98045-03-5Relevant articles and documents
Esterase-sensitive prodrugs of a potent bisubstrate inhibitor of nicotinamide n-methyltransferase (Nnmt) display cellular activity
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.
, (2021/09/16)
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.
Synthesis and Biological Evaluation of a Library of AGE-Related Amino Acid Triazole Crosslinkers
Agelidis, Nektarios,Altevogt, Luca,Baro, Angelika,Bilitewski, Ursula,Bugdayci, Bakiye,Icik, Esra,Jolly, Anthony,L?ffler, Paul,Laschat, Sabine
, (2020/09/01)
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).
Synthesis of triazole cages containing C3-symmetric α-cyclic tripeptide scaffold
Chakraborty, Subrata,Tai, Dar-Fu
, p. 2274 - 2276 (2014/04/17)
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.
Combined Lewis acid and Br?nsted acid-mediated reactivity of glycosyl trichloroacetimidate donors
Gould, Nathan D.,Liana Allen,Nam, Brandon C.,Schepartz, Alanna,Miller, Scott J.
, p. 36 - 42 (2013/11/19)
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.
Structure-guided design of α-amino acid-derived Pin1 inhibitors
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.
scheme or table, p. 586 - 590 (2010/04/26)
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.
AMINO ACID INHIBITORS OF CYTOCHROME P450
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, (2009/10/18)
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
Ruthenium tetroxide oxidation of cyclic N-acylamines by a single layer method: formation of ω-amino acids
Kaname, Mamoru,Yoshifuji, Shigeyuki,Sashida, Haruki
, p. 2786 - 2788 (2008/09/19)
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.
Synthesis, characterization and cytolytic activity of α-helical amphiphilic peptide nanostructures containing crown ethers
Boudreault, Pierre-Luc,Voyer, Normand
, p. 1459 - 1465 (2008/02/08)
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
Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase)
Ghosh, Arun K.,Devasamudram, Thippeswamy,Hong, Lin,Dezutter, Christopher,Xu, Xiaoming,Weerasena, Vajira,Koelsch, Gerald,Bilcer, Geoffrey,Tang, Jordan
, p. 15 - 20 (2007/10/03)
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
Synthesis of non-natural amino acids based on the ruthenium-catalysed oxidation of a phenyl group to carboxylic acid
Moutevelis-Minakakis, Panagiota,Sinanoglou, Charalambos,Loukas, Vassilios,Kokotos, George
, p. 933 - 938 (2007/10/03)
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