Biodegradable protections for nucleoside 5'-monophosphates: comparative study on the removal of O-acetyl and O-acetyloxymethyl protected 3-hydroxy-2,2-bis(ethoxycarbonyl)propyl groups.
The applicability of 3-acetyloxy-2,2-bis(ethoxycarbonyl)propyl and 3-acetyloxymethoxy-2,2-bis(ethoxycarbonyl)propyl groups as biodegradable phosphate protecting groups for nucleoside 5'-monophosphates has been studied in a HEPES buffer at pH 7.5. Enzymatic deacetylation with porcine carboxyesterase triggers the removal of the resulting 3-hydroxy-2,2-bis(ethoxycarbonyl)propyl and 3-hydroxymethoxy-2,2-bis(ethoxycarbonyl)propyl groups by retro-aldol condensation and consecutive half acetal hydrolysis and retro-aldol condensation, respectively. The kinetics of these multistep deprotection reactions have been followed by HPLC, using appropriately protected thymidine 5'-monophosphates as model compounds. The enzymatic deacetylation of the 3-acetyloxymethoxy-2,2-bis(ethoxycarbonyl)propyl 5'-triester (2) is 25-fold faster than the deacetylation of its 3-acetyloxy-2,2-bis(ethoxycarbonyl)propyl-protected counterpart 1, and the difference in the deacetylation rates of the resulting diesters, 12b and 12a, is even greater. With 2, conversion to thymidine 5'-monophosphate (5'-TMP) is quantitative, while conversion of 1 to 5'-TMP is accompanied by formation of thymidine. Consistent with the preceding observations, quantitative release of 5'-TMP from 2 has been shown to take place in a whole cell extract of human prostate cancer cells.
Ora
Mikko
M
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland. mikko.ora@utu.fi
Taherpour
Sharmin
S
Linna
Risto
R
Leisvuori
Anna
A
Hietamäki
Emilia
E
Poijärvi-Virta
Päivi
P
Beigelman
Leonid
L
Lönnberg
Harri
H
D000085:Acetates / Q000737:chemistry*; D000818:Animals; D043182:Carboxylesterase / Q000737:chemistry; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D011407:Propane / Q000031:analogs & derivatives* / Q000737:chemistry; D013552:Swine; D013938:Thymidine Monophosphate / Q000737:chemistry*; D013997:Time Factors
C543752:3-acetyloxymethoxy-2,2-bis(ethoxycarbonyl)propyl 5'-triester; D000085:Acetates; D013938:Thymidine Monophosphate; D043182:Carboxylesterase; D011407:Propane