Hydrolytic reactions of 3'-N-phosphoramidate and 3'-N-thiophosphoramidate analogs of thymidylyl-3',5'-thymidine.
The diastereomeric thiophosphoramidate analogs [(R(P))- and (S(P))-3[prime or minute],5[prime or minute]-Tnp(s)T] and the phosphoramidate analog [3[prime or minute],5[prime or minute]-TnpT] of thymidylyl-3[prime or minute],5[prime or minute]-thymidine were prepared and their hydrolytic reactions over the pH-range 1-8 at 363.2 K were followed by RP HPLC. At pH < 6, an acid-catalyzed P-N3[prime or minute] bond cleavage (first-order in [H(+)]) takes place with both 3[prime or minute],5[prime or minute]-Tnp(s)T and 3[prime or minute],5[prime or minute]-TnpT, the former being about 12 fold more stable than the latter. At pH > 4, Tnp(s)T undergoes two competing pH-independent reactions, desulfurization (yielding TnpT) and depyrimidination (cleavage of the N-glycosidic bond) the rates of which are of the same order of magnitude. Also with 3[prime or minute],5[prime or minute]-TnpT the pH-independent depyrimidination competes with P-N3[prime or minute] cleavage at pH > 5.
Ora
Mikko
M
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
Murtola
Merita
M
Aho
Sami
S
Oivanen
Mikko
M
D000577:Amides / Q000737:chemistry*; D015226:Dinucleoside Phosphates / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D015394:Molecular Structure; D063086:Organothiophosphates / Q000737:chemistry*; D010756:Phosphoric Acids / Q000737:chemistry*; D013237:Stereoisomerism
D000577:Amides; D015226:Dinucleoside Phosphates; D063086:Organothiophosphates; D010756:Phosphoric Acids; C017758:thymidylyl-(3'-5')-thymidine; C011067:phosphoramidic acid