- Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs
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Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic c
- Fujii, Shinya,Sekine, Ryota,Kano, Atsushi,Masuno, Hiroyuki,Songkram, Chalermkiat,Kawachi, Emiko,Hirano, Tomoya,Tanatani, Aya,Kagechika, Hiroyuki
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- Enzymatic and organocatalyzed asymmetric aldolization reactions for the synthesis of thiosugar scaffolds
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We studied the synthesis of original thiosugar scaffolds by enantioselective aldolization. L-Proline-catalyzed C-C bond formation was the key step in the synthesis of L-erythro-thioketoses (3S,4R), whereas fructose-6-phosphate aldolase-catalyzed reactions yielded the D-threo-thioketose series (3S,4S). By the organocatalytic approach, 5-thio-L-ribulofuranose (1) and 5-deoxy-6-thio-L-psicopyranose (2) were obtained in satisfactory overall yields from 2-haloacetaldehydes, whereas 5-thio-D-xylulofuranose (3) was synthesized in 50 % overall yield by an enzymatic aldolization reaction in only two steps from the same starting material.
- Fanton, Johan,Camps, Flora,Castillo, Jose A.,Guerard-Helaine, Christine,Lemaire, Marielle,Charmantray, Franck,Hecquet, Laurence
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- Glycodendrimersomes from Sequence-Defined Janus Glycodendrimers Reveal High Activity and Sensor Capacity for the Agglutination by Natural Variants of Human Lectins
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A library of eight amphiphilic Janus glycodendrimers (Janus-GDs) presenting d-lactose (Lac) and a combination of Lac with up to eight methoxytriethoxy (3EO) units in a sequence-defined arrangement was synthesized via an iterative modular methodology. The length of the linker between Lac and the hydrophobic part of the Janus-GDs was also varied. Self-assembly by injection from THF solution into phosphate-buffered saline led to unilamellar, monodisperse glycodendrimersomes (GDSs) with dimensions predicted by Janus-GD concentration. These GDSs provided a toolbox to measure bioactivity profiles in agglutination assays with sugar-binding proteins (lectins). Three naturally occurring forms of the human adhesion/growth-regulatory lectin galectin-8, Gal-8S and Gal-8L, which differ by the length of linker connecting their two active domains, and a single amino acid mutant (F19Y), were used as probes to study activity and sensor capacity. Unpredictably, the sequence of Lac on the Janus-GDs was demonstrated to determine bioactivity, with the highest level revealed for a Janus-GD with six 3EO groups and one Lac. A further increase in Lac density was invariably accompanied by a substantial decrease in agglutination, whereas a decrease in Lac density resulted in similar or lower bioactivity and sensor capacity. Both changes in topology of Lac presentation of the GDSs and seemingly subtle alterations in protein structure resulted in different levels of bioactivity, demonstrating the presence of regulation on both GDS surface and lectin. These results illustrate the applicability of Janus-GDs to dissect structure-activity relationships between programmable cell surface models and human lectins in a highly sensitive and physiologically relevant manner.
