditions and dormancy inducing hypoxic conditions. Compound 1 is also effective to Mycobacterium tuberculosis including the clinically isolated strains. The mechanistic analysis indicated that 1 bound to DNA and induces a unique morphological change to mycobacterial bacilli leading the bacterial cell death.
- Arai, Masayoshi,Kamiya, Kentaro,Pruksakorn, Patamaporn,Sumii, Yuji,Kotoku, Naoyuki,Joubert, Jean-Pierre,Moodley, Prashini,Han, Chisu,Shin, Dayoung,Kobayashi, Motomasa
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- Supramolecular assembly-induced enhanced emission of electrospun nanofibers
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A nucleobase-assembled supramolecular nanofiber is capable of forming network-like polymeric clusters through complementary hydrogen-bonding interactions. It behaves as an effective chromophore that greatly enhances the light emission efficiency of fluorescent fibers, reaching up to three times higher efficiency than the control samples. This journal is
- Cheng, Chih-Chia,Wang, Yeh-Sheng,Chang, Feng-Chih,Lee, Duu-Jong,Yang, Li-Chih,Chen, Jem-Kun
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- A flexible synthesis of 68Ga-labeled carbonic anhydrase IX (CAIX)-targeted molecules via CBT/1,2-aminothiol click reaction
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We herein describe a flexible synthesis of a small library of68Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1-3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives (8 and 9) yielded six new68Ga-labeled CAIX ligands with high radiochemical yields. The click reaction conditions were optimized to improve the reaction rate for applications with short half-life radionuclides. Overall, our methodology allows for a simple and efficient radiosynthetic route to produce a variety of68Ga-labeled imaging agents for tumor hypoxia.
- Chen, Kuo-Ting,Nguyen, Kevin,Ieritano, Christian,Gao, Feng,Seimbille, Yann
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- Synthesis and characterization of monosaccharide lipids as novel hydrogelators
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Self-assembly of small molecules is a useful strategy for forming functional supramolecular structures. Three new series of methyl α-d-glucopyranoside derivatives, including esters and carbamates, have been synthesized and characterized. Several of these
- Wang, Guijun,Cheuk, Sherwin,Williams, Kristopher,Sharma, Vibha,Dakessian, Lousi,Thorton, Zeus
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- Total synthesis of peroxyacarnoates A and D: Metal-mediated couplings as a convergent approach to polyunsaturated peroxides
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(Chemical Equation Presented) The first syntheses of peroxyacarnoates A and D, members of a family of enyne-containing alkoxydioxanes, have been achieved on the basis of chemoselective ozonolysis within a polyunsaturated framework and Pd-mediated cross-couplings of a functionalized 1,2-dioxane.
- Xu, Chunping,Raible, Joseph M.,Dussault, Patrick H.
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- NEW LONG-CHAIN TETRATHIAFULVALENE DERIVATIVES WITH A DIACETYLENE GROUP
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The multi-stage synthesis of new long-chain tetrathiafulvalene derivatives containing a diacetylene group at different distances from tetrathiafulvalene moiety - 2-(tetracosa-9,11-diynyl)-, 2-(heptadeca-9,11-diynyl)- and 2-(nonadeca-4,6-diynyl)-6,7-tetrathiafulvalene is described.
- Khodorkovsky, V. Yu.,Tormos, G. V.,Neilands, O. Ya.,Kolotilo, N. V.,Il'chenko, A. Ya.
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- Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia
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Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.
- Li, Jing,Li, Shanshan,Guo, Jianshuang,Li, Qiuying,Long, Jing,Ma, Cheng,Ding, Yahui,Yan, Chunli,Li, Liangwei,Wu, Zhigang,Zhu, He,Li, Keqin Kathy,Wen, Liuqing,Zhang, Quan,Xue, Qingqing,Zhao, Caili,Liu, Ning,Ivanov, Ivaylo,Luo, Ming,Xi, Rimo,Long, Haibo,Wang, Peng George,Chen, Yue
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- Small-molecule fluorophores with large stokes shifts: 9-iminopyronin analogues as clickable tags
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The design, synthesis, and both experimental and theoretical studies of several novel 9-(acylimino)- and 9-(sulfonylimino)pyronin derivatives containing either an oxygen or a silicon atom at position 10 are reported. These compounds, especially the Si analogues, exhibit remarkably large Stokes shifts (around 200 nm) while still possessing a high fluorophore brightness, absorption bands in the near-UV and visible part of the spectrum, and high thermal and photochemical stabilities in protic solvents. The reason for the observed large Stokes shifts is an intramolecular charge-transfer excitation of an electron from the HOMO to the LUMO of the chromophore, accompanied by elongation of the C9-N bond and considerable solvent reorganization due to hydrogen bonding to the solvent. Due to the photophysical properties of the studied compounds and their facile and high-yielding synthesis, as well as a simple protocol for their bioorthogonal ligation to a model saccharide using a Huisgen alkyne-azide cycloaddition, they represent excellent candidates for biochemical and biological applications as fluorescent tags and indicators for multichannel imaging. 9-(Acylimino)pyronins alter their optical properties upon protonation and may also be used as pH sensors.
