Synthesis and enantioselectivity of cyclopropavir phosphates for cellular GMP kinase.
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.
Li
Chengwei
C
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
Gentry
Brian G
BG
Drach
John C
JC
Zemlicka
Jiri
J
D000215:Acylation; D003521:Cyclopropanes / Q000737:chemistry*; D004950:Esterases / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D051528:Guanylate Kinases / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D013379:Substrate Specificity
D003521:Cyclopropanes; D009943:Organophosphorus Compounds; D006147:Guanine; C495219:cyclopropavir; D051528:Guanylate Kinases; D004950:Esterases