- Zhang, Shaodong,Xiao, Qi,Sherman, Samuel E.,Muncan, Adam,Ramos Vicente, Andrea D. M.,Wang, Zhichun,Hammer, Daniel A.,Williams, Dewight,Chen, Yingchao,Pochan, Darrin J.,Vértesy, Sabine,André, Sabine,Klein, Michael L.,Gabius, Hans-Joachim,Percec, Virgil
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- One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer Delivery Systems for mRNA
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Efficient viral or nonviral delivery of nucleic acids is the key step of genetic nanomedicine. Both viral and synthetic vectors have been successfully employed for genetic delivery with recent examples being DNA, adenoviral, and mRNA-based Covid-19 vaccines. Viral vectors can be target specific and very efficient but can also mediate severe immune response, cell toxicity, and mutations. Four-component lipid nanoparticles (LNPs) containing ionizable lipids, phospholipids, cholesterol for mechanical properties, and PEG-conjugated lipid for stability represent the current leading nonviral vectors for mRNA. However, the segregation of the neutral ionizable lipid as droplets in the core of the LNP, the "PEG dilemma", and the stability at only very low temperatures limit their efficiency. Here, we report the development of a one-component multifunctional ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA that exhibits high activity at a low concentration of ionizable amines organized in a sequence-defined arrangement. Six libraries containing 54 sequence-defined IAJDs were synthesized by an accelerated modular-orthogonal methodology and coassembled with mRNA into dendrimersome nanoparticles (DNPs) by a simple injection method rather than by the complex microfluidic technology often used for LNPs. Forty four (81%) showed activity in vitro and 31 (57%) in vivo. Some, exhibiting organ specificity, are stable at 5 °C and demonstrated higher transfection efficiency than positive control experiments in vitro and in vivo. Aside from practical applications, this proof of concept will help elucidate the mechanisms of packaging and release of mRNA from DNPs as a function of ionizable amine concentration, their sequence, and constitutional isomerism of IAJDs.
- Zhang, Dapeng,Atochina-Vasserman, Elena N.,Maurya, Devendra S.,Huang, Ning,Xiao, Qi,Ona, Nathan,Liu, Matthew,Shahnawaz, Hamna,Ni, Houping,Kim, Kyunghee,Billingsley, Margaret M.,Pochan, Darrin J.,Mitchell, Michael J.,Weissman, Drew,Percec, Virgil
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supporting information
p. 12315 - 12327
(2021/08/20)
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- A Condensed, Scalable Synthesis of Racemic Koningic Acid
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The natural product koningic acid (KA) is a selective covalent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical node in the glycolysis pathway. While KA is available commercially, sources are limited and its cost becomes rapidly prohibitive beyond the milligram scale. Additionally, a practical and flexible synthetic route to KA and analogs remains to be developed. Here we detail a new route that is operationally safer, scalable and offers a five-step reduction in the previously reported longest linear sequence.
- Barbe, Guillaume,Chai, David,Chen, Bin,Dechristopher, Brian,Guay, Daniel,Levesque, Eric,Mancuso, John
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p. 6788 - 6793
(2020/07/14)
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- Oxetanyl Amino Acids for Peptidomimetics
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Peptides are important in the drug discovery process. In analogy to nonpeptidic small-molecule counterparts, they can sometimes suffer from disadvantages such as their low bioavailability and poor metabolic stability. Herein, we report the synthesis of new oxetanyl dipeptides and their incorporation into Leu-enkephalin analogues as proof-of-principle studies. The modular approach that is described enables the incorporation of a variety of oxetanyl amino acids into potential peptide therapeutics.
- M?ller, Guido P.,Müller, Steffen,Wolfst?dter, Bernd T.,Wolfrum, Susanne,Schepmann, Dirk,Wünsch, Bernhard,Carreira, Erick M.
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supporting information
p. 2510 - 2513
(2017/05/24)
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- Novel lipid-mimetic prodrugs delivering active compounds to adipose tissue
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Obesity and associated pathologies are a dramatically growing problem. New therapies to prevent and/or cure them are strongly needed. Adipose tissue is a logical target for pharmacological intervention, since it is now recognized to exert an important endocrine function, secreting a variety of adipokines affecting, for example, adiposity and insulin resistance. This proof of principle work focuses on the development of novel lipid-mimetic prodrugs reaching fat deposits by the same lymphatic absorption route followed by dietary triglycerides. Pterostilbene, a natural phenolic compound with potential anti-obesity effects, was used as model “cargo”, attached via a carbamate group to an ω-aminodecanoate chain linked to either position 1 or position 2 of the glycerol moiety of synthetic triglycerides. The prodrugs underwent position-selective hydrolysis when challenged with pancreatic lipases in vitro. Pterostilbene-containing triglycerides as well as pterostilbene and its metabolites were present in the adipose tissue of mice fed an obesogenic diet containing one or the other of the derivatives. For the first time this approach is used to deliver an obesity antagonist to the adipose tissue. The results demonstrate the feasibility of delivering active compounds to adipose tissue by reversibly incorporating them into triglyceride-mimetic structures. Upon release in the target site these compounds are expected to exert their pharmacological activity precisely where needed.
