- Fluorogenic tagging of peptides via Cys residues using thiol-specific vinyl sulfone affinity tags
-
Fluorescent tagging of Cys-containing peptides is presented herein. The procedure follows a two-step sequential reaction scheme using thiol specific bifunctional chemical reporters and fluorogenic labels. Vinyl-sulfone bearing chemical reporters have been synthesized and demonstrated to selectively modify cysteine under physiological conditions in the presence of other nucleophilic amino acids. Bifunctional chemical reporters decorated with a terminal alkyne moiety, suitable for modification with azide containing fluorogenic labels were also synthesized. Such fluorogenic (turn on) labels in combination with these new vinyl-sulfone tags can be used generally in fluorescent modulation schemes of thiol-bearing biomolecules.
- Cserép, Gergely B.,Baranyai, Zsuzsa,Komáromy, Dávid,Horváti, Kata,Bosze, Szilvia,Kele, Péter
-
-
Read Online
- Observation of Circularly Polarized Luminescence of the Excimer from Two Perylene Cores in the Form of [4]Rotaxane
-
A perylene-based [4]rotaxane was synthesized by the Sonogashira coupling of the 2:2 inclusion complex consisting of two alkynylperylenes and two γ-cyclodextrins with terphenyl-type stopper molecules. The [4]rotaxane showed orange emission attributable to the spatially restricted alkynylperylene excimer with a high fluorescence quantum yield of Φf=0.15. The excimer emission was circularly polarized as a result of the asymmetrically twisted perylene pair under the influence of chirality of γ-cyclodextrin. The glum value of the excimer emission was determined to be ?2.1×10?2 at 573 nm, as large as those of the corresponding known pyrene-based series. This is the first example, in which circularly polarized luminescence was clearly observed from the excimer of a pair of perylene cores.
- Hayashi, Koichiro,Miyaoka, Yuta,Ohishi, Yuki,Uchida, Taka-aki,Iwamura, Munetaka,Nozaki, Koichi,Inouye, Masahiko
-
-
Read Online
- TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 0566; 0567; 1278; 1279
(2021/02/12)
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- BRANCHED MOIETY FOR USE IN CONJUGATES
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A tri-functional linker moiety: formula (I), where X and Y are linking chains, and its use for preparing dual-mechanistic drug conjugates, preferably in a site-specific manner.
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Page/Page column 38
(2021/04/30)
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- Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy
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Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.
- Vuorinen, Aini,Wilkinson, Isabel V.L.,Chatzopoulou, Maria,Edwards, Ben,Squire, Sarah E.,Fairclough, Rebecca J.,Bazan, Noelia Araujo,Milner, Josh A.,Conole, Daniel,Donald, James R.,Shah, Nandini,Willis, Nicky J.,Martínez, R. Fernando,Wilson, Francis X.,Wynne, Graham M.,Davies, Stephen G.,Davies, Kay E.,Russell, Angela J.
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supporting information
(2021/05/03)
-
- Novel camptothecin derivative, and preparation method and application thereof
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The invention relates to a novel camptothecin derivative and application thereof, a tumor cell growth inhibitor, a ternary complex, and a method for improving the solubility of the camptothecin derivative. The camptothecin derivative is formed by modifying a substance represented by formula I through glycosylated triazole in the position R3. In a structural formula represented by the formula I, R1represents H, alkyl of C1-10, deuterated alkyl of the C1-10, or halogenated alkyl of the C1-10; R2 represents H, CH2N(CH3)2 or CH2N(CD3)2; R4 represents H, and X represents N, O or S; L represents polypeptide, C1-20 linear alkyl or a derivative thereof, a C1-20 linear or branched acyl derivative, or C2-100 ethylene glycol or a derivative thereof. The camptothecin derivative has high solubility, prepared anticancer drugs have the advantages of wide anticancer spectrum and high safety, and the in-vivo anticancer activity is superior to that of irinotecan hydrochloride.