- Horváth, Peter,?ebej, Peter,?olomek, Tomá?,Klán, Petr
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- Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
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Proteolysis-targeting chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularit
- Brittain, Scott M.,Henning, Nathaniel J.,Manford, Andrew G.,McKenna, Jeffrey M.,Nomura, Daniel K.,Rape, Michael,Schirle, Markus,Spradlin, Jessica N.,Tallarico, John A.,Zhang, Erika
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supporting information
p. 701 - 708
(2022/02/05)
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- Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes
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A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-α-amino-β-hydroxy and α,β-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.
- Kennington, Stuart C. D.,Teloxa, Saul F.,Mellado-Hidalgo, Miguel,Galeote, Oriol,Puddu, Sabrina,Bellido, Marina,Romea, Pedro,Urpí, Fèlix,Aullón, Gabriel,Font-Bardia, Mercè
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supporting information
p. 15307 - 15312
(2021/06/11)
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- FEM1B PROTEIN BINDING AGENTS AND USES THEREOF
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Disclosed herein, inter alia, are compounds for binding FEMIB protein and uses thereof. In an aspect, provided herein is a pharmaceutical composition including a compound as described herein and a pharmaceutically acceptable excipient.
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Paragraph 0587-0588
(2021/09/17)
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- Decarboxylative Borylation of mCPBA-Activated Aliphatic Acids
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A decarboxylative borylation of aliphatic acids for the synthesis of a variety of alkylboronates has been developed by mixing m-chloroperoxybenzoic acid (mCPBA)-activated fatty acids with bis(catecholato)diboron in N,N-dimethylformamide (DMF) at room temperature. A radical chain process is involved in the reaction which initiates from the B-B bond homolysis followed by the radical transfer from the boron atom to the carbon atom with subsequent decarboxylation and borylation.
- Wei, Dian,Liu, Tu-Ming,Zhou, Bo,Han, Bing
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supporting information
p. 234 - 238
(2020/01/02)
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- Conjugable A3 adenosine receptor antagonists for the development of functionalized ligands and their use in fluorescent probes
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Compounds able to simultaneously bind a biological target and be conjugated to a second specific moiety are attractive tools for the development of multi-purpose ligands useful as multi-target ligands, receptor probes or drug delivery systems, with both therapeutic and diagnostic applications. The human A3 adenosine receptor is a G protein-coupled receptor involved in many physio-pathological conditions, e.g. cancer and inflammation, thus representing a promising research target. In this work, two series of conjugable hA3AR antagonists, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus, were developed. The introduction of an aromatic ring at the 5 position of the scaffold, before (phenylacetamido moiety) or after (1,2,3-triazole obtained by click chemistry) the conjugation is aimed to increase affinity and selectivity towards the hA3AR receptor. As expected, conjugable compounds showed good affinity towards the hA3AR. In order to prove their potential in the development of hA3AR ligands for different purposes, compounds were also functionalized with fluorescent probes. Unfortunately, conjugation decreased affinity and selectivity for the target as compared to the hA2AAR. Computational studies identified specific non-conserved residues of the extracellular loops which constitute a structural barrier able to discriminate between ligands, giving insights into the rational development of new highly selective ligands.
- Federico, Stephanie,Margiotta, Enrico,Moro, Stefano,Kozma, Eszter,Gao, Zhan-Guo,Jacobson, Kenneth A.,Spalluto, Giampiero
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- Synthesis of Exo- and Endocyclic Enamides Through Copper-Catalyzed Regioselective Intramolecular N-Halovinylation
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Cross-couplings between amides and 1,2-dihaloalkenes are an efficient and straightforward way to access β-haloenamides which, in turn, can be functionalized into complex, stereodefined enamide motifs. However, the intramolecular version of these cross-couplings, leading to cyclic β-haloenamides, has not been formally studied. In this paper, we report an investigation of factors affecting the efficiency of the reaction and its selectivity between potential exo and endo cyclization products. We demonstrate that exo/endo selectivity is largely determined by ring strain, whether it arises from the size of the resulting ring or from the structure of the starting compound, but that selectivity can also be modulated by varying reaction conditions. Finally, we show that resulting β-haloenamides readily undergo transition metal-catalyzed reactions, making this sequence a viable way to access highly functionalized cyclic enamides.
