Dinucleoside phosphates, synthesis

Schott H et al. Synthesis, characterization, and some properties of amphiphilic dinucleoside phosphate derivatives of 3 -azido-2, 3 -dideoxythymidine (AZT). Antivir Chem Chemother 1994 5 387. 

Schott H, et al. Synthesis and in vitro antitumor activity of 2 -deoxy-5-fluoro-uridylyl-(3 -5 )-2 -deoxy-5-fluoro-N -octadecylcytidine a new amphiphilic dinucleoside phosphate. Liebigs Annalen Chemie 1997 413. 

The synthesis of some dinucleoside phosphates has been achieved1680 by the reaction of 5 -chloro-5 -deoxynucleosides with nucleotide anions. In that work, the 5 -chloro-5 -deoxynucleosides were conveniently obtained by treatment of the corresponding 2, 3 -0-isopropylidene-nucleoside with thionyl chloride. 

The limited therapeutic activity of the fluorinated pyrimidines 5-fluorouracil (FU) and 5-fluoro-2 -deoxyuridine (FUdR) in certain forms of adenocarcinoma, principally of the digestive tract, have led to the synthesis of a variety of analogues. Dinucleoside phosphates containing FU... 

The methods of nucleotide synthesis thus far described have involved the activation of a phosphoric moiety by increase of the electrophilic nature of phosphorus, in order to facilitate nucleophilic attack by hydroxyl group(s) of nucleosides (alcoholysis). An alternative approach is the use of an activated nucleoside which will undergo attack by a phosphono-oxy anion on carbon (phosphorolysis). Although the latter approach has had little practical advantage in the synthesis of mononucleotides, it has shown some promise in the synthesis of dinucleoside phosphates. Theoretical considerations are sufficiently compelling to warrant discussion of this approach here. 

Scheme 19.1 The Michelson and Todd first synthesis of a dinucleoside phosphate, TpT.

Padyukova and Smrt (93) described the synthesis of dinucleoside phosphates containing S -o-bonded... 

Potter, B. V. L., Connolly, B. A, and Eckstein, F. (1983) Synthesis and configurational analysis of a dinucleoside phosphate isotopically chiral at phosphorus Stereochemical course of penicillium citrum nuclease PI reaction Biochemistry 1369-1377. 

Hall, R. H Todd, A., and Webb, R. F. (1957) Nucleotides. Part XLL Mixed anhydrides as intermediates in the synthesis of dinucleoside phosphates. J Chem. Soc. 3291-3296... 

The observation that the final digestion products of RNA by the enzyme are four nucleoside 2, 3 -cyclic phosphates led Ukita and coworkers (121) to utilize the enzyme for the synthesis of various dinucleoside monophosphates. Indeed they have successfully synthesized UpU, CpU, ApU, GpU, UpC, CpC, ApC, and GpC in good yields (from 20 to 75% based on initial nucleoside 2, 3 -cyclic phosphates) by the reaction... 

We first describe the synthesis of unsymmetrical a.y-dinucleoside triphosphates involving 7-methylguanosine. For the construction of the terminal cap structure, there might be two possible reaction modes where an activatable protecting group (X) was introduced into a nucleotide by direct displacement with phosphate hydroxyl group (Method A) and by pyrophosphorylation between Xp and pN (Method B). 

---