Synthesis and interaction with thymidylate synthase of 5'-dithiophosphate and 5'-fluorothiophosphate of thymidine.
Thymidine-5'-fluorothiophosphate, dTMP(S)-F, was synthesized by the oxathiaphospholane, and thymidine 5'-dithiophosphate, dTMPS2, by the dithiaphospholane, method. To estimate the role of 5'-phosphate group ionization in binding of pyrimidine nucleotides by thymidylate synthase, dTMP(S)-F was studied as an inhibitor of mouse tumour (L1210) enzyme, and its inhibitory properties were compared with those of dTMPS2, a close dTMP analogue. While dTMPS2 proved to be an inhibitor, competitive vs dUMP, with K(i)app = 94 microM, the 5'-fluorothiophosphate congener displayed no activity, indicating that the enzyme requires for binding the presence of a dianionic 5'-phosphate group in a nucleotide.
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw.
B
B
Gołos
K
K
Misiura
M
M
Olesiak
A
A
Okruszek
W J
WJ
Stec
W
W
Rode
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D063086:Organothiophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D063086:Organothiophosphates; C115027:thymidine-5'-dithiophosphate; C115028:thymidine-5'-fluorothiophosphate; D013940:Thymidylate Synthase