- Bergeron, Jodrey,Daoust, Benoit,Gilbert, Nicolas,Lambolez, Pierre,Ricard, Simon
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supporting information
(2020/05/04)
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- Synthesis of Dendritic Glycoclusters and Their Applications for Supramolecular Gelation and Catalysis
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Glycoclusters with three, four, and six arms of glycosyl triazoles were designed, synthesized, and characterized. The self-assembling properties of these molecules and their catalytic activity as ligands in copper-catalyzed azide and alkyne cycloaddition (CuAAC) reactions were studied. The compounds with a lower number of branches exhibit excellent gelation properties and can function as supramolecular gelators. The resulting gels were characterized using optical microcopy and atomic force microscopy. The glycoconjugates containing six branches showed significant catalytic activity for copper sulfate mediated cycloaddition reactions. In aqueous solutions, 1 mol % of glycoclusters to substrates was efficient at accelerating these reactions. Several trimeric compounds were found to be capable of forming co-gels with the catalytically active hexameric compounds. Using the organogels formed by the glycoconjugates as supramolecular catalysts, efficient catalysis was demonstrated for several CuAAC reactions. The metallogels with CuSO4 were also prepared as gel columns, which can be reused for the cycloaddition reactions several times. These include the preparation of a few glycosyl triazoles and aryl triazoles and isoxazoles. We expect that these sugar-based soft biomaterials will have applications beyond supramolecular catalysis for copper-catalyzed cycloaddition reactions. They may also be useful as ligands or gel matrixes for other metal-ion catalyzed organic reactions.
- Wang, Guijun,Wang, Dan,Bietsch, Jonathan,Chen, Anji,Sharma, Pooja
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p. 16136 - 16156
(2021/01/09)
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- FUNCTION-BASED PROBES FOR ENVIRONMENTAL MICROBIOME ANALYSIS AND METHODS OF MAKING AND USING THE SAME
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Probe embodiments for identifying analytes involved in biofuel or bioenergy production, bioremediation, or nutrient cycling as well as methods of making and use are described herein. In some embodiments, probes identifying cellulose degradation and/or sug
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Page/Page column 68
(2019/04/11)
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- Synthesis and characterization of 3-O-esters of N-acetyl-D-glucosamine derivatives as organogelators
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Carbohydrate derived low molecular weight organogelators are interesting compounds with many potential applications. Selective functionalization of the different hydroxyl substituents on d-glucose and d-glucosamine resulted in small molecular gelators. Previously we have found that the C-2 acylated derivatives including esters and carbamates of 4,6-O-benzylidene protected glucose and glucosamine derivatives have shown remarkable applications as molecular gelators. In this research, in order to probe the structural influence of sugar derivatives on molecular self-assembly, we introduced acylation functional groups to the 3-hydroxyl group of 4,6-O-benzylidene acetal protected N-acetyl glucosamine derivatives. A library of fourteen ester derivatives was synthesized and characterized. The ester derivatives typically formed gels in pump oil and aqueous mixtures of dimethyl sulfoxide or ethanol. The resulting gels were characterized using optical microscopy, and rheology, etc. All alkyl ester derivatives were gelators for pump oil. A short chain ester derivative was able to form gels in a few different oils and the corresponding oil water mixtures phase selectively. The compound was also used to trap naproxen sodium and formed a stable co-gel. The controlled release of the drug from the gel to the aqueous phase was analyzed using UV-vis spectroscopy. These results show that the functionalization at the 3-OH position of the N-acetyl glucosamine derivative is a feasible strategy in designing new classes of organogelators.
- Chen, Anji,Samankumara, Lalith P.,Garcia, Consuelo,Bashaw, Kristen,Wang, Guijun
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supporting information
p. 7950 - 7961
(2019/06/07)
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- Non- C2-Symmetric Chiral-at-Ruthenium Catalyst for Highly Efficient Enantioselective Intramolecular C(sp3)-H Amidation
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A new class of chiral ruthenium catalysts is introduced in which ruthenium is cyclometalated by two 7-methyl-1,7-phenanthrolinium heterocycles, resulting in chelating pyridylidene remote N-heterocyclic carbene ligands (rNHCs). The overall chirality results from a stereogenic metal center featuring either a or Δabsolute configuration. This work features the importance of the relative metal-centered stereochemistry. Only the non-C2-symmetric chiral-at-ruthenium complexes display unprecedented catalytic activity for the intramolecular C(sp3)-H amidation of 1,4,2-dioxazol-5-ones to provide chiral -lactams with up to 99:1 er and catalyst loadings down to 0.005 mol % (up to 11 ?200 TON), while the C2-symmetric diastereomer favors an undesired Curtius-type rearrangement. DFT calculations elucidate the origins of the superior C-H amidation reactivity displayed by the non-C2-symmetric catalysts compared to related C2-symmetric counterparts.
