- Synthesis and biological evaluation of aryl phosphoramidate prodrugs of fosfoxacin and its derivatives
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Aryl phosphoramidate prodrugs of fosfoxacin derivatives 15a-b and 8a-b were synthesized and investigated for their ability to target bacteria. No growth inhibition was observed neither for Mycobacterium smegmatis nor for Escherichia coli on solid medium,
- Munier, Mathilde,Tritsch, Denis,Lièvremont, Didier,Rohmer, Michel,Grosdemange-Billiard, Catherine
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- Phosphate prodrugs derived from N-acetylglucosamine have enhanced chondroprotective activity in explant cultures and represent a new lead in antiosteoarthritis drug discovery
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We report the application of the phosphoramidate ProTide approach, developed by us for antiviral nucleosides, to sugar derivatives with potential chondroprotection against osteoarthritis. In particular, N-acetylglucosamine was converted to a series of 06
- McGuigan, Christopher,Serpi, Michaela,Bibbo, Rita,Roberts, Helen,Hughes, Clare,Caterson, Bruce,Gibert, Ana Torrent,Verson, Carlos Raúl Alaez
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experimental part
p. 5807 - 5812
(2009/09/06)
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- Phosphoramidate and phosphate prodrugs of (-)-β-D-(2R,4R)-dioxolane- thymine: Synthesis, anti-HIV activity and stability studies
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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.
- Liang, Yuzeng,Narayanasamy, Janarthanan,Schinazi, Raymond F.,Chu, Chung K.
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p. 2178 - 2189
(2007/10/03)
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- Cytotoxic nucleoside analog compound 003 for treating cancer
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The present invention provides pharmaceutical compositions comprising Compound 003 or metabolites thereof in combination with one or more carboxylesterase inhibitors. The invention provides methods for inhibiting cellular proliferation associated with pro
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Page/Page column 6; 14-15
(2008/06/13)
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- Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT
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Novel aryl phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anti-HIV activity in CEM cells; the magnitude of the biological effect varied considerably depending on the nature of the phosphate blocking group. Moreover, several of the compounds retain marked antiviral activity in TK- (thymidine kinase-deficient) mutant CEM cells in which AZT was virtually inactive. These data strongly support the hypothesis that the AZT phosphate derivatives exert their biological effects via intracellular release of AZT nucleotide forms and suggest that the potential of nucleoside drugs in antiviral chemotherapy may be enhanced by suitable nucleotide delivery strategies.
- McGuigan,Pathirana,Balzarini,De Clercq
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p. 1048 - 1052
(2007/10/02)
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