66866-45-3Relevant academic research and scientific papers
Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists
Kambe, Tohru,Maruyama, Toru,Nagase, Toshihiko,Ogawa, Seiji,Minamoto, Chiaki,Sakata, Kiyoto,Maruyama, Takayuki,Nakai, Hisao,Toda, Masaaki
experimental part, p. 702 - 713 (2012/03/11)
To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.
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.
Design and synthesis of α-ketoamides as cathepsin s inhibitors with potential applications against tumor invasion and angiogenesis
Chen, Jo-Chun,Uang, Biing-Jiun,Lyu, Ping-Chiang,Chang, Jang-Yang,Liu, Ko-Jiunn,Kuo, Ching-Chuan,Hsieh, Hsing-Pang,Wang, Hsin-Chieh,Cheng, Chao-Sheng,Chang, Yi-Hsun,Chang, Margaret Dah-Tsyr,Chang, Wun-Shaing Wayne,Lin, Chun-Cheng
scheme or table, p. 4545 - 4549 (2010/08/19)
A series of small molecules bearing an α-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC50 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of α-ketoamide therapy for preventing or delaying cancer spread.
Biomimetic total synthesis and antimicrobial evaluation of anachelin H
Gademann, Karl,Bethuel, Yann,Locher, Hans H.,Hubschwerlen, Christian
, p. 8361 - 8370 (2008/09/18)
(Chemical Equation Presented) The first biomimetic total synthesis of the iron chelator anachelin H isolated from the cyanobacterium Anabaena cylindrica is reported. A first generation approach delivered one enantiomeric series of the polyketide fragment. Comparison of the 1H NMR data suggested the relative configuration of this anachelin fragment. The relative and absolute configuration of anachelin H was then established by total synthesis. A second generation approach involved the enzymatic conversion of N,N-dimethyltyramine to the anachelin chromophore. It was demonstrated that the enzyme tyrosinase is activated by the product during this reaction, the anachelin chromophore can serve as a tyrosinase activator. Anachelin H was evaluated against a panel of eleven bacterial and fungal pathogens, and moderate antibiotic activity (32 μg/mL) against Moraxella catarrhalis was found.
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.
Total synthesis of anachelin H
Gademann, Karl,Bethuel, Yann
, p. 4707 - 4710 (2007/10/03)
(Chemical Equation Presented) The first total synthesis of anachelin H is reported. Starting from L-Ser, a stereodivergent synthesis of the polyketide fragment resulting in all possible diastereoisomers is described. The alkaloid peptide fragment is prepa
Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design
Greenspan,Clark,Tommasi,Cowen,McQuire,Farley,Van Duzer,Goldberg,Zhou,Du,Fitt,Coppa,Fang,Macchia,Zhu,Capparelli,Goldstein,Wigg,Doughty,Bohacek,Knap
, p. 4524 - 4534 (2007/10/03)
Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH2CN (19, IC50 = 62 μM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P1, P2, and P3 substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S2′ pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon α to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.
Synthesis and biophysical studies of modified oligonucleotides containing acyclic amino alcohol nucleoside analogs
Ramasamy, Kanda S.,Stoisavljevic, Vesna
, p. 1845 - 1861 (2007/10/03)
Novel serine derivative of thymine was prepared and incorporated into oligonucleotides. These modified oligonucleotides were studied for their binding affinity with complementary DNA/RNA.
Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease
Ogilvie,Yoakim,Do,Hache,Lagace,Naud,O'Meara,Deziel
, p. 1521 - 1531 (2007/10/03)
A series of monobactam inhibitors of HCMV (N(o)) protease bearing a heterocycle linked by a methylene group at C-4 is described. Inhibitors containing a heterocycle such as a 2-furyl, 2-thiophenyl, 4-methyl-2-tetrazole and 2-benzothiazole were found to be active in a plaque reduction assay. Furthermore, 2-benzothiazole derivatives were shown to inhibit the HCMV protease activity inside cells by using a cell transfection assay, indicating that their antiviral activity in the plaque reduction assay could be attributed to protease inhibition. Copyright (C) 1999 Elsevier Science Ltd.
Direct synthesis of N-protected β-amino dimethylhydroxamates: Application to the solid-phase synthesis of a peptide incorporating a new amide bond surrogate ψ[CH2CH2NH]
Limal, David,Quesnel, Anne,Briand, Jean-Paul
, p. 4239 - 4242 (2007/10/03)
A rapid and efficient one-step synthesis of N-protected β-amino dimethylhydroxamates starting from diazo ketones is reported. A Fmoc- protected β-amino aldehyde obtained by reduction of its corresponding dimethylhydroxamate was incorporated during solid p