- Zhou, Zijun,Chen, Shuming,Hong, Yubiao,Winterling, Erik,Tan, Yuqi,Hemming, Marcel,Harms, Klaus,Houk,Meggers, Eric
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supporting information
p. 19048 - 19057
(2019/12/04)
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- Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases
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Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.
- Yang, Jian,Barniol-Xicota, Marta,Nguyen, Minh T.N.,Ticha, Anezka,Strisovsky, Kvido,Verhelst, Steven H.L.
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supporting information
p. 1423 - 1427
(2018/03/06)
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- Synthesis of Substituted Quinolizidines via a Gold-Catalyzed Double Cyclization Cascade
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A novel synthesis of quinolizidines by a cationic gold-catalyzed double cyclization cascade has been developed. The reaction was initiated by the gold-catalyzed 6-exo-dig cyclization of ynamides, which was followed by a second cyclization of an enamide intermediate to provide the corresponding quinolizidine derivatives. The utility of this reaction was demonstrated by application to the synthesis of multi-substituted quinolizidines and by the total synthesis of a quinolizidine alkaloid, (±)-lupinine.
- Nonaka, Shiori,Sugimoto, Kenji,Ueda, Hirofumi,Tokuyama, Hidetoshi
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supporting information
p. 380 - 385
(2016/02/12)
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- Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response
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Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram-negative Salmonella.
- Mandl, Franziska A.,Kirsch, Volker C.,Ugur, Ilke,Kunold, Elena,Vomacka, Jan,Fetzer, Christian,Schneider, Sabine,Richter, Klaus,Fuchs, Thilo M.,Antes, Iris,Sieber, Stephan A.
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supporting information
p. 14852 - 14857
(2016/11/23)
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- Solventless synthesis of acyl phosphonamidates, precursors to masked bisphosphonates
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A series of acyl phosphonamidates, the synthetic precursors to bisphosphonates, have been readily prepared from phosphoramidite type reagents and a range of acid chlorides. These reactions were performed using solventless conditions, where purification was easily achieved using column chromatography with yields ranging from 71-90%. Furthermore, we have demonstrated that these acyl phosphonamidates could be used for the preparation of unsymmetrical bisphosphonates, which do date are scarcely reported in the literature.
- Crossey, Kerri,Migaud, Marie E.
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supporting information
p. 11088 - 11091
(2015/07/07)
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- Gold-catalyzed spiro-N,O-ketal synthesis
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An efficient method for the synthesis of spiro-N,O-ketals with 5- and 6-membered rings was developed via a gold-catalyzed spiroamidoketalization of alkynyl amidoalcohols under mild conditions. This methodology has been successfully applied to the synthesis of a spiro-N,O-ketal analogue of marineosin A. This journal is
- Grammatikopoulou,Thysiadis,Sarli
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p. 1169 - 1178
(2015/03/04)
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- Active site-directed proteomic probes for adenylation domains in nonribosomal peptide synthetases
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We describe a general strategy for selective chemical labeling of individual adenylation (A) domains in nonribosomal peptide synthetases (NRPSs) using active site-directed proteomic probes coupled to the 5′-O-N-(aminoacyl)sulfamoyladenosine (AMS) scaffold
- Konno, Sho,Ishikawa, Fumihiro,Suzuki, Takehiro,Dohmae, Naoshi,Burkart, Michael D.,Kakeya, Hideaki
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supporting information
p. 2262 - 2265
(2015/02/05)
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- SMALL MOLECULE DRUG CONJUGATES
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A targeted therapeutic agent comprising a compound of formula (I): B–L–D, wherein: B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX); D is a drug moiety; and L is a linker group that undergoes cleavage in vivo for releasing said
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Page/Page column 47; 48
(2015/09/22)
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- β-Sultams exhibit discrete binding preferences for diverse bacterial enzymes with nucleophilic residues
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β-Sultams are potent electrophiles that modify nucleophilic residues in selected enzyme active sites. We here identify and characterize some of the specific bacterial targets and show a unique inhibition of the azoreductase family.
- Kolb, Roman,Bach, Nina C.,Sieber, Stephan A.