- -
-
Paragraph 0087-0088; 0095-0096
(2020/03/12)
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- Flavone derivative for treating tumor and application thereof
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The invention provides a flavone derivative represented by a formula I and pharmaceutically acceptable salt, hydrate or solvate thereof. In the formula I, R1 H, is 1-4 alkyl, amino or C1-4 acyl; R2 isisopentenyl or 2-hydroxy isopentyl; R3 is H, methyl or deuterated methyl; R4 represents C1-4 alkyl, amino or C1-4 acyl or R5 represents monosaccharide residue or oligosaccharide residue; and L represents polypeptide, C1-C20 straight chain alkyl or derivative thereof, C1-C20 straight chain or branched chain acyl derivative, C1-C20 ethylene glycol or derivative thereof, wherein Y is an integer of 0to 100, b is an integer of 1 to 100, C is an integer of 1 to 10, d is an integer of 0 to 100, and e is an integer of 0 to 100. The flavone derivative has high-efficiency broad-spectrum anticancer activity.
- -
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Paragraph 0121-0123
(2020/09/16)
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- CGRP ANTAGONIST COMPOUNDS
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The disclosures herein relate to novel compounds of Formula (1a): and salts thereof, wherein W, Z, L, R1and R2 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.
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Page/Page column 85
(2020/12/30)
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- TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 0858; 0859
(2018/05/24)
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- Synthetic antibody protein mimics of infliximab by molecular scaffolding on novel CycloTriVeratrilene (CTV) derivatives
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Syntheses of novel semi-orthogonally protected CycloTriVeratrilene (CTV) analogues with enhanced water solubility, that is 3 and 4, derived from the previously described CTV scaffold derivative 2 are described here. These scaffolds 2-4 enabled a sequential introduction of three different complementarity determining region (CDR) mimics via Cu(i)-catalysed azide-alkyne cycloaddition towards medium-sized protein mimics denoted as "synthetic antibodies". The highly optimised sequential introduction enabled selective attachment of three different CDR mimics in a one-pot fashion. This approach of obtaining synthetic antibodies, demonstrated by the synthesis of paratope mimics of monoclonal antibody infliximab (Remicade), provided a facile access to a range of (highly) pre-organised molecules bearing three different (cyclic) peptide segments and may find a wide range of applications in the field of protein-protein interaction disruptors as well as in the development of synthetic vaccines or lectin mimics. The prepared synthetic antibodies were tested for their affinity towards tumour necrosis factor alpha using surface plasmon resonance and synthetic antibodies with micromolar affinities were uncovered.
- Longin, Ond?ej,Hezwani, Mohammed,Van De Langemheen, Helmus,Liskamp, Rob M. J.
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p. 5254 - 5274
(2018/08/04)
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- Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs
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Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable. RNA is an emerging target for small molecules, but has it been an established one all along? Velagapudi et al. profiled the binding of medicines to thousands of RNA motifs, showing that broad drug classes bind RNA. Indeed, approved anti-cancer drugs target an oncogenic non-coding RNA, affecting its phenotype.
- Velagapudi, Sai Pradeep,Costales, Matthew G.,Vummidi, Balayeshwanth R.,Nakai, Yoshio,Angelbello, Alicia J.,Tran, Tuan,Haniff, Hafeez S.,Matsumoto, Yasumasa,Wang, Zi Fu,Chatterjee, Arnab K.,Childs-Disney, Jessica L.,Disney, Matthew D.
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p. 1086 - 7,1094
(2018/06/15)
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- Assembly of [2]Rotaxanes in Water
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Two [2]rotaxanes have been assembled in water from modular subunits through CuI-catalyzed azide–alkyne “click” chemistry. For this purpose, 2,6-disubstituted naphthalene axles with solubilizing oligo(ethylene glycol) (OEG) chains (n = 1–5) and propargyl terminal groups were synthesized and examined for their propensity to form inclusion complexes with a dicationic Diederich-type cyclophane host. The dependence of pseudorotaxane formation on the linkers between the naphthalene core and OEG chains, and in the case of ester linkers on different spacer lengths, was analyzed by titration experiments. In addition, the inclusion complexes of two [2]rotaxanes were trapped by using a water-soluble azide-functionalized stopper. Repetitive chromatography finally enabled the isolation of both mechanically interlocked [2]rotaxanes.
- Aeschi, Yves,Drayss-Orth, Sylvie,Valá?ek, Michal,Raps, Felix,H?ussinger, Daniel,Mayor, Marcel
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supporting information
p. 4091 - 4103
(2017/08/07)
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- mTORC1 INHIBITORS
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Disclosed herein, inter alia, are compounds and methods of using the same for modulating the activity of mTORCl.
