1542-23-0Relevant articles and documents
2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: Synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity
Bretner,Kulikowski,Dzik,Balinska,Rode,Shugar
, p. 3611 - 3617 (2007/10/02)
A convenient synthesis of 5-fluoro-2-thiouracil (11) is based on hydrolytic deamination of 5-fluoro-2-thiocytosine (9). Lewis acid-catalyzed condensation of di-TMS-5-fluoro-2-thiouracil (13) or di-TMS-2-thiouracil (14) with 2-deoxy-3,5-di-O-p-toluyl-D-ribofuranosyl chloride (15) led to mixtures of the β- and α-anomers of 3',5'-toluylated 2'-deoxy-5-fluoro-2-thiouridine (16 and 18) or 2'-deoxy-2-thiouridine (17 and 19), each of which was deblocked with MeOH-NH3 to give the desired free anomeric nucleoside pairs 1, 5 and 3, 7, respectively. These were selectively converted to the corresponding 5'-monophosphates 2, 6 and 4, 8, with the aid of the wheat shoot phosphotransferase system. Conformations of the nucleosides 1, 3, 5, 7 are deduced from 1H NMR spectra, and circular dichroism spectra for nucleotide anomeric pairs 2, 6 and 4, 8 are reported. Whereas β-2-thio-dUMP (4) was a good substrate (K(m) ? 10-5 M), β-5-fluoro-2-thio-dUMP (2) proved to be a potent competitive, slow-binding inhibitor (K(i) ? 10-8 M) of the purified enzymes from Ehrlich ascites carcinoma and L1210 cells. The α-anomer 6 was a weak inhibitor, with K(i) in the mM range, and its congener 8 hardly interacted with the enzyme. The β-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 ? 10-6 M), hence 40- 100-fold weaker than 5-fluoro-dUrd. Its α-anomer 5 was 10-fold less active, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the β-anomer 1.
