Polynucleoside Monophosphates

2 Polynucleoside Monophosphates. - The novel nucleotide prodrugs 46 based on salicyl phosphate have been prepared by reaction of salicylate or phenyl 

A series of 2 -5 oligoadenylate analogues (48) containing intemucleoside and ribose modifications has been prepared by solid-phase methods as potential interferon mimetics.  

A study of the conformational properties of 2 -0-phosphorylated diuridylate 50 has been made by NMR and CD, whilst the hydrolytic properties of 50 and its 2 -thiophosphate counterpart 51 have been made.  

A phosphotriester method has been developed for rapid synthesis of oligodeoxynucleoside phosphorodithioates in solution. Couplings are performed by the chemoselective oxygen activation of protected nucleoside dithiophosphate anions (56) with 4-nitro-6-trifluoromethylbenzotriazol-l-yl-oxy-tris(pyrrolidine)-phosphonium hexafluorophosphate (PyFNOP) (57) or 6-nitrotriazol-l-yl-oxy-tris(pyrrolidine)-phosphonium hexafluorophosphate (PyNOP) (58). Under optimised conditions, coupling yields above 95% were achieved in between 10 and 20 

The RNA dinucleotide phosphorothiolate, 3 -(thioinosylyl)-(3 -5 )-uridine 59 (IspU) containing a 3 -S-phosphorothiolate linkage has been prepared from 9-(3-deoxy-3-iodo-P-D-xylofuranosyl)hypoxanthine using Arbuzov chemistry. IspU was found to be a substrate for several RNA hydrolysing enzymes and is also labile to acid, base and silver ions. The analogue has also been used to study the 

2 Polynucleoside Monophosphates. - The isodideoxyadenosine containing dinucleotide (53) has been prepared by phosphoramidite chemistry as a potential HIV inhibitor which mimics the DNA terminus obtained by the incorporation of isoddATP by the enzyme. The physical properties of the dinucleotide have been investigated and indicate that it has a similar structure to that of ApA but is much more stable to the action of various phosphodiesterase enzymes. 

Several dinucleotide analogues have been reported as potential prodrugs of the 5 -monophosphates of biologically active nucleotides. These include the a-hydroxybenzylphosphonates of AZT (also see volume 27 in this series) (54), the benzyl phosphate triesters (55) and the 4-acyloxybenzyl phosphate triesters 

Cosstick and co-workers have reported an improved procedure for the synthesis of phosphorothiolate-containing DNA using Arbuzov chemistry in which the nucleoside disulfides are generated in situ from the corresponding thioesters. Several nucleoside disulfides have been prepared and in particular the regioselectivity of reaction of these with a phosphite has been examined. The disulfide (59) allows the preparation of the desired diribonucleoside phosphoro-thiolate (60) but the reaction is accompanied by some (2-10%) formation of the pyridyl phosphorothiolate. 

A number of novel dinucleotide phosphonate and phosphonamidate analogues 

An approach to the stereospecific, solid phase synthesis of methylphosphonates has been developed whereby an appropriately protected, stereochemically pure J p or 5p 3 -(p-nitrophenyl methylphosphonate) ester (65) is coupled to an activated S -hydroxyl group of a support-bound nucleoside. The 5 -hydroxyl group is activated by the addition of a Grignard reagent in pyridine and the release of p-nitrophenol is accompanied by stereospecific intemucleotide bond 

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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. 

Synthesis of a phosphodiester bond in nucleic acids requires energy input. As a result, the nucleoside monophosphates in nucleic acids are built up from hydrolysis of nucleoside triphosphates. Cleaving a pyrophosphate from a nucleoside triphosphate yields a nucleoside monophosphate and enough free energy to make the formation of polynucleoside monophosphates (i.e., polynucleotides) thermodynamically favorable. 

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