- Mattarei, Andrea,Rossa, Andrea,Bombardelli, Veronica,Azzolini, Michele,La Spina, Martina,Paradisi, Cristina,Zoratti, Mario,Biasutto, Lucia
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supporting information
p. 77 - 88
(2017/04/26)
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- Mimicking biological membranes with programmable glycan ligands self-assembled from amphiphilic Janus glycodendrimers
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An accelerated modular synthesis produced 18 amphiphilic Janus glycodendrimers with three different topologies formed from either two or one carbohydrate head groups or a mixed constellation with a noncarbohydrate hydrophilic arm. By simple injection of their THF solutions into water or buffer, all of the Janus compounds self-assembled into uniform, stable, and soft unilamellar vesicles, denoted glycodendrimersomes. The mixed constellation topology glycodendrimersomes were demonstrated to be most efficient in binding plant, bacterial, and human lectins. This evidence with biomedically relevant receptors offers a promising perspective for the application of such glycodendrimersomes in targeted drug delivery, vaccines, and other areas of nanomedicine.
- Zhang, Shaodong,Moussodia, Ralph-Olivier,Sun, Hao-Jan,Leowanawat, Pawaret,Muncan, Adam,Nusbaum, Christopher D.,Chelling, Kathleen M.,Heiney, Paul A.,Klein, Michael L.,André, Sabine,Roy, René,Gabius, Hans-J.,Percec, Virgil
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supporting information
p. 10899 - 10903
(2015/03/30)
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- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
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Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
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(2010/04/25)
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- CONTRAST AGENTS
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Compounds of formula (I) RA—CO—N(R2)—(CR12)n—N(R5)—RB and salts or optical active isomers thereof, wherein each R1 independently are the same or different and denotes
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- CONTRAST AGENTS
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The present invention relates to a class of compounds and to diagnostic compositions containing such compounds where the compounds are iodine containing compounds. More specifically the iodine containing compounds are chemical compounds containing two linked iodinated phenyl groups of the general formula (I) and salts or optical active isomers thereof, wherein each R1 independently are the same or different and denotes a hydrogen atom or a C1 to C4 straight or branched alkyl group which is optionally substituted by 1 to 4 - OH groups; each of R2 independently are the same or different and denote a hydrogen atom or a C1 to C4 straight or branched alkyl group; each R3 independently are the same or different and denotes a hydrogen atom or a C1 to C4 straight or branched alkyl group which is optionally substituted by 1 to 4 - OH groups; each R4 independently are the same or different and denote C1 to C6 straight or branched alkyl moieties substituted by up to 6 -OH groups; and each R5 independently are the same or different and denote C1 to C6 straight or branched alkyl moieties substituted by up to 6 -OH groups; and X denotes a straight chain alkylene moiety with 3 to 10 carbon atoms, a 1,4- cyclohexylene group, or X together with the adjacent -NR1 groups forms a 1,4- piperazine group or a 4-aminopiperidine group. The invention also relates to the use of such diagnostic compositions as contrast agents in diagnostic imaging and in particular in X-ray imaging, and to contrast media containing such compounds.
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(2009/05/30)
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- CONTRAST AGENTS
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Compounds of formula (I) RA-CO-N(R2)-(CR12)n-N(R5)-RB and salts or optical active isomers thereof, wherein each R1 independently are the same or different and denotes
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(2009/06/27)
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- Bifunctional dendrimers: From robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications
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A fourth wheel: Two sets of bifunctional AB2C dendrimers having internal acetylene/azides and external hydroxy groups were constructed utilizing benign synthetic protocols. An in situ postfunctionalization strategy was successfully carried out to illustrate the chemoselective nature of these dendrimers. The dendrimers were also transformed into dendritic nanoparticles or utilized as dendritic crosslinkers for the fabrication hydrogels. (Figure Presented).
