Synthesis and biological evaluation of prodrugs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate

Hamon, Nadège; Quintiliani, Maurizio; Balzarini, Jan; McGuigan, Christopher

doi:10.1016/j.bmcl.2013.02.117

Cited by 16 publications

(11 citation statements)

References 45 publications

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“…However, carbocations formed upon photolysis of the aryl sulfide precursors are potential alternative sources of abasic sites (Scheme ). 5-Benzoyl-2-deoxyribose ( 25 ) was synthesized from 23 (Scheme ) but was inseparable from other products in the photolysates in which 1 was generated . Consequently, the respective O -methyl oxime ( 26 ) obtained upon reaction of 25 was used to quantify the abasic site formation when 6 was photolyzed.…”

Section: Resultsmentioning

confidence: 99%

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Independent Generation and Reactivity of Thymidine Radical Cations

2017

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Thymidine radical cation (1) is produced by ionizing radiation and has been invoked as an intermediate in electron transfer in DNA. Previous studies on its structure and reactivity have utilized thymidine as a precursor, which limits quantitative product analysis because thymidine is readily reformed from 1. In this investigation, radical cation 1 is independently generated via β-heterolysis of a pyrimidine radical generated photochemically from an aryl sulfide. Thymidine is the major product (33%) from 1 at pH 7.2. Diastereomeric mixtures of thymidine glycol and the corresponding 5-hydroxperoxides resulting from water trapping of 1 are formed. Significantly lower yields of products such as 5-formyl-2′-deoxyuridine that are ascribable to deprotonation from the C5-methyl group of 1 are observed. Independent generation of the N3-methyl analogue of 1 (NMe-1) produces considerably higher yields of products derived from water trapping, and these products are formed in much higher yields than those attributable to the C5-methyl group deprotonation in NMe-1. N3-Methyl-thymidine is, however, the major product and is produced in as high as 70% yield when the radical cation is produced in the presence of excess thiol. The effects of exogenous reagents on product distributions are consistent with the formation of diffusively free radical cations (1, NMe-1). This method should be compatible with producing radical cations at defined positions within DNA.

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Section: Resultsmentioning

confidence: 99%

“…from 23 (Scheme 8) but was inseparable from other products in the photolysates in which 1 was generated. 35 Consequently,…”

Section: Figurementioning

confidence: 99%

Independent Generation and Reactivity of Thymidine Radical Cations

2017

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“…The established position of the ProTide approach in the antiviral and anticancer nucleotide prodrug field provided a foundation for its further expansion into additional research area and/or non-nucleoside type compounds. These include phosphoramidates of carbohydrates such as N- acetyl- d -glucosamine for the treatment of osteoarthritis, 81,82 2-fluoro-2-deoxyribose-1-phosphate, 83 2,2-difluoro-2-deoxyribose-1-phosphate, 83 2-deoxy- D -ribose-1-phosphate, 84 and phosphonamidates of 2-deoxy- D -ribose-1-phosphonate 85 as antivirals. More recently, application of the ProTide technology to N -(3–(5-(2′-deoxyuridine))prop-2-ynyl)octanamide, the Mycobacterium tuberculosis thymidylate synthase X inhibitor 86 and to fingolimod, an immunomodulating drug used for treating multiple sclerosis disease 87 was reported.…”

Section: Aryloxyphosphor(n)amidate Prodrugs (Protides)mentioning

confidence: 99%

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Ślusarczyk

Serpi

Pertusati

2018

Antivir Chem Chemother

105

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Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.

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“…The structures containing covalent P–N bonds as in phosphoramidates are ubiquitous in flame proof materials [ 88 ] and chemical fertilizers. McGuigan et al synthesized and evaluated the phosphoramidate ProTides of (fluoro) deoxyribose which are used as an antiviral prodrug 109 ( Figure 25 ) [ 89 ].…”

Section: Miscellaneous Application Of Compounds Containing P–n Bonmentioning

confidence: 99%

Nitrogenous Derivatives of Phosphorus and the Origins of Life: Plausible Prebiotic Phosphorylating Agents in Water

Karki

Gibard

Bhowmik

et al. 2017

Life

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Phosphorylation under plausible prebiotic conditions continues to be one of the defining issues for the role of phosphorus in the origins of life processes. In this review, we cover the reactions of alternative forms of phosphate, specifically the nitrogenous versions of phosphate (and other forms of reduced phosphorus species) from a prebiotic, synthetic organic and biochemistry perspective. The ease with which such amidophosphates or phosphoramidate derivatives phosphorylate a wide variety of substrates suggests that alternative forms of phosphate could have played a role in overcoming the “phosphorylation in water problem”. We submit that serious consideration should be given to the search for primordial sources of nitrogenous versions of phosphate and other versions of phosphorus.

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Synthesis and biological evaluation of prodrugs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate

Cited by 16 publications

References 45 publications

Independent Generation and Reactivity of Thymidine Radical Cations

Independent Generation and Reactivity of Thymidine Radical Cations

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Nitrogenous Derivatives of Phosphorus and the Origins of Life: Plausible Prebiotic Phosphorylating Agents in Water

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