Application of the protide strategy to some novel nucleoside analogues

Abdallah Alshaimaa Hassan, . and McGuigan C., . Application of the protide strategy to some novel nucleoside analogues. pp. 43-58. ISSN 2180-1983

The majority of HIV-Herpes nucleoside analogues share a common mode of action which is conversion via three successive phosphorylations to their bioactive 5-triphosphate forms by cellular or viral induced kinases. The protide strategy aims to deliver the monophosphate form of the parent nucleoside in order to by-pass the first phosphorylation step and thus the need for kinase-mediated activation. Indeed a number of protide analogues have retained full anti-viral activity in kinase-deficient cells suggesting that the protides effectively deliver the 5-monophosphate forms intracellularly. In this paper the phosphoramidate derivatives of the thymine nucleoside analogues as well as the 3-amino-AZT derivative were synthesized and assayed for their antiviral activities. These derivatives exhibited poor activities when compared to the parent nucleoside indicating a lack of successful nucleotide delivery. Nevertheless the formation of by-products during the synthesis of phosphoramidates via the phosphorochloridate strategy was overcome by controlling the conditions of the reaction and especially by choosing a selective coupling reagent such as tBuMgCl or N-methyl imidazole to avoid any N-1 or 3-phosphorylation. It is also clear from the results that phosphoramidates were sensitive to harsh conditions and reagents such as hydrogenation. The addition of the phosphochloridate should always be left to the last stage.

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Abstract

The majority of HIV-Herpes nucleoside analogues share a common mode of action which is conversion via three successive phosphorylations to their bioactive 5-triphosphate forms by cellular or viral induced kinases. The protide strategy aims to deliver the monophosphate form of the parent nucleoside in order to by-pass the first phosphorylation step and thus the need for kinase-mediated activation. Indeed a number of protide analogues have retained full anti-viral activity in kinase-deficient cells suggesting that the protides effectively deliver the 5-monophosphate forms intracellularly. In this paper the phosphoramidate derivatives of the thymine nucleoside analogues as well as the 3-amino-AZT derivative were synthesized and assayed for their antiviral activities. These derivatives exhibited poor activities when compared to the parent nucleoside indicating a lack of successful nucleotide delivery. Nevertheless the formation of by-products during the synthesis of phosphoramidates via the phosphorochloridate strategy was overcome by controlling the conditions of the reaction and especially by choosing a selective coupling reagent such as tBuMgCl or N-methyl imidazole to avoid any N-1 or 3-phosphorylation. It is also clear from the results that phosphoramidates were sensitive to harsh conditions and reagents such as hydrogenation. The addition of the phosphochloridate should always be left to the last stage.

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Item Type:	Article
AGROVOC Term:	Nucleosides
AGROVOC Term:	Human immunodeficiency virus
AGROVOC Term:	Human diseases
AGROVOC Term:	Chemical compounds
AGROVOC Term:	Mass spectrometry
AGROVOC Term:	Column chromatography
AGROVOC Term:	Phosphorus
AGROVOC Term:	Reduction
AGROVOC Term:	Thymine
AGROVOC Term:	Hydrogenation
Depositing User:	Ms. Suzila Mohamad Kasim
Last Modified:	24 Apr 2025 06:28
URI:	http://webagris.upm.edu.my/id/eprint/24123

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