Synthesis and interaction with thymidylate synthase of 5'-dithiophosphate and 5'-fluorothiophosphate of thymidine

• Autorzy: Golos B. , Misiura K. , Olesiak M. , Okruszek A. , Stec W.J. , Rode W.
• Języki publikacji: EN

Abstrakty

EN

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 Kiapp = 94 μM, 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.

Słowa kluczowe

EN

dianionic 5'-phosphate group; mouse; mice; thymidine 5'-fluorothiophosphate; enzyme; thymidylate synthase; thymidine 5'-dithiophosphate; tumour; 5'-dithiophosphate group

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 1998
• Tom: 45
• Numer: 1
• Opis fizyczny: p.83-86

Twórcy

autor

Golos B.

• Polish Academy of Sciences, L.Pasteura 3, 02-093 Warsaw, Poland

autor

Misiura K.

autor

Olesiak M.

autor

Okruszek A.

autor

Stec W.J.

autor

Rode W.

Bibliografia

• 1. CorreraB, C.W. & Santi, D.V. (1995) The cata­lytic mechanism and structure of thymidylate synthase. Annu. Rev. Biochem. 64, 721- 762.
• 2. Ealick, S.E. & Armstrong, S.R. (1993) Phar­macologically relevant proteins. Curr. Opin­ion Struct. Biol. 3. 861-867.
• 3. Okruszek, A., Olesiak, M. & Balzarini, J. (1994) The synthesis of nucleoside 5'-0-(l,l- dithiotriphosphates). J. Med, Chem. 37, 3850-3854.
• 4. Okruszek, A., Sierzchała, A., Fearon, K.L. & Stec, W.J. (1995) Synthesis of oligo(deoxyri- honucleoside phosphorodithioate)s (S^ODNs) by the dithiaphospholane approach. J. Org. Chem. 60, 5998-7005.
• 5. Okruszek, A., Olesiak, M., Krajewska, D. & Stec, W J. (1997) Efficient one-pot synthesis of 2'-deoxyribonucleoside-3'-0- and 5'-Ophos- phorodithicates. J. Org. Chem. 62, 2269- 2272.
• 6. Stec, W.J., Grajkowski, A., Karwowski, B., Ko­bylańska, A., Koziołkiewicz, M., Misiura, K., Okruszek, A., Wilk, A., Guga, P. & Bocz- kowska, M. (1995) Diastereomers of nucleo­side 3'-0-i2thio-l .3.2-oxathia(selena)phospho- lanesj: Building blocks for stereocontrolled synthesis of oligo(nucleoside phosphoro- thioate)s. J. Am. Chem. Soc. 117, 12019- 12029.
• 7. Rode, W., Zieliński, Z., Dzik, J.M.. Kulikowski, T., Bretner, M., Kierdaszuk, B., Cieśla, J. & Shugar, D. (1990) Mechanism of inhibition of mammalian tumor and other thymidylate syn­thases by i^-hydroxy-dCMP, A^-hydroxy-o- fluoro-dCMP, and related analogues. Biochem­istry 29, 10835-10842.
• 8. Seeberger, P.H., Yau, E. & Curuthers, M.H. (1995) 2'-Deoxynucleoside dithiophosphates: Synthesis and biological studies. J. Am. Chem. Soc. 117, 1472-1478.
• 9. Dąbkowski, W. & Tworowska, I. (1995) First synthesis of nucleosidyl phosphofluoridothio- ates and a convenient synthesis of nucleosidyl phosphorofluoriaates. Chemistry Lett. 727- 728.
• 10. Bollmark, M. & Stawiński, J. (1996) A facile access to nucleoside phosphorofluoridate, nu­cleoside phosphorofluoridothioate, and nu­cleoside phosphorofluoridodithioate monoes- ters. Tetrahedron Lett. 37, 5739-5742.
• 11. Gołos, B., Dzik, J.M., Rode, W., Jankowska, J., Kraszewski, A., Stawiński, J. & Shugar, D. (1997) Interaction of thymidylate synthase with the 5'-thiophosphates and 5'-H-phosphon- ates of 2'-deoxyuridine, thymidine and 5- fluoro-2'-deoxyuridine; in Chemistry and Biolo­gy of Pteńdines and Folates. 11th International Symposium 1997, Berchtesgaden (Pfleiderer, W. & Rokos, H., eds.) pp. 423-426, Blackwell Sei., Berlin.
• 12. Withers, S.G. & Madsen, N.B. (1980) Nucleo­tide activation of glycogen Phosphorylase b oc­curs only when the nucleotide phosphate is in a dianionic form. Biochem. Biophys. Res. Com- mun. 97, 513-519.