- Synthesis of unsymmetrically substituted α-aminoalkylphosphonate esters
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The title compounds were designed as haptens for production of monoclonal antibodies as potential catalysts for phosphoryl transfer reactions of phosphates and phosphonates. These haptens conform to the 'bait and switch' model.
- Moriarty,Liu,Zhuang,Lenz,Brimfield,Xia
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- Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors
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Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N-acetylated amino acid residues from proteins and peptides. Although the N-acylation occurs in 50–90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β-peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross-talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down-regulation of the ubiquitin-proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1-aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N-terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV-4-11 tumor cell lines.
- Walczak, Maciej,Chryplewicz, Agnieszka,Olewińska, Sandra,Psurski, Mateusz,Winiarski, ?ukasz,Torzyk, Karolina,Oleksyszyn, Józef,Sieńczyk, Marcin
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- Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists
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One of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based peptidyl antagonists of IAPs that mimic the endogenous Smac protein, which blocks the interaction between IAPs and caspases. Based on the structure of the IAP antagonist and recently reported thiadiazole derivatives, we designed and evaluated the biochemical properties of a series of phosphonic peptides bearing the N-Me-Ala-Val/Chg-Pro-OH motif (Chg: cyclohexylglycine). The ability of the obtained compounds to interact with the binding groove of the X-linked inhibitor of apoptosis protein baculovirus inhibitor of apoptosis protein repeat (XIAP BIR3) domain was examined by a fluorescence polarization assay, while their potential to induce autoubiquitination followed by proteasomal degradation of cellular IAP1 was examined using the MDA-MB-231 breast cancer cell line. The highest potency against BIR3 was observed among peptides containing C-terminal phosphonic phenylalanine analogs, which displayed nanomolar Ki values. Their antiproliferative potential as well as their proapoptotic action, manifested by an increase in caspase-3 activity, was examined using various cell lines.
- ?upicka-S?owik, Agnieszka,Psurski, Mateusz,Grzywa, Renata,Cuprych, Monika,Ciekot, Jaros?aw,Goldeman, Waldemar,Wojaczyńska, El?bieta,Wojaczyński, Jacek,Oleksyszyn, Józef,Sieńczyk, Marcin
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p. 1350 - 1364
(2020/04/24)
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- Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX
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VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC50 of 0.48-8.21 mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.
- Jia, Chao,Yang, Ke-Wu,Liu, Cheng-Cheng,Feng, Lei,Xiao, Jian-Min,Zhou, Li-Sheng,Zhang, Yi-Lin
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supporting information; experimental part
p. 482 - 484
(2012/03/11)
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- Convenient syntheses of novel 1-isothiocyano-alkylphosphonate diphenyl ester derivatives with potential biological activity
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Herein, we describe a convenient method for the syntheses of novel 1-isothiocyano-alkylphosphonate diaryl ester derivatives and their antiproliferative activity. The syntheses are based on dithiocarbamates obtained in situ with the use of carbon disulfide
- Psurski, Mateusz,Pigula, Marta,Winiarski, Lukasz,Oleksyszyn, Jozef,Ciekot, Jaroslaw,Wietrzyk, Joanna
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supporting information
p. 5845 - 5847,3
(2020/08/20)
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- Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX
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In an effort to develop inhibitors of VanX, the phosphonamidate analogs of d-Ala-d-Ala dipeptides, N-[(1-aminoethyl) hydroxyphosphinyl]-glycine (1a), -alanine (1b), -valine (1c), -leucine (1d) and -phenylalanine (1e) were synthesized, characterized and ev
- Yang, Ke-Wu,Cheng, Xu,Zhao, Chuan,Liu, Cheng-Cheng,Jia, Chao,Feng, Lei,Xiao, Jian-Min,Zhou, Li-Sheng,Gao, Hui-Zhou,Yang, Xia,Zhai, Le
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supporting information; experimental part
p. 7224 - 7227
(2012/02/02)
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- Phosphonic pseudopeptides as human neutrophil elastase inhibitors - A combinatorial approach
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Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries - products of Ugi and Passerini multicomponent condensations - leading to the selection of new biologically active phosphonic pseudopeptides.
