Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: Studies on the effect of chain elongation on biological activity

Curley, D.; McGuigan, Christopher; Devine, Kevin G.; O'Connor, Timothy J.; Jeffries, D. J.; Kinchington, D.

doi:10.1016/0166-3542(90)90053-a

Cited by 38 publications

(40 citation statements)

References 13 publications

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“…A synthetic strategy similar to that we have previously employed for phosphoramidates (Curley et al, 1990; McGuigan et aI., 1990c) was found to be successful in the cases herein described. Thus, trichloroethyl hexylalaninyl phosphorochloridate was prepared by the reaction of trichloroethyl phosphorodichloridate with the hexyl ester of alanine hydrochloride.…”

Section: Resultssupporting

confidence: 56%

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

McGuigan

Pathirana

Choi

et al. 1993

Antivir Chem Chemother

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SummaryNovel phosphoramidate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials carry carboxy-protected, arnlnor-aclds, 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.

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Section: Resultssupporting

confidence: 56%

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

McGuigan

Pathirana

Choi

et al. 1993

Antivir Chem Chemother

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“…In one study, a-amino acids were compared to their b and g derivatives (9), and it was found that the parent a system (glycine) provided maximal activity. [24] Increasing the alkyl spacer length resulted in a significant loss of activity, where changing the length from n = 2 to n = 1 leads to > 10-fold decrease in activity. [24] Bearing in mind the improvements seen with haloalkyl phosphates compared with their alkyl derivatives, we wondered whether haloalkyl phosphoramidates would also be more potent.…”

Section: Alkyloxy Phosphoramidatesmentioning

confidence: 98%

“…[24] Increasing the alkyl spacer length resulted in a significant loss of activity, where changing the length from n = 2 to n = 1 leads to > 10-fold decrease in activity. [24] Bearing in mind the improvements seen with haloalkyl phosphates compared with their alkyl derivatives, we wondered whether haloalkyl phosphoramidates would also be more potent. Therefore, a small series of haloalkyl phosphoramidates of AZT (10) were prepared and examined.…”

Section: Alkyloxy Phosphoramidatesmentioning

confidence: 98%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

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“…Phosphorochloridate is the term used to refer to the phosphorylating reagents used for the coupling with the nucleosides. According to the procedure of Curly et al, 41 these were obtained from the low temperature (-78 o C) coupling of aminoacid ester hydrochloride salts with phenyl dichlorophosophate in the presence of TEA in anhydrous DCM (Scheme 2). Phosphorochloridates are generally obtained as a 1:1 mixture of R p and S p diastereoisomers.…”

Section: Phosphoramidate Prodrugsmentioning

confidence: 99%

Antiviral Nucleoside and Nucleotide Analogs: A Review

Mahmoud

Hasabelnaby

Hammad

et al. 2018

Journal of Advanced Pharmacy Research

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Virus infections are an increasing and probably lasting global risk. Nucleoside and nucleotide analogs represent the largest class of antiviral drugs. Early success in the treatment of human immunodeficiency virus infection and the recent approval of sofosbuvir as phosphoramidate nucleoside prodrug for chronic hepatitis C have provided proof of concept for important this class of compounds as an antiviral agent. This review summarizes the antiviral activity of nucleoside and nucleotide analogs and their recent application.

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Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: Studies on the effect of chain elongation on biological activity

Cited by 38 publications

References 13 publications

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

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

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

Antiviral Nucleoside and Nucleotide Analogs: A Review

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