41445-61-8Relevant academic research and scientific papers
Active site mapping of trypsin, thrombin and matriptase-2 by sulfamoyl benzamidines
Dosa, Stefan,Stirnberg, Marit,Luelsdorff, Verena,Haeussler, Daniela,Maurer, Eva,Guetschow, Michael
, p. 6489 - 6505,17 (2012/12/11)
The benzamidine moiety, a well-known arginine mimetic, has been introduced in a variety of ligands, including peptidomimetic inhibitors of trypsin-like serine proteases. According to their primary substrate specificity, the benzamidine residue interacts with the negatively charged aspartate at the bottom of the S1 pocket of such enzymes. Six series of benzamidine derivatives (1-73) were synthesized and evaluated as inhibitors of two prototype serine proteases, that is, bovine trypsin and human thrombin. As a further target, human matriptase-2, a recently discovered type II transmembrane serine protease, was investigated. Matriptase-2 represents an important regulatory protease in iron homeostasis by down-regulation of the hepcidin expression. Compounds 1-73 were designed to contain a fixed sulfamoyl benzamidine moiety as arginine mimetic and a linker-connected additional substructure, such as a tert-butyl ester, carboxylate or second benzamidine functionality. A systematic mapping approach was performed with these inhibitors to scan the active site of the three target proteases. In particular, bisbenzamidines, able to interact with both the S1 and S3/S4 binding sites, showed notable affinity. In branched bisbenzamidines 66-73 containing a third hydrophobic residue, opposite effects of the stereochemistry on trypsin and thrombin inhibition were observed.
Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry
Yermolina, Maria V.,Wang, Jizhen,Caffrey, Michael,Rong, Lijun L.,Wardrop, Duncan J.
experimental part, p. 765 - 781 (2011/04/15)
Herein, we report the development of an antifiloviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC50 of 30 μM. To analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using "click" chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent antiviral agents with IC50 values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
Building functionalized peptidomimetics: Use of electroauxiliaries for introducing N-acyliminium ions into peptides
Sun, Haizhou,Martin, Connor,Kesselring, David,Keller, Rebecca,Moeller, Kevin D.
, p. 13761 - 13771 (2007/10/03)
A series of silyl-substituted amino acids have been synthesized, inserted into peptides, and then employed as precursors for oxidatively generating reactive N-acyliminium ions. Both electrochemical and chemical oxidation procedures have been employed. N-Acyliminium ion generation in a solid-phase substrate as well as application to a small library of functionalized dipeptides has been demonstrated. Limitations in terms of how electron-rich the silyl groups can be as well as the compatibility of multiple silyl groups within a longer peptide are defined.
Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides
Cordova, Armando,Zou, Weibiao,Dziedzic, Pawel,Ibrahem, Ismail,Reyes, Efraim,Xu, Yongmei
, p. 5383 - 5397 (2008/02/13)
In nature there are at least nineteen different acyclic amino acids that act as the building blocks of poly-peptides and proteins with different functions. Here we report that α-amino acids, β-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantio-selectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corre sponding aldol products with up to > 99% ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.
Synthesis and activity of phosphinic tripeptide inhibitors of cathepsin C
Mucha, Artur,Pawelczak, Malgorzata,Hurek, Jozef,Kafarski, Pawel
, p. 3113 - 3116 (2007/10/03)
Phosphinic tripeptide analogues Gly-Xaaψ[P(O)(OH)CH2]-Gly have been developed as inhibitors of cathepsin C (DPP I), a lysosomal, papain-like cysteine protease. The target compounds were synthesised by addition of methyl acrylate to the appropri
Synthesis of model compounds for potential contrast agents containing phosphonate and peptide moieties
Shalem, Hutti,Shatzmiller, Shimon,Feit, Ben-Ami
, p. 2831 - 2837 (2007/10/03)
The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these two compounds were prepared. These products are composed of a combination of structural/functional moieties which pave the way for their potential application as non-ionic selective X-ray contrast agents. The Royal Society of Chemistry 2000.
Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety
Lebreton, Luc,Annat, Jocelyne,Derrepas, Philippe,Dutartre, Patrick,Renaut, Patrice
, p. 277 - 290 (2007/10/03)
A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central 'C' region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl- guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the 'right- amide' of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.
Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors.
Belayev, Alexander,Zhang, Xuemei,Augustyns, Koen,Lambeir, Anne-Marie,Meester, Ingrid De,et al.
, p. 1041 - 1052 (2007/10/03)
The previously reported diphenyl 1-(S)-prolylpyrrolidine-2(R, S)-phosphonate (5) was used as a lead compound for the development of potent and irreversible inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). The synthesis of a series of diaryl 1-
Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: Potential conformational mimetics for cis-peptidyl prolinamides
Lenman, Morag M.,Lewis, Arwel,Gani, David
, p. 2297 - 2311 (2007/10/03)
The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, which is expected to mimic structural features of cis-peptldyl prolinamides, is described. The required parent heterocycle, corresponding to cis-glycy-(2S)-prolinamide, has been prepared in good yield by the cyclisation of N-(2-bromoacetylprolyl)-hydrazine which is itself generated in situ from the bromoacetyl proline methyl ester. Analogues corresponding to cis-(2R)-alanyl- and cis-(2S)-alanyl-(2S)-prolinamide have been similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, involving the displacement of bromide, has been shown to occur with inversion of configuration at C-2 of the propionyl moiety. Acylation at the N-3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamides. This has been achieved without incident using standard peptide coupling procedures. Extension at the 'C-terminal' has been achieved by preparing elaborated hydrazine precursors which are reacted with suitably activated esters of N-α-halogenoacylprolines, prior to cyclisation, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.
Effect of N(α)-acyl chain length on the membrane-modifying properties of synthetic analogs of the lipopeptaibol trichogin GA IV
Toniolo,Crisma,Formaggio,Peggion,Monaco,Goulard,Rebuffat,Bodo
, p. 4952 - 4958 (2007/10/03)
Trichogin GA IV, an1-residue lipopeptaibol blocked at the N-terminus by an n-octanoyl group and at the C-terminus by a 1,2-amino alcohol (L-leucinol), extracted from the fungus Trichoderma longibrachiatum, exhibits remarkable membrane-modifying properties