- Sieńczyk, Marcin,Podgórski, Dawid,B?aejewska, Aleksandra,Kulbacka, Julita,Saczko, Jolanta,Oleksyszyn, Józef
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experimental part
p. 1277 - 1284
(2011/04/12)
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- Synthesis of isocyanide derivatives of α-aminoalkylphosphonate diphenyl esters
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This letter describes the first example of the synthesis of isocyanide derivatives of α-aminoalkylphosphonate diphenyl esters. This method produces the title compounds in high purity and in very good yields. It also permits the generation of an α-aminopho
- Sieńczyk, Marcin,Kliszczak, Maciej,Oleksyszyn, Józef
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p. 4209 - 4211
(2007/10/03)
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- Synthesis of O,O-diphenyl [substituted (2-selenomorpholin-4-yl-acetyl amino)] alkyl phosphonates
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A series of O,O-diphenyl [substituted (2-selenomorpholin-4-yl-acetyl amino)] alkyl phosphonates were synthesized by the reactions of selenomorpholine with O,O-diphenyl 2-chloro- acetylamino alkyl phosphonates. The structures of all new compounds have been
- Hu, Liming,Chen, Zhiyuan,Lu, Shengmei,Li, Xueshu,Liu, Zhaojie,Xu, Hansheng
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p. 1065 - 1073
(2007/10/03)
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- Synthesis and bioactivities of 1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides containing α-aminophosphonate groups
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In order to search for novel antitumor and antiviral agents with high activity and low toxicity, a series of 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetrahydro-4-oxo-1, 3,2-benzodiazaphosphorin-2-carboxamide 2-oxides containing α-aminophosphonate groups have been designed and synthesized by a convenient one-pot procedure in good yields. The structures of products were confirmed by 1H NMR, 31P NMR, IR spectra, and elemental analyses. The bioassay results showed that some of them possess excellent anti-tobacco mosaic virus activities and exhibit higher inhibitory effects compared with that of the contrast drug 2,4-dioxyhexahydro-1,3,5-triazine.
- Huang, Junmin,Chen, Ruyu
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- Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX
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In an effort to prepare novel inhibitors of VanX, N-[(1-aminoethyl)hydroxyphosphinyl]-D-alanine 1 and S-[(aminoethyl)hydroxyphosphinyl]-thiolacetic acid 2 were synthesized and evaluated as inhibitors of VanX. Phosphonamidate 1 was shown to be a partial co
- Yang, Ke-Wu,Brandt, Jeffrey J.,Chatwood, Lisa L.,Crowder, Michael W.
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p. 1085 - 1087
(2007/10/03)
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- The formation of α-amino- and α-hydroxy-alkanephosphonic acids in the reactions of phosphite esters with aldehydes and alkyl carbamates
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The preparation of α-aminoalkanephosphonic acids from triphenyl phosphite, an aldehyde, and ethyl or benzyl carbamate in glacial acetic acid, followed by hydrolysis, is accompanied by the formation of the corresponding α-hydroxyphosphonic acid. Reaction in toluene, using boron trifluoride-etherate as catalyst, affords an alternative preparative procedure but does not prevent the formation of α-hydroxyphosphonic acid. 31P nmr reveals the presence of numerous intermediates. The reactions are discussed.
- Hudson, Harry R.,Ismail, Fatima,Pianka, Max,Wan, Chi-Wai
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p. 245 - 257
(2007/10/03)
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- Remote binding energy in antibody catalysis: Studies of a catalytically unoptimized specificity pocket
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Binding interactions remote from the hydrolytic reaction center have been probed with substrate and phosphonate transition state analogues to understand how these types of interactions are used to promote catalysis in the 17E8 system. We find that the hapten-generated recogniton pocket in 17E8 has properties that are analogous to those of specificity pockets in enzymes. We have also found that there are specific requirements to form catalytically productive interactions between the side chain and the recognition pocket including conformation, size, and geometry. An additional requirement includes favorable simultaneous interactions between the side chain and binding pocket along with favorable interactions with the oxyanion hole. The 17E8 side chain recognition pocket seems to be less catalytically efficient than analogous pockets in enzymatic systems. The apparent binding energy gained from the methylene-pocket interactions in the 17E8 system is significantly smaller than those observed in natural enzymes. Furthermore, 17E8 does not use specific interactions in the recognition pocket to significantly affect catalytic turnover (kcat) which is thought to be a trait of an unoptimized catalyst. Analysis of the crystal structure of the 17E8·hapten complex has allowed for the identification of differences between the active sites of 17E8 and several proteases. The identified differences give insight to the sources of the inefficient use of binding energy.
- Wade, Herschel,Scanlan, Thomas S.
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p. 1434 - 1443
(2007/10/03)
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- Synthesis of pentacoordinate phosphorus haptens for catalytic antibody production. Bait and switch concept
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Our objective is to obtain monoclonal antibodies which will catalyse the hydrolysis of phosphorus-based nerve agents. Our syntheses followed three strategies. The first was synthesis of stable pentacoordinate phosphoranes as haptens for the production of
- Moriarty, Robert M.,Liu, Kaiming,Tuladhar, Sudersan M.,Guo, Liang,Condeiu, Christian,Tao, Anping,Xu, Wei,Lenz, David,Brimfield, Alan
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p. 237 - 240
(2007/10/03)
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