共查询到20条相似文献,搜索用时 15 毫秒
1.
Anti-HIV Pronucleotides: SATE Versus Phenyl as a Protecting Group of AZT Phosphoramidate Derivatives
T. Beltran D. Egron I. Lefebvre C. Périgaud A. Pompon G. Gosselin 《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):973-975
Abstract We comparatively studied the decomposition pathways in CEM cell extract of several PHENYL phosphoramidate diesters of AZT. A correlation between anti-HIV activities in TK? cell lines and pharmacokinetic data has been observed. This study would help to design corresponding SATE phosphoramidate diesters which revealed potent anti-HIV properties. 相似文献
2.
D Egron C Périgaud G Gosselin A M Aubertin J L Imbach 《Nucleosides & nucleotides》1999,18(4-5):981-982
The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified alpha-amino acids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5'-mononucleotide. 相似文献
3.
Kers I Stawiński J Girardet JL Imbach JL Périgaud C Gosselin G Aubertin AM 《Nucleosides & nucleotides》1999,18(10):2317-2325
A simple and efficient protocol for the preparation of various symmetrical dinucleoside phosphoramidates derived from AZT, is presented. It consists of the phosphonylation of AZT with phosphonic acid in the presence of DCC to produce the symmetrical H-phosphonate diester, followed by its oxidative conversion to various phosphoramidate analogues. The synthesized compounds were evaluated for their anti-HIV activity in different cell cultures. 相似文献
4.
Inger Kers Jacek Stawiński Jean-Luc Girardet Jean-Louis Imbach Christian Perigaud Gilles Gosselin 《Nucleosides, nucleotides & nucleic acids》2013,32(10):2317-2325
Abstract A simple and efficient protocol for the preparation of various symmetrical dinucleoside phosphoramidates derived from AZT, is presented. It consists of the phosphonylation of AZT with phosphonic acid in the presence of DCC to produce the symmetrical H-phosphonate diester, followed by its oxidative conversion to various phosphoramidate analogues. The synthesized compounds were evaluated for their anti-HIV activity in different cell cultures. 相似文献
5.
Shirokova EA Jasko MV Khandazhinskaya AL Yanvarev DV Skoblov YS Pronayeva TR Fedyuk NV Pokrovsky AG Kukhanova MK 《Nucleosides, nucleotides & nucleic acids》2003,22(5-8):981-985
5'-Aminocarbonylphosphonyl and aminocarbonylmethylphosphonyl diesters of AZT and d4T were synthesized as potential anti-HIV agents. 相似文献
6.
Egron D Périgaud C Gosselin G Aubertin AM Imbach JL 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):751-754
The synthesis and the study of new mononucleoside phosphoramidate diesters bearing S-acyl-2-thioethyl (SATE) groups and an alkylamino residue are reported. The studied compounds appear to be able to deliver the corresponding 5'-mononucleotide inside the cells, and could be considered as prototypes for a new kind of mononucleotide prodrugs (pronucleotides). 相似文献
7.
Knaggs MH McGuigan C Harris SA Heshmati P Cahard D Gilbert IH Balzarini J 《Bioorganic & medicinal chemistry letters》2000,10(18):2075-2078
A QSAR study, involving the use of calculated physical properties (TSAR), and the use of a neural network approach (TSAR), has been performed concerning the anti-HIV activity and cytotoxic effects of a series of d4T phosphoramidate derivatives with varying L-alanine esters. Models were obtained which allow reliable predictions for the anti-HIV activity, and cytotoxicity, of these derivatives. 相似文献
8.
D. Egron C. Périgaud G. Gosselin A-M. Aubertin J-L. Imbach 《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):981-982
Abstract The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified α-aminoacids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5′-mononucleotide. 相似文献
9.
An efficient oxidizing reagent for the synthesis of mixed backbone oligonucleotides via the H-phosphonate approach 总被引:2,自引:0,他引:2
The mixture of carbon tetrachloride, N-methyl morpholine (NMM), pyridine and water in acetonitrile has been exploited for the oxidation of dinucleoside H-phosphonate diesters to the corresponding phosphates. The system is found to be inert to the phosphoramidate (P-N) and the phosphorothioate (P-S) linkages and has successfully been applied to the solid phase synthesis of mixed-backbone oligonucleotides (MBOs). 相似文献
10.
《Nucleosides, nucleotides & nucleic acids》2013,32(4-7):751-754
The synthesis and the study of new mononucleoside phosphoramidate diesters bearing S-acyl-2-thioethyl (SATE) groups and an alkylamino residue are reported. The studied compounds appear to be able to deliver the corresponding 5′-mononucleotide inside the cells, and could be considered as prototypes for a new kind of mononucleotide prodrugs (pronucleotides). 相似文献
11.