- -
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Paragraph 0310-0311
(2016/06/01)
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- Cyclization of gold acetylides: Synthesis of vinyl sulfonates via gold vinylidene complexes
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Differently substituted terminal alkynes that bear sulfonate leaving groups at an appropriate distance were converted in the presence of a propynyl gold(I) precatalyst. After initial formation of a gold acetylide, a cyclization takes place at the β-carbon atom of this species. Mechanistic studies support a mechanism that is related to that of dual gold-catalyzed reactions, but for the new substrates, only one gold atom is needed for substrate activation. After formation of a gold vinylidene complex, which forms a tight contact ion pair with the sulfonate leaving group, recombination of the two parts delivers vinyl sulfonates, which are valuable targets that can serve as precursors for cross-coupling reactions, for example. Gold vinylidene intermediates are generated by the cyclization of gold acetylides that carry a sulfonate leaving group. This result demonstrates for the first time that the formation of these species is not restricted to a dual activation mode. The cyclization products obtained herein contain a vinyl sulfonate moiety, which makes them useful building blocks for cross-coupling reactions.
- Bucher, Janina,Wurm, Thomas,Nalivela, Kumara Swamy,Rudolph, Matthias,Rominger, Frank,Hashmi, A. Stephen K.
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supporting information
p. 3854 - 3858
(2014/05/06)
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- MODULAR SYNTHESIS OF AMPHIPHILIC JANUS GLYCODENDRIMERS AND THEIR SELF-ASSEMBLY INTO GLYCODENDRIMERSOMES
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The invention concerns compounds of the formula (I) wherein: Y1 and Y2 are independently a monosaccharide or disaccharide; X1 and X2 are independently -(R9-O)m-, -(R10)P-, -O-(R11-O)q-, -R16-O-R17-O- or a covalent bond; Q1 and Q2 are independently a nitrogen-containing heterocycle moiety; Z1 and Z2 are independently -(O-R7)-, -(O-C(=O)-R8)a-, -O-C(=O)-R12-C(=0)-R13-, -O- C(=O)-R14-C(=O)-R15 or a covalent bond; R7-R17 are each independently C1-C6 alkyl; R1-R6 are each independently a linear or branched alkly group; b, c, d, e, f, and g are 0 or 1, provided b + c + d equals at least 2 and e + f + g equals at least 2; and a, m, p, and q are each an integer from 1-6.
- -
-
Paragraph 00137
(2014/12/12)
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- Bimetallic oxidative addition involving radical intermediates in nickel-catalyzed alkyl-alkyl Kumada coupling reactions
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Many nickel-based catalysts have been reported for cross-coupling reactions of nonactivated alkyl halides. The mechanistic understanding of these reactions is still primitive. Here we report a mechanistic study of alkyl-alkyl Kumada coupling catalyzed by a preformed nickel(II) pincer complex ([(N 2N)Ni-Cl]). The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is second-order in Grignard reagent, first-order in catalyst, and zero-order in alkyl halide. A transient species, [(N2N)Ni-alkyl 2](alkyl2-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis.
- Breitenfeld, Jan,Ruiz, Jesus,Wodrich, Matthew D.,Hu, Xile
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supporting information
p. 12004 - 12012
(2013/09/02)
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- Use of triazole-ring formation to attach a Ru/TsDPEN complex for asymmetric transfer hydrogenation to a soluble polymer
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The cycloaddition of a chiral ligand containing a terminal alkyne to a soluble polymer containing an azide provides a convenient means for the attachment of an asymmetric transfer hydrogenation catalyst to a soluble polymer support. Using these ligands in complexes with Ru(II), gave good results in terms of conversion and enantioselectivity (up to 95% ee) in ketone reduction reactions.