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supporting information
p. 427 - 429
(2014/01/06)
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- A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors
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Antibody-drug conjugates are a very promising class of new anticancer agents, but the use of small-molecule ligands for the targeted delivery of cytotoxic drugs into solid tumors is less well established. Here, we describe the first small-molecule drug co
- Krall, Nikolaus,Pretto, Francesca,Decurtins, Willy,Bernardes, Goncalo J. L.,Supuran, Claudiu T.,Neri, Dario
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supporting information
p. 4231 - 4235
(2014/05/06)
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- Enterobactin-mediated delivery of ?-lactam antibiotics enhances antibacterial activity against pathogenic escherichia coli
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The design, synthesis, and characterization of enterobactin-antibiotic conjugates, hereafter Ent-Amp/Amx, where the ?-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethy
- Zheng, Tengfei,Nolan, Elizabeth M.
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p. 9677 - 9691
(2014/07/22)
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- Synthesis of triple-bond-containing 1-hydroxy-1,1-bisphosphonic acid derivatives to be used as precursors in "click" chemistry: Two examples
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The synthesis of novel (alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid tetramethyl esters (1a-c), their P,P'-dimethyl esters (2a-c), and two trimethyl ester derivatives (3a and 3b) is reported. The prepared compounds can be attached to many kinds of molecules containing azide (-N3) functionalities using a "click" chemistry approach. As an example, bisphosphonate trimethyl ester 3a and P,P'-dimethyl ester 2b were attached to triethylene glycol to form triethylene glycol-bisphosphonate conjugates 4 and 5 as model compounds for further studies in, for example, nanoparticle targeting.
- Turhanen, Petri A.
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p. 6330 - 6335
(2014/07/21)
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- A DNA-templated synthesis of encoded small molecules by DNA self-assembly
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We report a novel method for the synthesis of DNA-encoded libraries without the need for discrete DNA template. Reactant DNAs self-assemble to enable chemical reactions and photo-cleavage transfers the product to the DNA terminus, making it suitable for the subsequent affinity-based selection and hit deconvolution. This journal is the Partner Organisations 2014.
- Cao, Cheng,Zhao, Peng,Li, Ze,Chen, Zitian,Huang, Yanyi,Bai, Yu,Li, Xiaoyu
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supporting information
p. 10997 - 10999
(2014/11/07)
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- Synthesis of OSW-1 derivatives by site-selective acylation and their biological evaluation
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A strategy to site-selectively monoacylate an antitumor saponin OSW-1 was developed using an organotin reagent to rapidly access its derivatives that are useful as chemical probes. 4″-O-Acylated OSW-1 derivatives bearing a fluorophore, an alkyne tag, or biotin were prepared in good yields and were shown to maintain highly cytotoxic activity.
- Sakurai, Kaori,Takeshita, Tomoya,Hiraizumi, Masato,Yamada, Rika
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supporting information
p. 6318 - 6321
(2015/02/19)
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- Converting an electrical insulator into a dielectric capacitor: End-capping polystyrene with oligoaniline
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We report a simple and low-cost strategy to enhance the dielectric permittivity of polystyrene by up to an order of magnitude via incorporating an oligoaniline trimer moiety at the end of the polymer chains. The oligoaniline-capped polystyrene was prepared by a copper-catalyzed click reaction between azide-capped polystyrene and an alkyne-containing aniline trimer, which was doped by different acids. By controlling molecular weight of polystyrene, the end-capped polymers can be induced to form nanoscale oligoaniline-rich domains embedded in an insulating matrix. Under an external electric field, this led to an increase in dielectric polarizability while maintaining a low dielectric loss. At frequencies as high as 0.1 MHz, the dielectric permittivity and dielectric loss (tan δ) were ~22.8 and ~0.02, respectively. This strategy may open a new avenue to increasing the dielectric permittivity of many other commodity polymers while maintaining relatively low dielectric loss.
