- Esterase-sensitive prodrugs of a potent bisubstrate inhibitor of nicotinamide n-methyltransferase (Nnmt) display cellular activity
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A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
- van Haren, Matthijs J.,Gao, Yongzhi,Buijs, Ned,Campagna, Roberto,Sartini, Davide,Emanuelli, Monica,Mateuszuk, Lukasz,Kij, Agnieszka,Chlopicki, Stefan,de Castilla, Pol Escudé Martinez,Schiffelers, Raymond,Martin, Nathaniel I.
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- Synthesis and Biological Evaluation of a Library of AGE-Related Amino Acid Triazole Crosslinkers
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Three N-Boc-protected amino acids, l-serine, l-aspartic, and l-glutamic acid, were either converted into their methyl azidoalkanoates or various alkynes via Bestmann-Ohira strategy or via reaction with propargylamine and propargyl bromide, respectively. The Cu-catalyzed click reaction provided a library of amino acid based triazoles, which were further N-methylated to triazolium iodides or deprotected and precipitated as free amino acid triazole dihydrochlorides. The biological properties of all derivatives were investigated by cytotoxicity assay (against L929 mouse fibroblasts) and broth microdilution method (E. coli ΔTolC and S. aureus). First results reveal complete inactivity for triazolium iodides with cell viabilities and microbial growths nearly 100 %, indicating them as possible analogs of advanced glycation endproducts (AGEs).
- Agelidis, Nektarios,Altevogt, Luca,Baro, Angelika,Bilitewski, Ursula,Bugdayci, Bakiye,Icik, Esra,Jolly, Anthony,L?ffler, Paul,Laschat, Sabine
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- Synthesis of triazole cages containing C3-symmetric α-cyclic tripeptide scaffold
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Two water-soluble C3-symmetric 1,2,3-triazole cages containing α-cyclic tripeptide were efficiently synthesized. The key steps include a click reaction to incorporate l-glutamic or l-aspartic acids to a tripodal linker and a unique one-pot cyclotrimerization.
- Chakraborty, Subrata,Tai, Dar-Fu
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supporting information
p. 2274 - 2276
(2014/04/17)
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- Combined Lewis acid and Br?nsted acid-mediated reactivity of glycosyl trichloroacetimidate donors
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Biomimetic conditions for a synthetic glycosylation reaction, inspired by the highly conserved functionality of carbohydrate active enzymes, were explored. At the outset, we sought to generate proof of principle for this approach to developing catalytic systems for glycosylation. However, control reactions and subsequent kinetic studies showed that a stoichiometric, irreversible reaction of the catalyst and glycosyl donor was occurring, with a remarkable rate variance depending upon the structure of the carboxylic acid. It was subsequently found that a combination of Br?nsted acid (carboxylic acid) and Lewis acid (MgBr2) was unique in catalyzing the desired glycosylation reaction. Thus, it was concluded that the two acids act synergistically to catalyze the desired transformation. The role of the catalytic components was tested with a number of control reactions and based on these studies a mechanism is proposed herein.
- Gould, Nathan D.,Liana Allen,Nam, Brandon C.,Schepartz, Alanna,Miller, Scott J.
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supporting information
p. 36 - 42
(2013/11/19)
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- Structure-guided design of α-amino acid-derived Pin1 inhibitors
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The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of α-benzimidazolyl-substituted amino acids.
- Potter, Andrew J.,Ray, Stuart,Gueritz, Louisa,Nunns, Claire L.,Bryant, Christopher J.,Scrace, Simon F.,Matassova, Natalia,Baker, Lisa,Dokurno, Pawel,Robinson, David A.,Surgenor, Allan E.,Davis, Ben,Murray, James B.,Richardson, Christine M.,Moore, Jonathan D.
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scheme or table
p. 586 - 590
(2010/04/26)
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- AMINO ACID INHIBITORS OF CYTOCHROME P450
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Page/Page column 75-76
(2009/10/18)
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- Ruthenium tetroxide oxidation of cyclic N-acylamines by a single layer method: formation of ω-amino acids
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The ruthenium tetroxide oxidation of cyclic N-acyl amines by a 10% NaIO4 aqueous solution containing tert-butanol as a single layer system resulted in the endo-cyclic C-N bond cleavage to afford the ω-amino acids as almost sole products in good yields, while a similar oxidation under the double layer using a NaIO4 aqueous solution, and ethyl acetate gave the N-acyl lactams.
