Synthesis and biological activity of Nα-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenyl-acetyl]-L-glutamic acid.

• Authors: Anna Kusakiewicz-Dawid , Marta Bugaj , Jolanta M Dzik , Barbara Gołos , Patrycja Wińska , Krzysztof Pawełczak , Barbara Rzeszotarska , Wojciech Rode
• Languages of publication: EN

Abstracts

EN

2-Deamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) is a potent inhibitor of thymidylate synthase. Its analogue, Nα-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenylacetyl]-L-glutamic acid, containing p-aminophenylacetic acid residue substituting p-aminobenzoic acid residue, was synthesized. The new analogue exhibited a moderately potent thymidylate synthase inhibition, of linear mixed type vs. the cofactor, N5,10 -methylenetetrahydrofolate. The Ki value of 0.34 μM, determined with a purified recombinant rat hepatoma enzyme, was about 30-fold higher than that reported for inhibition of thymidylate synthase from mouse leukemia L1210 cells by ICI 198583 (Hughes et al., 1990, J. Med. Chem. 33, 3060). Growth of mouse leukemia L5178Y cells was inhibited by the analogue (IC50 = 1.26 μM) 180-fold weaker than by ICI 198583 (IC50 = 6.9 μM).

Keywords

EN

ICI 198583 analogue; inhibition; thymidylate synthase

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2002
• Volume: 49
• Issue: 1
• Pages: 197-202

Dates

published

2002

received

2001-09-10

revised

2002-01-07

accepted

2002-02-02

Contributors

author

Anna Kusakiewicz-Dawid

• Institute of Chemistry, University of Opole, Opole, Poland

author

Marta Bugaj

• Institute of Chemistry, University of Opole, Opole, Poland

author

Jolanta M Dzik

• Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland

author

Barbara Gołos

• Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland

author

Patrycja Wińska

• Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland

author

Krzysztof Pawełczak

• Institute of Chemistry, University of Opole, Opole, Poland

author

Barbara Rzeszotarska

• Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland

author

Wojciech Rode

• Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland

References

• Carreras, C.W. & Santi, D.V. (1995) The catalytic mechanism and structure of thymidylate synthase. Ann. Rev. Biochem. 64, 721-762.
• Cieśla, J., Weiner, K.X., Weiner, R.S., Reston, J.T., Maley, G.F. & Maley, F. (1995) Isolation and expression of rat thymidylate synthase cDNA: Phylogenetic comparison with human and mouse thymidylate synthases. Biochim. Biophys. Acta 1261, 233-242.
• Dąbrowska, M., Zieliński, Z., Wranicz, M., Michalski, R., Pawełczak, K. & Rode, W. (1996) Trichinella spiralis thymidylate synthase: Developmental pattern, isolation, molecular properties and inhibition by substrate and cofactor analogues. Biochem. Biophys. Res. Commun. 228, 440-445.
• Georgopapadakou, N.H. & Walsh, T.J. (1996) Antifungal agents: Chemotherapeutic targets and immunologic strategies. Antimicrob. Agents Chemother. 40, 279-291.
• Greenstein, J.P. & Winitz, M. (1961) Chemistry of Amino Acids; vol. 2, p. 934, Wiley, New York.
• Harrap, K.R. (1995) Initiatives with platinum- and quinazoline-based antitumor molecules - Fourteenth Bruce F. Cain memorial award lecture. Cancer Res. 55, 2761-2768.
• Heidelberger, C., Danenberg, P.V. & Moran, R.G. (1983) Fluorinated pyrimidines and their nucleosides. Adv. Enzymol. 54, 58-119.
• Hughes, L.R., Jackman, A.L., Oldfield, J., Smith, R.C., Burrows, K.D., Marsham, P.R., Bishop, J.A.M., Jones, T.R., O'Connor, B.M. & Calvert, A.H. (1990) Quinazoline antifolate thymidylate synthase inhibitors: Alkyl, substituted alkyl, and aryl substituents in the C2 position. J. Med. Chem. 33, 3060-3067.
• Jackman, A.L., Farrugia, D.C., Gibson, W., Kimbell, R., Harrap, K.R., Stephens, T.C., Azab, M. & Boyle, F.T. (1995) ZD1694 (Tomudex): A new thymidylate synthase inhibitor with activity in colorectal cancer. Eur. J. Cancer 31A, 1277-1282.
• Kunishima, M., Kawachi, C., Iwasaki, F., Terao, K. & Tani, S. (1999) Synthesis and characterization of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)- 4-methylmorpholinium chloride. Tetrahedron Lett. 40, 5327-5330.
• Montgomery, J.A., Piper, J.R., Elliot, R.D., Temple, C., Jr., Roberts, E.C. & Shealy, Y.F. (1979) Analogues of methotrexate. J. Med. Chem. 22, 862-868.
• Rathod, P.K.(1997) Antimalarial agents directed at thymidylate synthase. J. Pharm. Pharmacol. 49 (Suppl. 2), 704-711.
• Roberts, E.C. & Shealy, Y.F. (1973) Folic acid analogs. Modifications in the benzene-ring region. 3. Neohomofolic and neobishomofolic acids. An improved synthesis method of folic acid and its analogs. J. Med. Chem. 16, 697-699.
• 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 N4-hydroxy-dCMP, N4-hydroxy5-fluoro-dCMP, and related analogues. Biochemistry 29, 10835-10842.
• Rode, W., Dąbrowska, M., Zieliński, Z., Gołos, B., Wranicz, M., Felczak, K. & Kulikowski, T. (2000) Trichinella spiralis and Trichinella pseudospiralis: Developmental patterns of enzymes involved in thymidylate biosynthesis and pyrimidine salvage. Parasitology 120, 593-600.
• Sotelo-Mundo, R.R., Ciesla, J., Dzik, J.M., Rode, W., Maley, F., Maley, G.F., Hardy, L.W. & Montfort, W.R. (1999) Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug. Biochemistry 38, 1087-1094.
• Takemura, Y. & Jackman, A.L. (1997) Folate-based thymidylate synthase inhibitors in cancer chemotherapy. Anti-Cancer Drugs 8, 3-16.