- Antoni, Per,Hed, Yvonne,Nordberg, Axel,Nystroem, Daniel,Von Holst, Hans,Hult, Anders,Malkoch, Michael
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supporting information; experimental part
p. 2126 - 2130
(2009/08/14)
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- Enhancing and reversing the stereoselectivity of Escherichia coli transketolase via single-point mutations
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Chiral auxiliary methodology and chiral assays have been developed to establish the enantiomeric purities of erythrulose and 1,3-dihydroxypentan-2-one generated using wild-type (WT) Escherichia coli transketolase (TK). L-Erythrulose was formed in 95% ee and (3S)-1,3-dihydroxypentan-2-one in 58% ee. Since the latter compound was formed in moderate ee, TK libraries were screened to identify higher performing mutants. A colorimetric screen and chiral assay were successfully applied to a 96-well format, and new active TK mutants were identified, which gave 1,3-dihydroxypentan-2-one in high stereoselectivities. Remarkably, activesite single-point mutants were identified that were able to both enhance and reverse the stereoselectivity of TK.
- Smith, Mark E. B.,Hibbert, Edward G.,Jones, Alexander B.,Dalby, Paul A.,Hailesa, Helen C.
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scheme or table
p. 2631 - 2638
(2009/09/28)
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- Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1- phosphate and FTY720: Discovery of potent S1P1 receptor agonists
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The novel immunosuppressant FTY720 has been demonstrated to elicit immunomodulating effects via interaction with the G-protein coupled receptor S1P1. FTY720 induced agonism at the S1P3 receptor, however, has been shown to result in m
- Clemens, Jeremy J.,Davis, Michael D.,Lynch, Kevin R.,Macdonald, Timothy L.
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p. 3568 - 3572
(2007/10/03)
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- ORALLY AVAILABLE SPHINGOSINE 1-PHOSPHATE RECEPTOR AGONISTS AND ANTAGONISTS
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The present invention relates to S1P analogs that have activity as S1Preceptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds have the general structure (I) wherein R11 is C5-C18 alkyl or C5-C18 alkenyl; Q is selected from the group consisting of C3-C6 optionally substituted cycloalkyl, C3-C6 optionally substituted heterocyclic, C3-C6 optionally substituted aryl C3-C6 optionally substituted heteroaryl and; R2 is selected from the group consisting of H, C1-C4 alkyl, (C1-C4 alkyl)OH and (C1-C4 alkyl)NH2; R23 is H or C1-C4 alkyl, and R15 is a phosphonate ester or a phosphate ester or a pharmaceutically acceptable salt or tautomer thereof.
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(2008/06/13)
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- Synthesis and evaluation of chromogenic and fluorogenic analogs of glycerol for enzyme assays
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The branched glycerol analogs 1 and 2 were prepared. Mono-ester derivatives of these triols undergo a chromogenic or fluorogenic reaction in the presence of NaIO4. In contrast, both the diesters and the triols are themselves not chromogenic or fluorogenic. Diester derivatives of these triols can be used as probes for lipases. The tris-phosphate derivative of 1 is a fluorogenic substrate for various phosphatases.
- Gonzalez-Garcia, Eva Maria,Grognux, Johann,Wahler, Denis,Reymond, Jean-Louis
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p. 2458 - 2470
(2007/10/03)
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- Preparation and reactions of 2,2-dimethyl-1,3-dioxan-5-one-SAMP-hydrazone: A versatile chiral dihydroxyacetone equivalent
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The SAMP-hydrazone of 2,2-dimethyl-1,3-dioxan-5-one represents a valuable chiral dihydroxyacetone equivalent. Asymmetric mono- or α,α′-bisalkylations followed by auxiliary cleavage leads to the corresponding mono- or α,α′-disubstituted, acetonide protected ketodiols in excellent diastereo- and enantiomeric excesses.
