Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine

Abstract

The following derivatives of 2'-deoxy-5'-O-1",3",2"-dioxaphosphacyclohex-2" -yluridine 2"-oxide have been synthesised: 5-fluoro (4), 5"-(benzyloxy)-5-methyl (6), 5"-(benzyloxy)-5-fluoro (7), 5"-hydroxy-5-methyl (8), 5-fluoro-5"-hydroxy (9), 5",5"-difluoro-5-methyl (11), and 5,5",5"-trifluoro (12). Compounds 4, 9, and 12 have been evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Compound 12 was nearly as potent as 2'-deoxy-5-fluorouridine in its inhibitory effect on these cells (ID50 = 0.003 and 0.001 micrograms/mL, respectively). Compounds 4 and 9 were about 300 times less active than 12. None of the compounds was an inhibitor of the cell-free thymidylate synthetase, although their antiproliferative effects were achieved by the inhibition of this enzyme.

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

“…37 A series of cyclic phosphates of FUdR and thymidine were synthesized and evaluated for cytotoxicity towards murine leukemia L1210 cells. 38…”

“…The comparable activity of the cyclic phosphate in the thymidine kinase-de®cient L1210/BdUrd cell line to that of FUdR and FUdR-MP (ID 50 2.42 AE 0.4 mg/ml, 1.75 AE 0.4 mg/ml, and 2.43 AE 0.43 mg/ml, respectively) suggested that the compound was hydrolyzed extracellularly to FUdR, before cellular uptake. 38…”

Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

“…The straightforward use of simple nucleotides to by-pass the kinase dependence is precluded on account of their poor membrane penetration (Leibman and Heidelberger, 1955;Lichtenstein et al, 1960). However, there has been much interest in the use of masked phosphate esters as membrane-soluble depot forms of the bio-active nucleotides of several chemotherapeutic nucleoside analogues (Hunston et et., 1984;McGUigan et el., 1989a, b;Jones, 1989).…”

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

“…Thus, uncharged phosphate triester derivatives of seve~al_c~e':! '!~t~el"a= peutic nucleosides have been investigated as membranesoluble pro-drug forms (Farquhar, 1985;Hunston, 1984;Chawla, 1984;McGuigan, 1989). Here, we report the first application of these strategies to the potent anti-HIV compound AZT.…”