- Hardy, Christopher G.,Islam, Md. Sayful,Gonzalez-Delozier, Dioni,Morgan, Joel E.,Cash, Brandon,Benicewicz, Brian C.,Ploehn, Harry J.,Tang, Chuanbing
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p. 799 - 807
(2013/04/24)
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- Protecting-group-free total synthesis of (-)-rhazinilam and (-)-rhazinicine using a gold-catalyzed cascade cyclization
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'Rhaz'zmatazz: A total synthesis of (-)-rhazinilam and the first asymmetric total synthesis of (-)-rhazinicine were accomplished by using constructing the indolizinone core through the gold-catalyzed cyclization of a fully elaborated linear ynamide. The scope and generality of this cascade reaction for the construction of highly substituted indolizinones were also investigated. Copyright
- Sugimoto, Kenji,Toyoshima, Kazuki,Nonaka, Shiori,Kotaki, Kenta,Ueda, Hirofumi,Tokuyama, Hidetoshi
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supporting information
p. 7168 - 7171
(2013/07/26)
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- Cyclization of 5-hexynoic acid to 3-alkoxy-2-cyclohexenones
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The one-pot cyclization of 5-hexynoic acid to produce 3-alkoxy-2- cyclohexenones proceeds in good yields (58-90%). 3-Hexynoic acid was converted to its acyl chloride with the aid of oxalyl chloride and was cyclized to 3-chloro-2-cyclohexenone upon addition of indium(III) chloride. Subsequent addition of alcohol nucleophiles led to the desired 3-alkoxy-2-cyclohexenones.
- Hylden, Anne T.,Uzelac, Eric J.,Ostojic, Zeljko,Wu, Ting-Ting,Sacry, Keely L.,Sacry, Krista L.,Xi, Lin,Jones, T. Nicholas
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body text
p. 1323 - 1326
(2011/11/06)
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- Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry
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2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and four to six carbon bridge lengths (compounds 1-3) were synthesized as substrates for folate receptors (FRs) and the proton-coupled folate transporter (PCFT). Conversion of acetylene carboxylic acids to α-bromomethylketones and condensation with 2, 4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2, 3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FRα, reduced folate carrier (RFC), and PCFT. The analogs were selective for FR and PCFT over RFC. Glycinamide ribonucleotide formyltransferase was the principal cellular target. In SCID mice with KB tumors, 1 was highly active against both early (3.5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC. 2010 American Chemical Society.
- Wang, Lei,Cherian, Christina,Desmoulin, Sita Kugel,Polin, Lisa,Deng, Yijun,Wu, Jianmei,Hou, Zhanjun,White, Kathryn,Kushner, Juiwanna,Matherly, Larry H.,Gangjee, Aleem
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experimental part
p. 1306 - 1318
(2010/08/07)
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- Modulating the development of E. coli biofilms with 2-aminoimidazoles
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The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC50 of 13 μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400 μM.
- Reed, Catherine S.,Huigens III, Robert W.,Rogers, Steven A.,Melander, Christian
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supporting information; experimental part
p. 6310 - 6312
(2010/11/18)
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- Trimethylsilyldiazomethane as a versatile stitching agent for the introduction of aziridines into functionalized organic molecules
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A highly enantioselective route for the introduction of aziridines into functionalized organic molecules was developed via a tandem acylation and aziridination of TMSCHN2.
- Ren, Hong,Wulff, William D.
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supporting information; experimental part
p. 4908 - 4911
(2011/02/21)
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- Facile synthesis of β-cyclodextrin-dextran polymers by "click" chemistry
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Three series of novel water-soluble β-cyclodextrin-dextran polymers have been prepared by "click" chemistry. The polymers were synthesized from alkyne-modified dextrans (AMDs) onto which mono-6-O-deoxy-monoazido- βCD (N3βCD) was grafted by a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polymers have been characterized by NMR spectroscopy and size exclusion chromatography (SEC). The binding properties have been characterized by isothermal titration calorimetry (ITC) and show excellent accessibility of the βCDs.
- Nielsen, Thorbjorn Terndrup,Wintgens, Veronique,Amiel, Catherine,Wimmer, Reinhard,Larsen, Kim Lambertsen
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experimental part
p. 1710 - 1715
(2011/04/22)
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- Cyclization of propargylic amides: Mild access to oxazole derivatives
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The substrate scope, the mechanistic aspects of the gold-catalyzed oxazole synthesis, and substrates with different aliphatic, aromatic, and functional groups in the side chain were investigated. Even molecules with several propargyl amide groups could easily be converted, delivering di- and trioxazoles with interesting optical properties. Furthermore, the scope of the gold(I)-catalyzed alkylidene synthesis was investigated. Further functionalizations of these isolable intermediates of the oxazole synthesis were developed and chelate ligands can be obtained. The use of Barluenga's reagent offers a new and mild access to the synthetically valuable iodoalkylideneoxazoles from propargylic amides, this reagent being superior to other sources of halogens.
- Weyrauch, Jan P.,Hashmi, A. Stephen K.,Schuster, Andreas,Hengst, Tobias,Schetter, Stefanie,Littmann, Anna,Rudolph, Matthias,Hamzic, Melissa,Visus, Jorge,Rominger, Frank,Frey, Wolfgang,Bats, Jan W.
