- Synthesis of AD-Dihydrodipyrrins Equipped with Latent Substituents of Native Chlorophylls and Bacteriochlorophylls
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Native chlorophylls and bacteriochlorophylls share a common trans-substituted pyrroline ring D (17-propionic acid, 18-methyl), whereas diversity occurs in ring A particularly at the 3-position. Two dihydrodipyrrins equipped with native-like D-ring substit
- Wang, Pengzhi,Lindsey, Jonathan S.
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p. 11794 - 11811
(2021/08/24)
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- DEZOCINE ANALOGUE
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Disclosed in the present invention is a Dezocine analogue, and particularly disclosed are compounds represented by formula (I), (II) and (III), a pharmaceutically acceptable salt or tautomer thereof.
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Paragraph 0193; 0194
(2018/11/27)
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- A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
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Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
- Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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supporting information
p. 14192 - 14197
(2017/10/17)
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- Novel activity-based probes for: N -acylethanolamine acid amidase
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The cysteine hydrolase, N-acylethanolamine acid amidase (NAAA) is a promising target for analgesic and anti-inflammatory drugs. Here, we describe the development of two unprecedented NAAA-reactive activity-based probes as research tools for application in the discovery of new inhibitors and for the in-depth characterization of NAAA in its cellular environment.
- Petracca, Rita,Romeo, Elisa,Baggelaar, Marc P.,Artola, Marta,Pontis, Silvia,Ponzano, Stefano,Overkleeft, Herman S.,Van Der Stelt, Mario,Piomelli, Daniele
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supporting information
p. 11810 - 11813
(2017/11/03)
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- Mild deprotection of PMB ethers using tert-butyl bromide
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A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
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- Radical Cyclization Followed by the Fragmentation of Carbonyl Compounds: Effect of an α-Benzoyl Group
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To study a recently developed radical cyclization reaction followed by a fragmentation process in more detail, a series of α-benzoyl carbonyl compounds were prepared, including precursors with aldehyde and ketone moieties. Initiated by tributyltin hydride
- Chien, Li-An,Chang, Che-Chien
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p. 11294 - 11301
(2015/12/01)
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- Highly efficient synthesis of monodisperse poly(ethylene glycols) and derivatives through macrocyclization of oligo(ethylene glycols)
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A macrocyclic sulfate (MCS)-based approach to monodisperse poly(ethylene glycols) (M-PEGs) and their monofunctionalized derivatives has been developed. Macrocyclization of oligo(ethylene glycols) (OEGs) provides MCS (up to a 62-membered macrocycle) as versatile precursors for a range of monofunctionalized M-PEGs. Through iterative nucleophilic ring-opening reactions of MCS without performing group protection and activation, a series of M-PEGs, including the unprecedented 64-mer (2850Da), can be readily prepared. Synthetic simplicity coupled with versatility of this new strategy may pave the way for broader applications of M-PEGs. Macrocycles make synthesis easier: Convenient macrocyclization of the OEGs provides versatile macrocyclic sulfates. These compounds are cornerstones for both monofunctionalization of OEGs and highly efficient synthesis of monodisperse PEGs and derivatives, including an unprecedented 64-mer.
- Zhang, Hua,Li, Xuefei,Shi, Qiuyan,Li, Yu,Xia, Guiquan,Chen, Long,Yang, Zhigang,Jiang, Zhong-Xing
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supporting information
p. 3763 - 3767
(2015/03/18)
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- Identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase/neutral glucosylceramidase inhibitors
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This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.
- Ghisaidoobe, Amar T.,Van Den Berg, Richard J. B. H. N.,Butt, Saleem S.,Strijland, Anneke,Donker-Koopman, Wilma E.,Scheij, Saskia,Van Den Nieuwendijk, Adrianus M. C. H.,Koomen, Gerrit-Jan,Van Loevezijn, Arnold,Leemhuis, Mark,Wennekes, Tom,Van Der Stelt, Mario,Van Der Marel, Gijsbert A.,Van Boeckel, Constant A. A.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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supporting information
p. 9096 - 9104
(2015/03/14)
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- Formal Alder-ene reaction of a bicyclo[1.1.0]butane in the synthesis of the tricyclic quaternary ammonium core of daphniglaucins
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A tricyclic substructure of the tetracyclic nitrogen core of the daphniglaucins was formed by an oxidative activation of the allyl side chain of a bicyclo[1.1.0]butylmethylamine, a spontaneous intramolecular formal Alder-ene reaction, and a selective cycl
- Ueda, Masafumi,Walczak, Maciej A.A.,Wipf, Peter
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scheme or table
p. 5986 - 5989
(2009/04/11)
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- N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors
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Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleosid
- Hernández, Ana-Isabel,Familiar, Olga,Negri, Ana,Rodríguez-Barrios, Fátima,Gago, Federico,Karlsson, Anna,Camarasa, María-José,Balzarini, Jan,Pérez-Pérez, María-Jesús
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p. 7766 - 7773
(2007/10/03)
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- Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase
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We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of
- Nguyen, Corinne,Ruda, Gian Filippo,Schipani, Alessandro,Kasinathan, Ganasan,Leal, Isabel,Musso-Buendia, Alexander,Kaiser, Marcel,Brun, Reto,Ruiz-Pérez, Luis M.,Sahlberg, Britt-Louise,Johansson, Nils Gunnar,González-Pacanowska, Dolores,Gilbert, Ian H.