- Kaname, Mamoru,Yoshifuji, Shigeyuki,Sashida, Haruki
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p. 2786 - 2788
(2008/09/19)
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- Synthesis, characterization and cytolytic activity of α-helical amphiphilic peptide nanostructures containing crown ethers
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Many natural α-helical amphiphilic peptides are known to have lytic activity toward different cells. Herein, we describe the synthesis and the characterization of synthetic α-helical amphiphilic peptide nanostructures containing crown ethers, as well as t
- Boudreault, Pierre-Luc,Voyer, Normand
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p. 1459 - 1465
(2008/02/08)
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- Synthesis of non-natural amino acids based on the ruthenium-catalysed oxidation of a phenyl group to carboxylic acid
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An efficient method for the synthesis of enantiopure β-, β-, and δ-amino acids with proteinogenic side chains, starting from natural α-amino acids, was developed. The method is based on the ruthenium-catalyzed oxidation of a phenyl group to a carboxylic a
- Moutevelis-Minakakis, Panagiota,Sinanoglou, Charalambos,Loukas, Vassilios,Kokotos, George
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p. 933 - 938
(2007/10/03)
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- Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase)
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A series of novel macrocyclic amide-urethanes was designed and synthesized based upon the X-ray crystal structure. Inhibitors containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against memapsin 2. A series of novel macrocycli
- Ghosh, Arun K.,Devasamudram, Thippeswamy,Hong, Lin,Dezutter, Christopher,Xu, Xiaoming,Weerasena, Vajira,Koelsch, Gerald,Bilcer, Geoffrey,Tang, Jordan
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- Design and preparation of serine-threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 1. Evaluation of key inhibitory features and synthesis of a rationally stripped-down nodularin macrocycle
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The natural nodularin and microcystin toxins are powerful but non-selective inhibitors of the ubiquitous and structurally related eukaryotic Ser-Thr protein phosphatases, PP1 and PP2A, enzymes that are intimately involved in controlling cellular metabolism. Both families of toxin are cyclic tri-isopeptides typified by the presence of two free carboxylic acid groups, a dehydroamino acid moiety, and a large, rigid exocyclic lipophilic side-chain. To learn how to design specific inhibitors for each enzyme, the nature of specific interactions with potential inhibitor-conferring moieties in the toxin was considered. Borohydride reduction of the dehydroalanine residue present in microcystin-LR, a potential Michael acceptor, gave two diastereoisomeric dihydromicrocystin products. Each of these displayed subnanomolar activities as inhibitors for PP2A, as for the parent compound, indicating that the dehydroamino acid residue in microcystin and, probably, in nodularin, is not essential for activity. Other conserved features appeared to be required to confer activity, hence strategies towards the synthesis of simplified non-dehydroamino acid-containing analogues of each macrocycle type were considered. In each case it was planned to elaborate the lipophilic side-chain functionality after the formation of the macrocyclic ring. In order to synthesize the precursor nodularin-type macrolactam, two peptide-bond disconnections of the ring were investigated using a model system, cyclo-[β-Ala-(R)-Glu-α-OMe-γ-Sar-(R)-Asp-α-OMe-β-(S) -Phe-], one bond disconnecting between the sarcosine carboxy group and the (2R)-Asp N-atom and the other disconnecting between the (2R)-Asp β-carboxy group and the (2S)-PhC N-atom. Preparation of the linear precursors was achieved using solution-phase chemistry without incident. Macrolactamisation via the displacement of the β-pentafluorophenyl ester of the (2R)-Asp α-methyl ester residue by the free amino group of the (2S)-phenylalanine residue proceeded in excellent yield (89%), but the alternative strategy failed. Application of the successful macrolactamisation strategy to other nodularin macrocycles and to the construction of the microcystin-type macrocycle is described in the following article.
- Mehrotra, Amit P.,Webster, Kerri L.,Gani, David
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p. 2495 - 2511
(2007/10/03)
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- Design and Enantioselective Synthesis of a Peptidomimetic of the Turn in the Helix-Turn-Helix DNA-Binding Protein Motif
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A peptidomimetic of the turn in the helix-turn-helix (HTH) motif of DNA-binding proteins was designed and synthesized. Conformational constraint was achieved by an unusual linking of two amino acids with a side chain carbon-carbon bond. A phenyl ring provides the potential for new hydrophobic contacts with the hydrophobic core of the HTH motif. In the mimic, the peptide backbone and the central residue were retained in native form within a 12-membered cyclic tripeptide. The target compound 1b was synthesized by two sequential Horner-Wittig couplings followed by enantioselective hydrogenation with Rh(MeDuPHOS) in eight steps and 35% overall yield. The stereochemical outcome of the key hydrogenation was determined by aromatic ring oxidation with RuO2/NaIO4 to give 2 equiv of Boc-Asp-OMe.
- Travins, Jeremy M.,Etzkorn, Felicia A.
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p. 8387 - 8393
(2007/10/03)
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- New Allyl Group Acceptors for Palladium Catalyzed Removal of Allylic Protections and Transacylation of Allyl Carbamates.
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Key words: allylic protecting groups, palladium catalysis, transacylation, phenyltrihydrosilane, N-methyl-N-(trimethylsilyl)trifluoroacetamide.Allyl carboxylates, carbamates and phenoxides may be cleaved or transacylated in the presence of palladium catalyst and either phenyltrihydridosilane or N-methyl-N-(trimethylsilyl)trifluoroacetamide.These reactions are totally compatible with the presence of Boc and, as far as phenyltrihydrosilane is concerned, Fmoc protections.
- Dessolin, Michele,Guillerez, Marie-George,Thieriet, Nathalie,Guibe, Francois,Loffet, Albert
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p. 5741 - 5744
(2007/10/02)
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- OPTIMIZATION OF THE PAPAIN CATALYZED ESTERIFICATION OF AMINO ACIDS BY ALCOHOLS AND DIOLS
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Esterification of Boc-Alanine and Boc-Aspartic acids by alcohols CnH2n+1OH and diols HO(CH2)nOH with immobilized papain (XAD-7 or Sepharose) is discussed.Great improvement is obtained for the esterification of Boc-Ala-OH i
- Cantacuzene, D,Guerreiro, C
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p. 741 - 748
(2007/10/02)
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