- Enders, Dieter,Voith, Matthias,Ince, Stuart J.
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p. 1775 - 1779
(2007/10/03)
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- 9,10-Dihydroxy-1,8-cineole (1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-10,11-diol)
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The title compound (3) has been synthesized and its presence sought in the urinary metabolites of the brushtail possum.
- Carman, Raymond M.,Handley, Paul N.
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p. 769 - 776
(2007/10/03)
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- Stereoselective synthesis of substituted 5-hydroxy-1,3-dioxanes
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A series of 5-hydroxy-1,3-dioxanes has been synthesized using a practical three-step strategy beginning with acetal/ketal formation of tris(hydroxymethyl)aminomethane followed by oxidative cleavage of the amino alcohol. After the ketone was revealed, stereoselective reduction with common hydride reagents, LiAlH4 for the trans isomers and L-Selectride for the cis analogues, gave the target compounds in high yield.
- Forbes, David C.,Ene, Doina G.,Doyle, Michael P.
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p. 879 - 882
(2007/10/03)
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- Syntheses of 4-deoxy-D-fructose and enzymatic affinity study
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Enantiomerically pure 4-deoxy-D-fructose has been prepared and characterised in a protected form, acidic hydrolysis of which led to an aqueous solution of 4-deoxy-D-fructose. Activities of this compound with enzymes of the glycolysis pathway involved in glucose metabolism make possible access to 4-deoxy-D-fructose-6-phosphate, 4-deoxy-D-glucose-6- phosphate and 4-deoxy-D-gluconate-6-phosphate.
- Andre, Corinne,Bolte, Jean,Demuynck, Colette
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p. 3737 - 3739
(2007/10/03)
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- 1,3-Dioxan-5-ones: synthesis, deprotonation, and reactions of their lithium enolates
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A general synthetic route to 2-alkyl- and 2,2-dialkyl-1,3-dioxan-5-ones, using tris(hydroxymethyl)nitromethane as the starting material, is described.Deprotonation of these compounds was studied.It was established that these dioxanones could be deprotonated with LDA; however, the reduction of the carbonyl group via a hydride transfer from LDA, giving the corresponding dioxanols, often competed with deprotonation.The reduction could be minimized by using Corey's internal quench procedure to form silyl enol ethers and was less pronounced in 2,2-dialkyldioxanones (ketals) than in 2-alkyldioxanones (acetals).Self-aldol products were observed when dioxanone lithium enolates were quenched with H2O.Addition reactions of lithium enolates of dioxanones to aldehydes were threo-selective as predicted by the Zimmerman-Traxler model.Dioxanones having two different alkyl groups at the 2-position were deprotonated enantioselectively by chiral lithium amide bases with enantiomeric excess (ee) of up to 70percent. - Key words: 1,3-dioxan-5-ones, enantioselective deprotonation, chiral lithium amides.
- Majewski, Marek,Gleave, D. Mark,Nowak, Pawel
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p. 1616 - 1626
(2007/10/02)
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- INVESTIGATIONS IN THE SERIES OF HETEROCYCLES. LVI. COMPOUNDS WITH ELECTROPHILIC REACTIVITY. SYNTHESIS AND PROPERTIES OF NEW 2,2-DIMETHYL-5--1,3-DIOXANES AND 2--1
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5-Substituted 5-(2,4-dichloro-1,3,5-triazin-6-ylamino)-1,3-dioxanes were synthesized by the reaction of cyanuric chloride with 5-substituted (CHMe2, CH2F, CH2OPh) 5-amino-2,2-dimethyl-1,3-dioxane.The product were hydrolyzed with the calculated amount of 3
- Kraiz, B. O.,Shenberg, N. N.,Ivin, B. A.
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p. 379 - 386
(2007/10/02)
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