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The design, synthesis and Anti-HIV activity of a selected group of 2 ',3 '-didehydro-2 ',3 '-dideoxyguanosine (d4G) and 2 ',3 '-dideoxyguanosine (ddG) 'ProTide' derivatives

Mehellou, Youcef, McGuigan, Christopher and Balzarini, J. 2007. The design, synthesis and Anti-HIV activity of a selected group of 2 ',3 '-didehydro-2 ',3 '-dideoxyguanosine (d4G) and 2 ',3 '-dideoxyguanosine (ddG) 'ProTide' derivatives. Antiviral Research 74 (3) , 50. 10.1016/j.antiviral.2007.01.063

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Abstract

2′,3′-Dideoxyguanosine (ddG) is a nucleoside analogue that has been found to exert a relatively modest anti-HIV activity. This was attributed to the poor phosphorylation of ddG to its corresponding triphosphate form. Since the triphosphate of ddG was found to possess potent anti-HIV activity, we hypothesised that using a prodrug approach to deliver the monophosphate of ddG may improve the anti-HIV activity of this agent. As well as ddG, we decided to study the anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxyguanosine (d4G) and some of its pronucleotide derivatives, since 2′3′-dideydro-dideoxy nucleoside analogues, such as d4T, are useful therapeutics. The pronucleotide approach that we decided to apply for d4G and ddG is called the ‘ProTide’ approach. In this approach, the phosphate group is masked to improve the poor membrane permeability seen when the free nucleotides are used. Upon entering the cell, the group masking the phosphate moiety may undergo enzymatic metabolism to release the nucleoside monophosphate, which may be subsequently phosphorylated by cellular kinases into the di- and triphosphates of d4G or ddG. Hence, we synthesised d4G, ddG and a selected group of their ‘ProTide’ derivatives, general structure given below, and tested them against HIV-1 and HIV-2 (Fig. 1). The synthesis of these agents as well as the biological data will be presented at the meeting.

Item Type: Article
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Publisher: Elsevier
ISSN: 0166-3542
Last Modified: 18 Oct 2017 13:14
URI: http://orca.cf.ac.uk/id/eprint/6649

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