Preparation of novel nucleoside analogues from cyclobutane precursors as potential antiviral agents

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2′,3′-dideoxy-2′,3′-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2′,3′-dideoxy-2′,3′-difluoro and a 2′-deoxy-2′-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

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Synthesis of several pyrimidine l-nucleoside analogues as potential antiviral agents

Tetrahedron ◽

10.1016/0040-4020(94)00997-9 ◽

1995 ◽

Vol 51 (4) ◽

pp. 1055-1068 ◽

Cited By ~ 24

Author(s):

Tai-Shun Lin ◽

Mei-Zhen Luo ◽

Mao-Chin Liu

Keyword(s):

Antiviral Agents ◽

Nucleoside Analogues

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Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Antiviral Chemistry and Chemotherapy ◽

10.1177/2040206618775243 ◽

2018 ◽

Vol 26 ◽

pp. 204020661877524 ◽

Cited By ~ 29

Author(s):

Magdalena Slusarczyk ◽

Michaela Serpi ◽

Fabrizio Pertusati

Keyword(s):

Amino Acid ◽

Antiviral Activity ◽

Antiviral Agents ◽

Resistance Mechanisms ◽

Amino Acid Ester ◽

Nucleoside Analogues ◽

Hydroxyl Groups ◽

Extensive Investigation ◽

Vast Number ◽

Seminal Contribution

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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