- Solid-phase synthesis of a novel phalloidin analog with on-bead and off-bead actin-binding activity
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Specific effectors of actin polymerization have found use as dynamic probes of cellular morphology that may be used to gauge cellular response to stimuli and drugs. Of various natural products that target actin, phalloidin is one of the most potent and selective inhibitors of actin depolymerization. Phalloidin and related members of the phallotoxin family are macrocyclic heptapeptides bearing a characteristic and rigidifying transannular tryptathionine bridge. Here we describe a solid-phase synthesis of a new phalloidin analog as a prototype for library development with the potential for on- and off-bead screening. To validate our method, we labelled the phalloidin derivative with a fluorescent dye which stained actin in CHO cells. Furthermore, a bioassay was developed allowing actin polymerization on beads carrying a phalloidin derivative.
- Blanc, Antoine,Todorovic, Mihajlo,Perrin, David M.
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Read Online
- Aza-wittig-supported synthesis of the a ring of nosiheptide
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An array of aza-Wittig reactions: In the unique synthesis of the A ring of the potent thiopeptide antibiotic nosiheptide, mild aza-Wittig thiazole ring closure, a ScIII-mediated regioselective ester hydrolysis, and a highly efficient macrolactam formation
- Lu, Jin-Yong,Riedrich, Matthias,Mikyna, Martin,Arndt, Hans-Dieter
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Read Online
- Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates
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Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin.
- Braun, Alexandra,Gallo, Francesca,Hambira, Chido M.,Hechler, Torsten,Kato, Brandon,Müller, Christoph,Matinkhoo, Kaveh,Pahl, Andreas,Perrin, David M.,Wei, Charlie,Wong, Antonio A. W. L.
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supporting information
p. 10282 - 10292
(2021/06/25)
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- Automated Radiosynthesis of cis- And trans-4-[18F]Fluoro- l -proline Using [18F]Fluoride
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The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates.
- Morgan, Timaeus E. F.,Riley, Leanne M.,Tavares, Adriana A. S.,Sutherland, Andrew
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p. 14054 - 14060
(2021/05/29)
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- cis-4-Alkoxydialkyl- and cis-4-Alkoxydiarylprolinol Organocatalysts: High Throughput Experimentation (HTE)-Based and Design of Experiments (DoE)-Guided Development of a Highly Enantioselective aza-Michael Addition of Cyclic Imides to α,β-Unsaturated Aldehydes
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A diverse family (37 compounds) of cis-4-alkoxydiorganylprolinol derivatives has been prepared and evaluated in organocatalysis for the first time. The combined use of high throughput experimentation (HTE) techniques with efficient analytical methods has led to the identification of two superior catalysts for the enantioselective addition of succinimide to α,β-unsaturated aldehydes. Further optimization of the reaction conditions with design of experiments (DoE) techniques established the catalyst of choice for the considered aza-Michael reaction, the corresponding adducts (12 examples) being obtained in good yields and excellent enantioselectivities (succinimide and maleimide donors). The synthetic versatility of these Michael adducts is illustrated by a two-step sequence leading to enantiopure 1,3-amino alcohols. (Figure presented.).
- Arenas, Ismael,Ferrali, Alessandro,Rodríguez-Escrich, Carles,Bravo, Fernando,Pericàs, Miquel A.
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supporting information
p. 2414 - 2424
(2017/07/22)
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- Synthesis of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane derivatives by an epimerization-lactamization cascade reaction
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An epimerization-lactamization cascade of functionalized (2S,4R)-4-aminoproline methyl esters is developed and applied in synthesizing (1R,4R)-2,5-diazabicyclo[2.2.1]heptane (DBH) derivatives. (2S,4R)-4-Aminoproline methyl esters are likely to undergo 2-epimerization under basic conditions, followed by an intramolecular aminolysis of the (2R)-epimer to form the bridged lactam intermediates. Key factors identified for this cascade reaction include the electron-withdrawal N-protective group in the substrates and a strong base as the promoter.
- Cui, Benqiang,Yu, Jie,Yu, Fu-Chao,Li, Ya-Min,Chang, Kwen-Jen,Shen, Yuehai
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p. 10386 - 10392
(2015/01/30)
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- Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives
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Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc) protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l-hydroxyproline and also for d-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.
- Krishnamurthy, Suvratha,Arai, Toru,Nakanishi, Kanae,Nishino, Norikazu
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p. 2482 - 2490
(2014/01/06)
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- Assembly of the nosiheptide A-ring: A fruitful lesson
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The synthesis of a 28-membered thiopeptide macrocycle is described. Key steps are mild aza-Wittig thiazole ring closures, a scandium(III)-mediated regioselective ester hydrolysis, and a highly efficient macrolactam formation with its 3-hydroxypyridine nucleus orthogonally protected. Georg Thieme Verlag Stuttgart, New York.
- Lu, Jin-Yong,Riedrich, Matthias,Wojtas, K.Philip,Arndt, Hans-Dieter
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supporting information
p. 1300 - 1311
(2013/07/04)
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- Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines
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Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.
- Le Quement, Sebastian T.,Ishoey, Mette,Petersen, Mette T.,Thastrup, Jacob,Hagel, Grith,Nielsen, Thomas E.
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scheme or table
p. 667 - 675
(2012/03/22)
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- ANTIBACTERIAL FLUOROQUINOLONE ANALOGS
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Compounds having antibacterial activity are disclosed. The compunds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein A, B, D, E, G, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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- Practical syntheses of 4-fluoroprolines
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4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.