Mammalian proteases have not been implicated in the metabolism of any nucleoside phosphoramidate prodrug. The results presented herein provide unprecedented and conclusive experimental evidence that mammalian proteases are capable of hydrolyzing stavudine phosphoramidates. Specifically, cathepsin B and Proteinase K are able to metabolize stampidine and other phosphoramidate derivatives of stavudine. Additionally, cathepsin B exhibits chiral selectivity at the phosphorus center. The elucidation of the metabolic pathways leading to activation of stampidine may provide the basis for pharmacologic interventions aimed at modulating the metabolism and thereby improving the therapeutic window of stampidine as an anti-HIV agent. 相似文献
12.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):981-985
Abstract 5′-Aminocarbonylphosphonyl and aminocarbonylmethylphosphonyl diesters of AZT and d4T were synthesized as potential anti-HIV agents. 相似文献
13.
Christopher Mcguigan B. Colin N. M. Jones Kevin G. Devine Simon R. Nicholls Derek Kinchington 《Bioorganic & medicinal chemistry letters》1991,1(12):729-732
Phosphate, phosphoramidate, and phosphorodiamidate derivatives of the anti-HIV nucleoside analogue FdT were prepared as potential pro-drugs of the bio-active free nucleotide. Two synthetic routes were adopted. The anti-viral activity of the derivatives varies greatly with the phosphate structure, but several are active below 1μM. 相似文献
14.
Chapman H Kernan M Rohloff J Sparacino M Terhorst T 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):1085-1090
The diastereomers of GS-7171, aryl phosphoramidate derivatives of the anti-HIV nucleotide analog 9-[2-R-(phosphonomethoxy)propyl]adenine (tenofovir, PMPA), were isolated by batch elution chromatography and continuous simulated moving bed chromatography. The absolute configuration of the more pharmacologically active diastereomer, GS-7340, was determined to be (R,S,S) by single crystal x-ray crystallography. 相似文献
15.
A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8- to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity. 相似文献
16.
Söderberg L Lavén G Kalek M Stawinski J 《Nucleosides, nucleotides & nucleic acids》2011,30(7-8):552-564
31P NMR spectroscopy was used to investigate a stereochemical course of a nitrite-promoted conversion of phosphoramidate diesters into the corresponding phosphotriesters. It was found that this reaction occurred with almost complete epimerization at the phosphorus center and at the C1 atom in the amine moiety. On the basis of the 31P NMR data, a plausible mechanism for the reaction was proposed. The density functional theory calculation of the key step of the reaction, i.e., breaking of the P-N bond and formation of the P-O bond, suggested a one-step S(N)2(P) process with retention of configuration at the phosphorus center. 相似文献
17.
Mehellou Y McGuigan C Brancale A Balzarini J 《Bioorganic & medicinal chemistry letters》2007,17(13):3666-3669
We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates. 相似文献
18.
《Nucleosides, nucleotides & nucleic acids》2013,32(4-7):1085-1090
The diastereomers of GS-7171, aryl phosphoramidate derivatives of the anti-HIV nucleotide analog 9-[2-R-(phosphonomethoxy)propyl]adenine (tenofovir, PMPA), were isolated by batch elution chromatography and continuous simulated moving bed chromatography. The absolute configuration of the more pharmacologically active diastereomer, GS-7340, was determined to be (R,S,S) by single crystal x-ray crystallography. 相似文献
19.
Ladurée D Fossey C Delbederi Z Sugeac E Schmidt S Laumond G Aubertin AM 《Journal of enzyme inhibition and medicinal chemistry》2005,20(6):533-549
We have previously reported the synthesis and evaluation of potent anti-human immunodeficiency virus compounds based on beta-D-d4T analogues bearing a tether attached at the C-5 position and their beta-L-counterparts. Initial study revealed a requirement for an alkyl side-chain with an optimal length of 12 carbons for a weak antiviral activity. As a continuation of that work, we have now prepared the corresponding phosphoramidate derivatives as possible membrane-permeable prodrugs. Phosphorochloridate chemistry gave the target phosphoramidates which were tested for anti-human immunodeficiency virus type 1 activity; unfortunately, they were devoid of anti-HIV activity. 相似文献
20.
Linda Söderberg Gaston Lavén Marcin Kalek Professor Jacek Stawinski 《Nucleosides, nucleotides & nucleic acids》2013,32(7-8):552-564
31P NMR spectroscopy was used to investigate a stereochemical course of a nitrite-promoted conversion of phosphoramidate diesters into the corresponding phosphotriesters. It was found that this reaction occurred with almost complete epimerization at the phosphorus center and at the C1 atom in the amine moiety. On the basis of the 31P NMR data, a plausible mechanism for the reaction was proposed. The density functional theory calculation of the key step of the reaction, i.e., breaking of the P–N bond and formation of the P–O bond, suggested a one-step SN2(P) process with retention of configuration at the phosphorus center. 相似文献