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p. 4183 - 4195
(2007/10/03)
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- DUTPASE INHIBITORS
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Deoxyuridine derivatives of the formula (I) where R1 is H or various substituents; D is -NHCO-, -CONH-, -0-, -C(=O)-, -CH=CH, -CΞC-, -NR5-; R4 is hydrogen or various substituents; R5 is H, C1-C4 alkyl, C1-C4 alkanoyl; E is Si or C; R6, R7 and R8 are independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or a stable monocyclic, bicyclic or tricyclic ring system; G is -O-, -S-, -CHR10-, -C(=O)-; J is -CH2-, or when G is CHR10 may also be -O- or -NH-; R10 is H, F, -CH3, -CH2NH2, -CH2OH; -OH R11 is H, F, -CH3, -CH2 NH2, -CH2OH, CH(OH)CH3, CH(NH3)CH3; or R10 and R11 together define an olefinic bond, or together form a -CH2-group, thereby defining a cis or trans cyclopropyl group; have utility in the prophylaxis or treatment of protozoal diseases such as malaria.
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Page/Page column 29
(2008/06/13)
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- Cerium(III) triflate versus cerium(III) chloride: Anion dependence of Lewis acid behavior in the deprotection of PMB ethers
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Cerium(III) triflate deprotects p-methoxybenzyl ethers of simple alcohols better than the cerium(III) chloride/sodium iodide system. It can be used in 1% M instead of equimolecular amounts, giving better yields. Aromatic alcohols rearrange, but the addition of a scavenger overcomes this drawback. Unfortunately, unsaturated alcohols are deprotected with decomposition, probably due to side electrophilic additions to double bonds. A comparison between the mechanisms of cerium triflate and cerium chloride is reported. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Bartoli, Giuseppe,Dalpozzo, Renato,De Nino, Antonio,Maiuolo, Loredana,Nardi, Monica,Procopio, Antonio,Tagarelli, Antonio
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p. 2176 - 2180
(2007/10/03)
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- New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine
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Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.
- Angehrn, Peter,Buchmann, Stefan,Funk, Christoph,Goetschi, Erwin,Gmuender, Hans,Hebeisen, Paul,Kostrewa, Dirk,Link, Helmut,Luebbers, Thomas,Masciadri, Raffaello,Nielsen, Joergen,Reindl, Peter,Ricklin, Fabienne,Schmitt-Hoffmann, Anne,Theil, Frank-Peter
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p. 1487 - 1513
(2007/10/03)
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- A highly efficient, mild, and selective cleavage of beta-methoxyethoxymethyl (MEM) ethers by cerium(III) chloride in acetonitrile.
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[structure: see text]. A highly selective cleavage of MEM ethers has been achieved in high yields using CeCl3.7H2O in refluxing acetonitrile under mild and neutral reaction conditions. The method is very rapid and compatible with other hydroxyl protecting groups such as Bn, TBDPS, Ac, Me, Tr, PMB, benzylidene, THP, MOM, BOM, and NHAc present in the substrate.
- Sabitha,Babu,Rajkumar,Srividya,Yadav
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p. 1149 - 1151
(2007/10/03)
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- Synthetic studies on altohyrtins (spongistatins): Synthesis of the C29-C44 (EF) portion
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The C29-C44 portion of altohyrtins (spongistatins) has been prepared from 1,5-pentanediol and D-glucose in a stereoselective manner. The convergent synthesis relied on a coupling reaction of the C29-C37 vinyl bromide and the C38-C44 Weinreb amide, diaster
- Terauchi, Takeshi,Morita, Masataka,Kimijima, Kyoko,Nakamura, Yasuhiro,Hayashi, Gouichirou,Tanaka, Taisaku,Kanoh, Naoki,Nakata, Masaya
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p. 5505 - 5508
(2007/10/03)
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- Solid-support synthesis of di- and tetramannosylated tetrathymidylic acid
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The easy accessible building units 5-O-(2,3,4,6-tetra-O-benzoyI-α-D-mannopyranosyl)penyl 2-cyanoethyl N,N-diisopropylphosphoramidite (9) and 2,2-bis(4,4′-dimethoxytrityloxymethyl)propyl 2-cyanoethyl N,N-diisopropylphosphoramidite (12) were used for the sequential elongation of immobilized tetrametric thymidylic acid according to a DNA synthesis protocol. Ammonolysis of the individual immobilized adducts led to the isolation of the target compounds 1 and 2.
- Wijsman,Filippov,Valentijn,Van Der Marel,Van Boom
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p. 397 - 401
(2007/10/03)
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- Preparation of monotritylated symmetric 1,n-diols
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A convenient method has been developed to selectively form the monotriphenylmethyl derivatives of symmetric 1,n-diols, both straight chain and cyclic, in moderate to high yields.
- Komiotis,Currie,LeBreton,Venton
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p. 531 - 534
(2007/10/02)
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