scholarly journals Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

1996 ◽  
Vol 7 (1) ◽  
pp. 31-36 ◽  
Author(s):  
C. McGuigan ◽  
D. Cahard ◽  
A. Salgado ◽  
E. De Clercq ◽  
J. Balzarini
Keyword(s):  
Amino Acid ◽  
Vital Role ◽  
Nucleoside Analogues ◽  
Acid Moiety ◽  
Hiv Replication ◽  
Amino Acid Moiety ◽  
Free Nucleotides ◽  
Derivatives Of ◽  
Anti Hiv

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characterised by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was that any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activity. Such simple phenyl alkylamino phosphate derivatives of either d4T or AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the vital role played by the amino acid in the antiviral efficacy of the blocked phosphoramidates.

TSAO-T Analogues Bearing Amino Acids at Position N-3 of Thymine: Synthesis and Anti-Human Immunodeficiency Virus Activity

2000 ◽  
Vol 11 (1) ◽  
pp. 61-69 ◽  
Author(s):  
C Chamorro ◽  
E De Clercq ◽  
J Balzarini ◽  
M-J Camarasa ◽  
A San-Félix
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Inhibitory Effect ◽  
Acid Moiety ◽  
Hiv Replication ◽  
Virus Activity ◽  
Immunodeficiency Virus ◽  
Amino Acid Moiety ◽  
Anti Hiv ◽  
Hiv 1

Novel analogues of the anti-HIV-1 lead compound [1-[2‘,5’-bis- O-( tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3‘-spiro-5’-(4“-amino-1”,2“-oxathiole-2‘,2’-dioxide) (TSAO-T) bearing different amino acids at position N-3 of thymine were prepared and evaluated as inhibitors of HIV replication. The synthesis of the target compounds was accomplished by coupling of the appropriate TSAO intermediate with a conveniently protected (L) amino acid in the presence of BOP and triethylamine, followed by depro-tection of the amino acid moiety. Several TSAO derivatives, bearing at N-3 position of the thymine base an L-amino acid retaining the free carboxylic acid, acquired activity against HIV-2, in addition to their inhibitory effect on HIV-1.

Metabolism and anti-HIV activity of phosphoramidate derivatives of D4T-MP with variations in the amino acid moiety

1997 ◽  
Vol 30 (3) ◽  
pp. 271
Author(s):  
L. Naesens ◽  
D. Cahard ◽  
A. Salgado ◽  
L. Bidois ◽  
E. De Clercq ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acid Moiety ◽  
Amino Acid Moiety ◽  
Derivatives Of ◽  
Anti Hiv

Anti-HIV activity and metabolism of phosphoramidate derivatives of D4T-MP with variations in the amino acid moiety

1997 ◽  
Vol 34 (2) ◽  
pp. A54 ◽  
Author(s):  
L. Naesens ◽  
D. Cahard ◽  
A. Salgado ◽  
L. Bidois ◽  
E. De Clercq ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acid Moiety ◽  
Amino Acid Moiety ◽  
Derivatives Of ◽  
Anti Hiv

scholarly journals Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents

1996 ◽  
Vol 7 (6) ◽  
pp. 330-337 ◽  
Author(s):  
C. McGuigan ◽  
H.-W. Tsang ◽  
N. Mahmood ◽  
A. J. Hay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Analytical Data ◽  
Modified Nucleosides ◽  
Nucleoside Analogues ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.

Phosphoramidate Derivatives of AZT as Inhibitors of HIV: Studies on the Carboxyl Terminus

1993 ◽  
Vol 4 (2) ◽  
pp. 97-101 ◽  
Author(s):  
C. McGuigan ◽  
R. N. Pathirana ◽  
S. S.-M. Choi ◽  
D. Kinchington ◽  
T. J. O'Connor
Keyword(s):  
Amino Acids ◽  
Biological Activity ◽  
Carboxyl Terminus ◽  
Amino Ester ◽  
Carboxy Terminus ◽  
Free Nucleotides ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Ester Lead

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials carry carboxy-protected, amino acids, and are designed to act as membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective antiviral activity. In particular, variation in the carboxy terminus region is studied. For alkyl phosphates small changes in the structure of the amino ester lead to marked changes in biological activity. However, for analogous aryl phosphates there is little dependence on the structure of the ester. This suggests a different mechanism of action for these two categories of phosphate prodrug.

scholarly journals Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

1996 ◽  
Vol 7 (4) ◽  
pp. 184-188 ◽  
Author(s):  
C. McGuigan ◽  
A. Salgado ◽  
C. Yarnold ◽  
T.Y. Harries ◽  
E. De Clercq ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Antiviral Activity ◽  
Antiviral Effect ◽  
Amino Acid Derivatives ◽  
Free Nucleotides ◽  
Nucleoside Phosphoramidates ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Marked Dependence

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogue d4T were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotide d4TMP. We herein reveal the very marked dependence of the antiviral activity of these phosphoramidates upon the stereochemistry of the amino acid attached to the phosphate centre; with a strong preference for the L-stereochemistry. These phosphate triesters were shown to liberate amino acid derivatives of the nucleotide intracellularly. These novel analogues, typified by alaninyl d4T monophosphate, may act as intracellular sources of the free nucleotides. The alaninyl d4T adducts themselves exert an antiviral effect when administered extracellularly, but again with clear distinctions between the L- and D-series. This evidence indicates that extracellularly administered blocked triesters derived from L-amino acids can generate d4TMP intracellularly, by a new pathway which is highly dependent on the amino acid stereochemistry.

Haloalkyl Phosphate Derivatives of AZT as Inhibitors of HIV: Studies in the Phosphate Region

1994 ◽  
Vol 5 (3) ◽  
pp. 162-168 ◽  
Author(s):  
C. McGuigan ◽  
S. Turner ◽  
S. R. Nicholls ◽  
T. J. O'Connor ◽  
D. Kinchington
Keyword(s):  
Biological Activity ◽  
Alkyl Chain ◽  
Antiviral Action ◽  
Alkyl Phosphate ◽  
Free Nucleotides ◽  
Order Of Magnitude ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analogue AZT were prepared by phosphorochloridate chemistry. These materials were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral action, which varied greatly with the structure of the phosphate moiety. By comparison to simple dialkyl phosphates, which are inactive against HIV-1, the introduction of halogen atoms into the alkyl (phosphate) chains led to anti-HIV activity. Although halogen substitution in just one alkyl chain was sufficient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second chain, by conversion to a phosphonate, led to a reduction in activity. In one case, the diastereo-isomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activity by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activity.

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