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supporting information; experimental part
p. 956 - 963
(2010/06/12)
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- SELECTIVE PROTON COUPLED FOLATE TRANSPORTER AND FOLATE RECEPTOR, AND GARFTASE INHIBITOR COMPOUNDS AND METHODS OF USING THE SAME
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Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.
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Page/Page column 14-17
(2010/04/25)
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- Synthesis of (S)-jamaicamide C carboxylic acid
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"Chemical Equation Presented" The jamaicamides are natural product sodium channel blockers derived from the cyanobacterium Lyngbya majuscula. The carboxylic acid fragment of jamaicamide C contains a methyl stereocenter and a trisubstituted E chloroolefin.
- Graf, Kristin M.,Tabor, Martin G.,Brown, Milton L.,Paige, Mikell
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supporting information; experimental part
p. 5382 - 5385
(2010/02/28)
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- Identification of protein targets of 4-hydroxynonenal using click chemistry for ex vivo biotinylation of azido and alkynyl derivatives
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Polyunsaturated fatty acids (PUFA) are primary targets of free radical damage during oxidative stress. Diffusible electrophilic α,β- unsaturated aldehydes, such as 4-hydroxynonenal (HNE), have been shown to modify proteins that mediate cell signaling (e.g., IKK and Keap1) and alter gene expression pathways responsible for inducing antioxidant genes, heat shock proteins, and the DNA damage response. To fully understand cellular responses to HNE, it is important to determine its protein targets in an unbiased fashion. This requires a strategy for detecting and isolating HNE-modified proteins regardless of the nature of the chemical linkage between HNE and its targets. Azido or alkynyl derivatives of HNE were synthesized and demonstrated to be equivalent to HNE in their ability to induce heme oxygenase induction and induce apoptosis in colon cancer (RKO) cells. Cells exposed to the tagged HNE derivatives were lysed and exposed to reagents to effect Staudinger ligation or copper-catalyzed Huisgen 1,3 dipolar cycloaddition reaction (click chemistry) to conjugate HNE-adducted proteins with biotin for subsequent affinity purification. Both strategies yielded efficient biotinylation of tagged HNE-protein conjugates, but click chemistry was found to be superior for the recovery of biotinylated proteins from streptavidin-coated beads. Biotinylated proteins were detected in lysates from RKO cell incubations with azido-HNE at concentrations as low as 1 μM. These proteins were affinity purified with streptavidin beads, and proteomic analysis was performed by linear ion trap mass spectrometry. Proteomic analysis revealed a dose-dependent increase in labeled proteins with increased sequence coverage at higher concentrations. Several proteins involved in stress signaling (heat shock proteins 70 and 90 and the 78-kDa glucose-regulated protein) were selectively adducted by azido- and alkynyl-HNE. The use of azido and alkynyl derivatives in conjunction with click chemistry appears to be a valuable approach for the identification of the protein targets of HNE.
- Vila, Andrew,Tallman, Keri A.,Jacobs, Aaron T.,Liebler, Daniel C.,Porter, Ned A.,Marnett, Lawrence J.
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p. 432 - 444
(2008/12/22)
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- The extraordinary reactions of phenyldimethylsilyllithium with N,N-disubstituted amides
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The reactions of the silyllithium reagent with tertiary amides was discussed. The enediamines were easily isomerized from cis to trans, easily oxidized to dienediamines and were hydrolyzed to α-aminoketones. If the two equivalents of the silyllithium reagent were used, the product was an α-silylamine. The results show that each member of the homologous series of amides gives rise to a substantially different product.
- Buswell, Marina,Fleming, Ian,Ghosh, Usha,Mack, Stephen,Russell, Matthew,Clark, Barry P.
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p. 3006 - 3017
(2007/10/03)
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- The biological effects of structural variation at the meta position of the aromatic rings and at the end of the alkenyl chain in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors
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In an effort to elucidate a set of structure-activity relationships in the alkenyldiarylmethane (ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications were made at two locations: (1) the meta positions of the two aromatic rings and (2) the end of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cell culture and for inhibition of HIV-1 reverse transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with optimal activity appearing with Cl, CH3, and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF3) substituents. The substituents at the end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity associated with methyl or ethyl ester groups and with diminished activity resulting from substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals, ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar EC50 values for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. Selected ADAMs, 19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1 clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype representative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were more effective against the A98G mutation (found in association with nevirapine resistance in vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21 was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at preventing virus replication. Thus, we have identified a novel series of reverse transcriptase inhibitors with a favorable profile of antiviral activity against the primary mutation involved in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain activity against a multidrug-resistant virus.