- Zammit, Charlotte M.,Wills, Martin
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p. 844 - 852
(2013/08/23)
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- Synthesis of a suite of bioorthogonal glutathione s-transferase substrates and their enzymatic incorporation for protein immobilization
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Label-free protein immobilization allows precise detection of biomolecular events. Preserving enzyme function is intrinsically challenging for these strategies. Considering that glutathione S-transferase (GST) is a broadly employed enzymatic fusion tag, we reported a label-free self-catalyzed immobilization for Schistosoma japonicum GST. We now report the synthesis, structure, and enzymology of a set of 20 smSNAREs (small molecule S NAr-electrophiles). These smSNAREs mimic (electronically) the canonical GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), and bear a wide variety of bioorthogonal functionalities such as alkynes, aldehydes, acetals, and azides. Sixteen analogues including the chloro- and nitro-substituted 1, 3, 5, 6, 7, 11, 12, and 13 participated in the GST-catalyzed conjugation, indicating the substrate tolerance of the enzymatic H-site of SjGST. Using UV-vis spectroscopy, we estimate the efficiency of conjugation as a function of substrate diversity. Using LC-MS, we characterized the conjugates formed under each enzymatic transformation. Significant deviations from the canonical CDNB architecture are tolerated. Relative rates between nitro and chloro substituents indicate the nucleophilic addition step is rate determining. Enzyme immobilization on glass slides is affected by additional surface interactions and therefore does not reflect kinetic profiles observed in solution. This new class of heterobifunctional linkers enables a single-step and uniform protein capture on designer surfaces.
- Voelker, Alden E.,Viswanathan, Rajesh
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p. 9647 - 9658
(2013/10/22)
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- Modular synthesis of amphiphilic Janus glycodendrimers and their self-assembly into glycodendrimersomes and other complex architectures with bioactivity to biomedically relevant lectins
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The modular synthesis of 7 libraries containing 51 self-assembling amphiphilic Janus dendrimers with the monosaccharides d-mannose and d-galactose and the disaccharide d-lactose in their hydrophilic part is reported. These unprecedented sugar-containing dendrimers are named amphiphilic Janus glycodendrimers. Their self-assembly by simple injection of THF or ethanol solution into water or buffer and by hydration was analyzed by a combination of methods including dynamic light scattering, confocal microscopy, cryogenic transmission electron microscopy, Fourier transform analysis, and micropipet-aspiration experiments to assess mechanical properties. These libraries revealed a diversity of hard and soft assemblies, including unilamellar spherical, polygonal, and tubular vesicles denoted glycodendrimersomes, aggregates of Janus glycodendrimers and rodlike micelles named glycodendrimer aggregates and glycodendrimermicelles, cubosomes denoted glycodendrimercubosomes, and solid lamellae. These assemblies are stable over time in water and in buffer, exhibit narrow molecular-weight distribution, and display dimensions that are programmable by the concentration of the solution from which they are injected. This study elaborated the molecular principles leading to single-type soft glycodendrimersomes assembled from amphiphilic Janus glycodendrimers. The multivalency of glycodendrimersomes with different sizes and their ligand bioactivity were demonstrated by selective agglutination with a diversity of sugar-binding protein receptors such as the plant lectins concanavalin A and the highly toxic mistletoe Viscum album L. agglutinin, the bacterial lectin PA-IL from Pseudomonas aeruginosa, and, of special biomedical relevance, human adhesion/growth-regulatory galectin-3 and galectin-4. These results demonstrated the candidacy of glycodendrimersomes as new mimics of biological membranes with programmable glycan ligand presentations, as supramolecular lectin blockers, vaccines, and targeted delivery devices.
- Percec, Virgil,Leowanawat, Pawaret,Sun, Hao-Jan,Kulikov, Oleg,Nusbaum, Christopher D.,Tran, Tam M.,Bertin, Annabelle,Wilson, Daniela A.,Peterca, Mihai,Zhang, Shaodong,Kamat, Neha P.,Vargo, Kevin,Moock, Diana,Johnston, Eric D.,Hammer, Daniel A.,Pochan, Darrin J.,Chen, Yingchao,Chabre, Yoann M.,Shiao, Tze C.,Bergeron-Brlek, Milan,Andre, Sabine,Roy, Rene,Gabius, Hans-J.,Heiney, Paul A.
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supporting information
p. 9055 - 9077
(2013/07/26)
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- Multidirectional cobalt-catalyzed diels-alder/1,4-hydrovinylation sequences
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The combination of two powerful cobalt-catalyzed carbon-carbon bond forming transformations, namely, the Diels-Alder and the 1,4-hydrovinylation reaction, in a tandem or a sequential one-pot procedure, opened up a concise and efficient route to polysubstituted aromatic systems and cyclohex-3-enone derivatives. Furthermore, ozonolysis of the latter products led to polycarbonyl compounds with tailored carbonyl group distances which could be characterized via their respective BF2-borinane complexes. The cobalt catalysts tolerated several functional groups, and a flexible approach to polyfunctionalized compounds in concise fashion was described.
