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Symmetrical diamidate prodrugs of nucleotide analogues for drug delivery

Pertusati, Fabrizio, McGuigan, Christopher and Serpi, Michaela 2015. Symmetrical diamidate prodrugs of nucleotide analogues for drug delivery. Current Protocols in Nucleic Acid Chemistry, Wiley-Blackwell, 60:15.6.1-15.6.10. (10.1002/0471142700.nc1506s60)

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Abstract

The use of pronucleotides to circumvent the well-known drawbacks of nucleotide analogs has played a significant role in the area of antiviral and anticancer drug delivery. Several motifs have been designed to mask the negative charges on the phosphorus moiety of either nucleoside monophosphates or nucleoside phosphonates, in order to increase their hydrophobicity and allow entry of the compound into the cell. Among them the bis-amidate analogs, having two identical amino acids as masking groups through a P–N bond, represent a more recent approach for the delivery of nucleotide analogs, endowed with antiviral or anticancer activity. Different synthetic strategies are commonly used for preparing phosphorodiamidates of nucleosides. In this protocol, we would like to focus on the description of the synthetic methodology that in our hand gave the best results using 2′-3′-didehydro-2′-3′-dideoxythymidine (d4T, Stavudine) as model nucleoside. A second strategy for preparing diamidates of nucleoside phosphonates will be reported using {[2-(6-amino-9 H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA, adefovir) as model substrate.

Item Type: Book Section
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: Wiley-Blackwell
ISBN: 9780471142706
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 17 October 2014
Last Modified: 26 Oct 2017 02:40
URI: http://orca.cf.ac.uk/id/eprint/85117

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