Pyrophosphoryl derivatives of 1-(2-deoxy-3-O-phosphono-methyl-beta- and -alpha-D-erythro-pentofuranosyl)thymine: synthesis and substrate properties towards some DNA polymerases.
The synthesis of 1-(2-deoxy-3-O-phosphonomethyl-beta-D-erythropentofuranosyl)thymine (17) and its alpha-anomer 18 is described. Attempts to prepare 1-[2-deoxy-3-O-(pyrophosphoryl)phosphonomethyl-beta-D-erythro-pentofuranosyl]thymine (19) by an activation of the respective phosphonate 17 with 1,1'-carbonyldiimidazole (Im2CO) resulted in the quantitative formation of the corresponding pyrophosphonate derivative 21 (Scheme 2). Activation of inorganic pyrophosphate with Im2CO followed by the condensation with the phosphonates 17 and 18 afforded the desired analogues of nucleoside triphosphate 19 (35%) and its alpha-anomer 20 (27%) along with the respective pyrophosphonate derivatives 21 (37%) and 24 (38%) (Scheme 3). It was found that compounds 19 and 20 display (i) no substrate properties toward calf thymus terminal deoxynucleotidyl transferase (TDT) and AMV reverse transcriptase, and (ii) moderate substrate activity with E. coli DNA polymerase I (Klenow fragment).
Mikhailopulo
I A
IA
Institute of Bioorganic Chemistry, National Academy of Sciences, Minsk, Belarus.
Kulak
T I
TI
Tkachenko
O V
OV
Sentyureva
S L
SL
Victorova
L S
LS
Rosemeyer
H
H
Seela
F
F
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D011756:Diphosphates / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism
C423488:1-(2-deoxy-3-O-phosphonomethyl-erythropentofuranosyl)thymine; D011756:Diphosphates; D004259:DNA-Directed DNA Polymerase; D013936:Thymidine