Quinazoline antifolate thymidylate synthase inhibitors: 2'-fluoro-N10-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C2 position

J Med Chem. 1990 Nov;33(11):3067-71. doi: 10.1021/jm00173a025.


The synthesis of 2'-fluoro-10-propargyl-5,8-dideazafolic acid and its 2-desamino, 2-desamino-2-hydroxymethyl, and 2-desamino-2-methoxy analogues is described. In general the synthetic route involved the coupling of diethyl N-[2-fluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate with the appropriate 6-(bromomethyl)quinazoline followed by deprotection with mild alkali. These four compounds together with the 2-desamino-2-methyl analogue were tested for their activity against L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of the L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates. Compared with their non-fluorinated parent compounds, the 2'-fluoro analogues were all approximately 2-fold more potent as TS inhibitors. Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and this activity was prevented by co-incubation with thymidine. All had retained or improved activity against both the L1210:R7A and L1210:1565 cell lines.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Chemical Phenomena
  • Chemistry
  • Drug Resistance
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / chemistry
  • Folic Acid / pharmacology
  • Folic Acid Antagonists / chemical synthesis*
  • Folic Acid Antagonists / pharmacology
  • Leukemia L1210 / enzymology
  • Leukemia L1210 / pathology
  • Mice
  • Molecular Structure
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Structure-Activity Relationship
  • Thymidylate Synthase / antagonists & inhibitors*


  • Antineoplastic Agents
  • Folic Acid Antagonists
  • Quinazolines
  • Folic Acid
  • Thymidylate Synthase