- Xu,Micklatcher,Silvestri,Hartman,Burrier,Osterling,Wargo,Turpin,Buckheit Jr.,Cushman
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p. 4092 - 4113
(2007/10/03)
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- Solid-phase synthesis of the alkenyldiarylmethane (ADAM) series of non-nucleoside HIV-1 reverse transcriptase inhibitors
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The Sonogashira and Stille cross-coupling reactions have been employed in the synthesis of several non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the alkenyldiarylmethane (ADAM) series. The synthesis has been carried out both in solution and on a solid support. In contrast to previous syntheses of NNRTIs in the ADAM series, the present strategy allows the incorporation of differently substituted aromatic rings in a stereochemically defined fashion. The most potent of the new ADAMs inhibited the cytopathic effect of HIV-1RF in CEM-SS cell culture with an EC50 value of 20 nM.
- Xu,Loftus,Wargo,Turpin,Buckheit Jr.,Cushman
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p. 5958 - 5964
(2007/10/03)
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- Novel [1,5] sigmatropic rearrangements of cyclohexadienones generated from fischer carbene complexes. A new strategy for installing the C-20 angular ethyl group in aspidospermidine alkaloids
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(Equation Presented) We report here the first examples of a [1,5] sigmatropic rearrangement in a 4a-alkyl-4a-hydrocarbazol-4-one to yield a 3-alkylcarbazol-4-one with a re-aromatized indole nucleus. The reaction of 1-methyl-3-substituted-indole-2-carbene
- Quinn, John F.,Bos, Mary Ellen,Wulff, William D.
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p. 161 - 164
(2008/03/11)
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- Tandem radical reactions of isonitriles with 2-pyridonyl and other aryl radicals: Scope and limitations, and a first generation synthesis of (±)-camptothecin
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Photolysis of N-propargyl-6-halo-2-pyridones and related aromatic halides in the presence of aryl isonitriles provides tetra- and penta-cyclic products in a single step by a sequence of radical addition to the isonitrile followed by two cyclizations. The scope and limitations of the process are described along with a first generation synthesis of racemic camptothecin.
- Curran, Dennis P.,Liu, Hui,Josien, Hubert,Ko, Sung-Bo
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p. 11385 - 11404
(2007/10/03)
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- Preparation and Diels-Alder Reactivity of Thieneo- and Thienopyran-3-ones, Stable 2,3-Dimethylenethiophene Derivatives; Synthesis of Benzothiophenes
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The thienopyran-3-ones (7) and the isomeric pyranones, e.g. (26) are stable derivatives of 2,3-dimethylenethiophene (3).When heated with alkynes they undergo Diels-Alder reaction to give, after loss of carbon dioxide, benzothiophenes.With un
- Jackson, P. Mark,Moody, Christopher J.,Shah, Pritom
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p. 2909 - 2918
(2007/10/02)
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- Intramolecular Cycloadditions of Mesionic Carbonyl Ylides with Alkynes. Synthesis of 5,6-Dihydro-4H-cyclopenta- and 4,5,6,7-Tetrahydrobenzofuran Derivatives
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Intramolecular cycloaddition reactions of acetylenic isomuenchnones, formed in situ by rhodium acetate catalyzed decomposition of N-(diazoacetyl)-N-methylalkynamide derivatives 16a-c, 18c, and 18d have been studied.The intermediate cycloadducts fragmentate spontaneously under the reaction conditions (110 deg C) to afford the annulated furans 19a-c, 20c, and 20d. - Keywords: Carbonyl ylides; Furans; Intramolecular cycloadditions; Isomuenchnones
- Maier, Martin E.,Schoeffling, Baerbel
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p. 1081 - 1088
(2007/10/02)
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- Intramolecular Reactions of N-Nitrenes with Alkynes: Conformational Anchoring in Spiro-fused 2H-Azirines
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Oxidations of N-aminoquinazolin-4(3H)-ones (7)-(11) with lead tetra-acetate in dichloromethane results in the intramolecular addition of the N-nitrene to the triple bond in each case and azirines (20), (22), (17), (23), and (30), respectively, are isolated with (31) identified as a by-product in the oxidation of compound (11).An X-ray crystal structure determination on compound (17) reveals a remarkable deformation of bond angles at the spiro centre and this feature appears to be common to all azirines.The five membered ring in the azirines (17), (20), (22), and (23) has the envelope conformation (26) and the six-membered ring in the azirine (30) has the twist-boat conformation (32): a possible explanation for this conformational anchoring is offered.
- Atkinson, Robert S.,Grimshire, Michael J.
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p. 1215 - 1224
(2007/10/02)
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