- Erver, Florian,Kuttner, Julian R.,Hilt, Gerhard
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p. 8375 - 8385
(2012/11/07)
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- Degradable conjugates from oxanorbornadiene reagents
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Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels-Alder fragmentation. A study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at a mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by the reaction with thiol-depleted BSA. The OND-amine adducts were found to be up to 15 times more stable than OND-thiol adducts, and to be sensitive to acid by virtue of a stereochemically dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 min to 7 days at 37 °C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.
- Kislukhin, Alexander A.,Higginson, Cody J.,Hong, Vu P.,Finn
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supporting information; experimental part
p. 6491 - 6497
(2012/05/07)
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- SUBSTITUTED 8 - AMINO - IMIDAZO [1, 2-A] PYRAZ1NES AS ANTIBACTERIAL AGENTS
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The present invention relates to substituted imidazo[1,2-a]pyrazines of Formula (I) and their use as antibacterial agents.
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Page/Page column 105-106
(2013/02/27)
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- Kinetic studies exploring the role of anion templation in the slippage formation of rotaxane-like structures
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The first examples of the slippage formation of rotaxane-like structures in the presence of an anion template are reported between a macrocycle, synthesised by exploiting Eglinton coupling, and stoppered pyridinium axle components. The role of the anion template in the slippage process has been explored by kinetic studies. 1HNMR spectroscopic investigations reveal the slippage species formed are not rotaxanes but pseudorotaxanes with some rotaxane character. The anion template significantly influences the amount of rotaxane character and the rate of slippage. Importantly, the fastest slippage rates, kon, are achieved with the non-coordinating hexafluorophosphate anion, whereas the slowest slippage off rates, k off, are observed in the presence of coordinating anions, such as chloride. Since the koff rates are significantly smaller than the kon rates in the presence of coordinating anions, these anions act as templates favouring formation of the slippage species thermodynamically. Consequently, the resulting pseudorotaxanes with coordinating anions have greater rotaxane character. Two strategies for converting the slippage pseudorotaxanes into rotaxanes using hydrogenation or complexation with cobalt carbonyl are investigated.
- McConnell, Anna J.,Beer, Paul D.
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supporting information; scheme or table
p. 2724 - 2733
(2011/04/16)
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- Ring-annulated dihydropyrrolo[2,1-alpha]isoquinolines
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The invention relates to ring-annulated dihydropyrrolo[2,1-a]isoquinoline compounds according to general Formula I or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of infertility.
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Page/Page column 34; 36
(2011/02/25)
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- RING-ANNULATED DIHYDROPYRROLO[2,1-A]ISOQUINOLINES
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The invention relates to ring-annulated dihydropyrrolo[2,1-a]isoquinoline compounds according to general Formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of infertility
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Page/Page column 73-74
(2011/02/24)
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- Modifications of C-2 on the pyrroloquinoline template aimed at the development of potent herpesvirus antivirals with improved aqueous solubility
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A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility.
- Nieman, James A.,Nair, Sajiv K.,Heasley, Steven E.,Schultz, Brenda L.,Zerth, Herbert M.,Nugent, Richard A.,Chen, Ke,Stephanski, Kevin J.,Hopkins, Todd A.,Knechtel, Mary L.,Oien, Nancee L.,Wieber, Janet L.,Wathen, Michael W.
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supporting information; experimental part
p. 3039 - 3042
(2010/07/03)
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- Carbocyclization reaction of ω-iodo- and 1,ω-diiodo-1-alkynes without the loss of iodine atoms through a carbenoid-chain process
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(Chemical Equation Presented) Atom-economical carbocyclization reactions of ω-iodo-1-alkynes and 1,ω-diiodo-1-alkynes to give products with incorporation of iodine atoms is described. Cycloisomerization of 2-(2-propynyloxy)ethyl iodides is initiated by a catalytic amount of LDA to give 3-(iodomethylene)tetrahydrofurans in high yields. Upon treatment of with a catalytic amount of 1-hexynyllithium, 1ω-diiodo-1-alkynes efficiently undergo cycloisomerization to give (diiodomethylene)cycloalkanes. The diiodomethylene products are also obtained by iodine atom-transfer-type cyclization of ω-iodo-1-alkynes, using 1-iodo-1-hexyne as an external iodine atom source. Bromine atom-transfer and proton-transfer cyclization proceed as well by employing 1-bromo-1-octyne and 1-octyne, respectively. These reactions are proposed to proceed through a carbenoid-chain process involving exo-cyclization of the lithium acetylide intermediates to give Li,I-alkylidene carbenoids. It is shown that the exo-cyclization proceeded stereospecifically through inversion of the stereochemistry at the electrophilic carbon.
