Synthesis and enantioselectivity of cyclopropavir phosphates for cellular GMP kinase
Chengwei Li, Brian G Gentry, John C Drach, Jiri Zemlicka, Chengwei Li, Brian G Gentry, John C Drach, Jiri Zemlicka
Abstract
Enantiomeric cyclopropavir phosphates (+)-9 and (-)-9 were synthesized and investigated as substrates for GMP kinase. N(2)-Isobutyryl-di-O-acetylcyclopropavir (11) was converted to (+)-monoacetate 12 using hydrolysis catalyzed by porcine liver esterase. Phosphorylation via phosphite 13 gave after deacylation, phosphate (+)-9. Acid-catalyzed tetrahydropyranylation of (+)-monoacetate 12 gave, after deacylation, tetrahydropyranyl derivative 14. Phosphorylation via phosphite 15 furnished, after deprotection, enantiomeric phosphate (-)-9. Racemic diphosphate 16 was also synthesized. The phosphate (+)-9 is a relatively good substrate for GMP kinase with a K(M) value of 57 microM that is similar to that of the natural substrates GMP (61 microM) and dGMP (82 microM). In contrast, the enantiomer (-)-9 is not a good substrate (K(M) 1200 microM) indicating a significant enantioselectivity for the GMP kinase catalyzed reaction of monophosphate to diphosphate.
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Source: PubMed