Synthesis and antitumour properties of 2-thio-5-chloro-nucleosides

K. Felczak, M. Bretner, T. Kulikowski, W. Rode

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Abstract

Four methods are described for the synthesis of 2-thio-5-chlorouracil (I). p- and a-5-Chloro-2-thio-2‘-deoxyuridines (12 and 13) were obtained by Lewis acid catalysed condensation of TMS derivative of 1 with 2-deoxy-3,5-di-0-p-toluyl-a-D-ribosyl chloride and deblocking of toluylated derivatives with methanolic ammonia. Selective enzymatic phosphorylation of 12 led to its 5’-monophosphate, the latter being a moderate inhibitor of thymidylate synthase, while 12 showed moderate cytotoxicity in vitro against mouse leukemic cells L15178Y.

Original languageEnglish (US)
Pages (from-to)653-656
Number of pages4
JournalNucleosides and Nucleotides
Volume14
Issue number3-5
DOIs
StatePublished - May 1 1995
Externally publishedYes

Bibliographical note

Funding Information:
2'-deoxyuridine (CD,, 5 x 10~'M ). To explain the mechanism of anlilumour activity of 12, the interaction of its 5'-monophosphate with thymidylate synthasc was investigated. Preparations of purified Ehrlich ascites carcinoma (EAC) and LI 2 10 thymidylate synthase (TS) were as previously reporled.' Commercial L. casei TS was purified by aflinily chromatography to eleclrophorelical honiogeneily. E q eassays and identification of the lype of mhibilion were as previously described.6 Spectrophotometric monitoring at 340 nm of the reaction mixture containing 0.30 mM 2-thio-S-chloredUMP in place of dUMP. exhibited no substrate activity with L. casei thymidylate synthase. To test whether thymidylate synthase may dehalogenate this nucleoside, absorbance at 280 nm of a mixture 0.30 mM halogenated compound and 5 mM P-mercaptoethanol with TS was recorded. 2- lhb-S-chlorodUMP was not dehalogenaled by L. casei enzyme. Garret el al.' reporled that TS easily dehalogenates BrdUMP and IdUMP but not CldUMP. Inhibition of Ehrlich ascites carcinoma and LI 210 thymidylate synthase by 2-thio-5-chloro-dUMP was tested by varying the dUMP concentration with different concentrations of inhibitor added simultaneously to the reaction mixture. Competitive inhibition, reflected by the intersection at the ordinates of Linaveaver-Burk plots led to apparent K, values of 6.0 and 23.2 pM for EAC and L I2 10 TS, respectively. The K,of L1210 TS for 2-thio-5-chloro-dUMP was over 300-fold higher than that for 2-thio-5-fluoro-dUMP. 2-Thio-5-chloro-dUMP did not cause time-dependent inactivation of thymidylate synthase, while 2-thio-5-fluoro-dUMP is a time-dependent inactivator of TS from many sources.' Supported by KBN grant 662539203pl0 1 and 007 1 PY9203 REFERENCES 1. Wataya, Y., Santi, D. Biophys. Res. Commun., 1975,67, 8 18. 2. Balmrini, J., De Clercq, E., Mertes, M.P., Shugar, D., Torrence, P.F. Biochem. Pharmacology, 1982,2,3673. 3. Giziewicz, I., Shugar, D., Acta Biochim. Polon., 1975,22, 87. 4. Bretner, M., Kulikowski, T., Dzik, J.M., Balinska, M., Rode, W., Shugar, D. J. Med. Chem., 1993,x, 361 1. 5. Rode, W., Kulikowski, T., Kdzierska, B., Shugar, D. Biochem. Pharmacoloa, 1987,36,203. 6. Rode, W., Kulikowski, T., Jastreboff, M., B., Shugar, D. Biochem. Pharmacology, 1984,_33,2798. 7. Garret, Ch., Wataya, Y., Santi, D.V. Biochemistry, 1979,13,2798. 8. Dzik, J.M., Zielinski, Z., Ciesla, J., Bretner, M., Kulikowski, Shugar, D., Bertino, J.R., Rode, W. Biochem. Biophys. Res. Commun. 1993,195, 1301

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