- Harada, Toshiro,Muramatsu, Keiko,Mizunashi, Kenia,Kitano, Chie,Imaoka, Daisuke,Fujiwara, Takayuki,Kataoka, Hiroshi
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p. 249 - 258
(2008/09/17)
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- Enantioseiective aryiative cyclization of allenyl aldehydes with arylboronic acids under Pd(II)-diphosphine catalysis
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A Pd(OAc)2-SEGPHOS combination catalyzes the first enantioseiective aryiative cyclization of allenyl aldehydes with aryiboronic acids to provide c/s-fused fiveand six-membered cyclic homoallylic alcohols. The excellent diastereoand enantioselectivity and the fact that the reaction proceeds at room temperature in the absence of any additives make the process highly practical.
- Tsukamoto, Hirokazu,Matsumoto, Tomotaka,Kondo, Yoshinori
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supporting information; experimental part
p. 1047 - 1050
(2009/04/06)
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- Design and synthesis of a tag-free chemical probe for photoaffinity labeling
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The novel aromatic diazirine-containing benzoic acid 22 was prepared via the diazirine 11 as the key intermediate. After formylation of the aryl ring and cleavage of the methyl ether function of aldehyde 12, the phenolic hydroxy group was converted into the ether 21 terminating in an alkyne function. Oxidation of the aldehyde to the carboxylic acid provided the chemical probe 22 designed for tag-free photoaffinity labeling. In a proof-of-concept study it could be shown that irradiation of the simple ester 23 indeed yields the methanol insertion product 24. A subsequent click reaction with benzyl azide 20 led to the triazole 25. A more complicated example was realized with the esterification of bafilomycin A1 (27) with acid 22. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Mayer, Timo,Maier, Martin E.
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p. 4711 - 4720
(2008/03/13)
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- BIFUNCTIONAL HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING SAME
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The invention provides a family of bifunctional heterocyclic compounds useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. The invention also provides methods of making the bifunctional hetercyclic compounds, and methods of using such compounds as anti-infective, anti-proliferative agents, anti-inflammatory, and/or prokinetic agents.
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Page/Page column 281
(2010/02/06)
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- 4-Alkenyl- and 4-alkynyloxindoles
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Disclosed are novel 4-alkenyl- and 4-alkynyl oxindoles having the formula and the pharmaceutically acceptable salts thereof, wherein R1, R2, R3, a, b, and X are as defined herein. These compounds inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are anti-proliferative agents useful in the treatment or control of cell proliferative disorders, in particular cancer, more particularly, the treatment or control of breast and colon tumors. Also disclosed are pharmaceutical compositions containing the compounds of formula I and II as well as intermediates useful in the preparation of the compounds of formula I and II.
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- Synthesis of a series of symmetrically disubstituted diacetylenes with polychlorophenyl rings as side groups and linear polyether chains as spacers
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Aryl disubstituted diacetylenes with spacers of different lengths (CH2O, CH2OCH2CH2O, and CH2OCH2CH2CH2O) have been synthesized. Smaller homologues of the series were readily obtained by nucleophilic substitutions on 2,4-hexadiynylene bis(p-toluenesulfonate). However higher homologues could not be prepared by this method from the corresponding extended bistosylates due to their low reactivities. The observed decrease of reactivity with phenoxides of such extended bistosylates is ascribed to folded conformations adopted by these derivatives. Consequently, the synthesis of higher members of the series was carried out by a multistep procedure involving appropriately functionalized monoacetylenes.
- Hernandez,Galan,Rovira,Veciana
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p. 1164 - 1169
(2007/10/02)
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- Catecholborane reductive cleavage of allyl and propargyl acetals and ketals: A simple route to allyl and prop-2-ynyl ethers
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The chemoselective conversion of allyl and prop-2-ynyl acetals as well as ketals by reductive cleavage with catecholborane into the corresponding allyl and prop-2-ynyl ethers is described.
- Bovicelli,Mincione,Patamia
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p. 907 - 913
(2007/10/02)
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