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

Abstract

2-Deamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) is a potent inhibitor of thymidylate synthase. Its analogue, N(alpha)-[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, N(5,10)-methylenetetrahydrofolate. The Ki value of 0.34 microM, 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 mM) 180-fold weaker than by ICI 198583 (IC50 = 6.9 microM).

• Authors: Anna Kusakiewicz-Dawid, Marta Bugaj, Jolanta M Dzik, Barbara Gołos, Patrycja Wińska, Krzysztof Pawełczak, Barbara Rzeszotarska, Wojciech Rode
• Journal: Acta biochimica Polonica (Acta Biochim Pol) Vol. 49 Issue 1 Pg. 197-203 ( 2002) ISSN: 0001-527X [Print] Poland
• PMID: 12136941 (Publication Type: Journal Article)

Chemical References

• Glutamic Acid
• Folic Acid
• ICI 198583

Topics

• Animals
• Folic Acid (analogs & derivatives, chemical synthesis)
• Glutamic Acid (chemical synthesis, chemistry)
• Leukemia (drug therapy)
• Mice
• Rats