Aryloxy phosphoramidates

While many have used phosphorus esters to prepare prodmgs, others have developed phosphoramidate derivatives (reviewed by Mehellou [116]). As early as 1990, Devine and McGuigan had hypothesized that nucleotides containing at least one phosphoramidate linkage would exhibit cellular conversion to the free phosphate, potentially enhanced by activity of HIV protease [117]. Extensive studies in the intervening years have amply demonstrated the validity of that hypothesis with both diamidates and aryloxy phosphoramidates (reviewed in [118]), and each class offers advantages. Examples are described in the following sections (Table 2). 

Mehellou Y, Balzarini J, McGuigan C (2009) Aryloxy phosphoramidate triesters a technology for delivering monophosphorylated nucleosides and sugars into cells. Chemmedchem 4 1779-1791... 

Arbelo Roman C, Wasserthal P, Balzarini J, Meier C (2011) Diastereoselective synthesis of (aryloxy)phosphoramidate prodmgs. Eur J Org Chem 2011 4899 909... 

Arbelo Roman C, Balzarini J, Meier C (2010) Diastereoselective s)mthesis of aryloxy phosphoramidate prodrugs of 3 -deoxy-2 ,3 -didehydrothymidine monophosphate. J Med Chem 53 7675-7681... 

The SAR study on phosphoramidate prodrugs of PSI-6206 was focused on the aryloxy-phosphoramidate side chain. Compared to the common aryloxy-phosphoramidate prodrugs, modifications at amino acid ester, aryl phosphate ester, and amino acid side chain were conducted on PSI-6206 phosphoramidate. An examination of these modifications for 29 compounds found that a small simple alkyl and branched alkyl at the amino acid ester, phenyl and halogenated aryl at the phosphate ester, and a-methyl at the amino acid side chain produced better antiviral activity and the least cytotoxicity. The groups for the amino acid ester part (R ) were chosen from methyl, ethyl, isopropyl, and cyclohexyl the groups for the aryl phosphate ester (R ) were selected from phenyl and para-halogenated phenyl and the substituent for the amino acid side chain was fixed with a-methyl (r-alanine). These combinations of modifications resulted in 16 compounds (12-27, Table 1) for further evaluation. 

Full details have appeared of experiments reported earlier (Organophosphorus Chemistry, 1986, 1, 156) on the iodine-induced cyclization of the unsacurated phosphates and phosphoramidates (and also phosphonic acid derivatives) (108 X=0,NH,NMe, or CH2 Y=alkoxy or aryloxy). For a fixed atom or group X, the ease of the cyclization is profoundly affected by changes in group Y. Electron donation to the phosphoryl group by X, e.g., when X=0, which would adversely affect the cyclization, may be offset by an appropriate change in Y. ... 

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