- Chorghade, Mukund S.,Mohapatra, Debendra K.,Sahoo, Gokarneswar,Gurjar, Mukund K.,Mandlecha, Manish V.,Bhoite, Nitin,Moghe, Santosh,Raines, Ronald T.
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experimental part
p. 781 - 784
(2009/04/04)
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- Synthesis and DNA-binding ability of C2R-fluoro substituted DC-81 and its dimers
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C2R-Fluoro substituted DC-81 and its dimers have been synthesized that exhibit significant DNA-binding ability, particularly the five carbon alkane spacer compound (6c) showed the helix melting temperature (ΔTm) of 18.8 °C after incubation of 36 h at 37 °C.
- Kamal, Ahmed,Rajasekhar Reddy,Murali Mohan Reddy
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p. 803 - 806
(2007/10/03)
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- Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors
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Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-amino)ethylamino]pentyl}-N′-nitroguanidine (l-Arg(NO2)-l-Dbu-NH2 (1) and 4-N-(Nω-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), a series of descarboxamide analogues was designed and synthesized (3-7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. Nα-Methylated analogues (8-11) also were prepared for increased lipophilicity of the inhibitors, but they had 4- to 5-fold weaker binding affinity compared to their parent compounds.
- Seo, Jiwon,Martasek, Pavel,Roman, Linda J.,Silverman, Richard B.
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p. 1928 - 1938
(2007/10/03)
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- Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis
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A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metath
- Yee, Nathan K.,Farina, Vittorio,Houpis, Ioannis N.,Haddad, Nizar,Frutos, Rogelio P.,Gallou, Fabrice,Wang, Xiao-Jun,Wei, Xudong,Simpson, Robert D.,Feng, Xuwu,Fuchs, Victor,Xu, Yibo,Tan, Jonathan,Zhang, Li,Xu, Jinghua,Smith-Keenan, Lana L.,Vitous, Jana,Ridges, Michael D.,Spinelli, Earl M.,Johnson, Michael,Donsbach, Kai,Nicola, Thomas,Brenner, Michael,Winter, Eric,Kreye, Paul,Samstag, Wendelin
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p. 7133 - 7145
(2007/10/03)
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- Analogs of 4-hydroxyisoleucine and uses thereof
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The invention relates to analogs of 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The analogs of the invention stimulate both glucose uptake and insulin secretion, and may thus be useful for the prevention and treatment of disorders of carbohydrate or lipid metabolism, including diabetes mellitus (type 1 and type 2 diabetes), pre-diabetes, and Metabolic Syndrome.
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Page/Page column 47
(2008/06/13)
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- QUINAZOLINE DERIVATIVES
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The invention concerns quinazoline derivatives of Formula (I) wherein each of R1, R3, R20, X1, X2, Z, W, (a) and (q) have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of turnours which are sensitive to inhibition of erbB receptor tyrosine kinases, particularly EGFR tyrosine kinase.
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Page/Page column 95-96
(2008/06/13)
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- Short, highly efficient syntheses of protected 3-azido- and 4-azidoproline and their precursors
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matrix presented An improved synthesis of protected cis- and trans-3-azido-L-proline and cis- and frans-4-azido-L- and -D-proline is reported. These compounds have been synthesized from the corresponding hydroxyproline precursors using diphenylphosphoryl azide under Mitsunobu conditions. Short, highly efficient syntheses of these precursors are described, based on a new lactone-opening reaction and p-nitrobenzoate hydrolysis under very mild conditions.
- Gomez-Vidal, Jose A.,Silverman, Richard B.
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p. 2481 - 2484
(2007/10/03)
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- Inhibitors of HIV protease
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Compounds of formula (I): STR1 wherein: R1 is hydrogen, alkyl, aralkyl, --CORa, --CORb, --CSRa, --CSRb, --SO2 Rb, --CONHRb, --CSNHRb, --CONRb Rb or --CSNRb Rb ; R2 is hydrogen or alkyl; R3 is hydrogen, alkylidene, substituted alkyl, or Rb ; R4 is optionally substituted alkyl, cycloalkyl, or aryl; R5 is Rb O--, Rb Rb N--, Rb HN--, aralkyloxycarbonyloxy or aralkyloxycarbonylamino, or R5 is --(CH2)p --D--(CH2)r --, where D is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH2 =CH2)-- or --NHCO--; and p and r are each 0 or an integer from 1 to 5; A is --(CH2)m --B--(CH2)n -- where B is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH2 =CH2)-- or --NHCO--; and m and n are each 0 or an integer from 1 to 5; Ra is alkoxy, aralkyloxy, aryloxy or alkoxycarbonyl; Rb is optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or arylalkenyl; and pharmaceutically acceptable salts and esters thereof and pro-drugs therefor, have the ability to inhibit the activity of HIV protease and may thus be used for the treatment and prophylaxis of AIDS.
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- A SHORT IMPROVED SYSTHESIS OF N-SUBSTITUTED 5-AZA-2-OXA-3-OXO-BICYCLOHEPTANES
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N-Substituted 5-aza-2-oxa-3-oxo-bicycloheptanes are conformationally rigid models that have been used in several 1H-NMR studies.They have previously been obtained by multistep processes.We have devised a one step synthesis for these compounds.The utility of this new route has been demonstrated for five differently N-substituted substrates.
- Bowers-Nemia, Margaret M.,Joullie, Madeleine M.
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p. 817 - 828
(2007/10/02)
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