Synthesis and Enantioselectivity of Cyclopropavir Phosphates for Cellular GMP Kinase |
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| Authors: | Chengwei Li Brian G. Gentry John C. Drach Jiri Zemlicka |
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| Affiliation: | 1. Developmental Therapeutics Program , Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, Michigan, USA;2. Department of Biologic and Materials Science, School of Dentistry , University of Michigan , Ann Arbor, Michigan, USA |
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| Abstract: | Enantiomeric cyclopropavir phosphates (+)-9 and (?)-9 were synthesized and investigated as substrates for GMP kinase. N2-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 KM value of 57 μM that is similar to that of the natural substrates GMP (61 μM) and dGMP (82 μM). In contrast, the enantiomer (?)-9 is not a good substrate (KM 1200 μM) indicating a significant enantioselectivity for the GMP kinase catalyzed reaction of monophosphate to diphosphate. |
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| Keywords: | Methylenecyclopropanes nucleoside analogues cyclopropavir phosphates enantiomers enantioselectivity antivirals GMP kinase |
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