Polynucleoside Monophosphate Derivatives

2 Polynucleoside Monophosphate Derivatives. Amphiphilic heterodinucleoside derivatives (61, 62), specifically the A -palmitoylated 2, 3 -dideoxycyti-dine linked to AZT or ddl via a (5, 5 )-phosphate diester linkage have been prepared to compare their activity as anti-HIV agents to the activity of their hydrophilic heterodimer counterpart. The dimers exhibited strong activity against HIV wild type and an AZT-resistant virus variant. 

Symmetrical dinucleoside phosphoramidates and iV-substituted phosphora-midates (63) and (64) were obtained after oxidative coupling of the symmetrical //-phosphonate diester of AZT with the appropriate amine Biological evaluation on HIV-infected TK-deficient cell lines suggested that such dinucleoside phosphoramidates could not be regarded as pronucleotides, as they were unable to deliver the corresponding 5 -nucleotide inside the cells. 

The first synthesis of a dinucleotide analogue combining phosphorothioate and boranophosphate features has been reported. To prepare dithymidine boranophosphorothioate (71), Fmoc-protected thymidine was phosphitylated by bis(diisopropylamino)-chlorophosphine in the presence of DMAP. The resulting phosphoramidite was treated in situ with a 3 -protected thymidine and tetrazole and was then converted to a phosphite triester with nitrophenol. The phosphite triester was subsequently treated with BH3-SMe2 followed by LiS2 in the presence of 18-crown-6 to yield (71). This novel type of dinucleoside 

While the introduction of heteroatoms at non-bridging positions of the phosphodiester bond can be easily achieved, modifications involving bridging positions of the phosphorus centre often require elaborated chemical approaches. A novel P3 - N5 dinucleotide linkage (74) has now been described. Thymidine-3 -W-(thymidine-5 -yl)-/7-phosphonamidate (74a) was synthesised by reacting the appropriately protected 3 -aryl /7-phosphonate derivative of thymidine with the 3 -protected-5 -amino-thymidine in the presence of pivaloyl chloride. The phosphonamidate was subsequently oxidised to yield the dinucleoside phosphoramidate (74b) and dinucleoside phosphoramidothioate derivatives (74c). 

The preparation of a phosphate diester hydrolysing-hammerhead ribozyme substrate analogue containing an amide linkage in place of the normal phosphate diester linkage (75) has been reported. The dinucleoside analogue was incorporated in a dodecamer, which displayed high affinity for the ribozyme but did not act as a substrate. 

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