Folate analogues. 26. Syntheses and antifolate activity of 10-substituted derivatives of 5,8-dideazafolic acid and of the poly-gamma-glutamyl metabolites of N10-propargyl-5,8-dideazafolic acid (PDDF)

J Med Chem. 1986 Sep;29(9):1754-60. doi: 10.1021/jm00159a032.


The poly-gamma-glutamyl derivatives of n10-propargyl-5,8-dideazafolic acid (PDDF) with a chain length of up to five glutamate residues were synthesized from N10-propargyl-5,8-dideazapteroic acid by the solid-phase procedure. These compounds were evaluated for their antifolate activity using folate-requiring microorganisms and intact and permeabilized L1210 cells and as inhibitors of dihydrofolate reductase and thymidylate synthase derived from L. casei. The polyglutamylated derivatives of PDDF (1) were more active than the parent compound in inhibiting the growth of L. casei, thymidylate synthesis in permeabilized L1210 cells, and L. casei thymidylate synthase. Two analogues of 5,8-dideazafolic acid (2 and 3), one with a 2-butyne and another with a cyclopropylmethyl substituent at N10, were also synthesized and evaluated for their antifolate activities using the above-mentioned test systems. They were considerably less active than PDDF or its polyglutamylated derivatives. N10-Propargyl-5,8-dideazapteroyl tri-, tetra-, and pentaglutamates were equipotent with 5-fluorodeoxyuridylate as inhibitors of thymidylate synthesis in permeabilized L1210 cells. The polyglutamyl metabolites of PDDF were shown to be the most potent antifolate inhibitors of L. casei and L1210 thymidylate synthases yet described.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chemical Phenomena
  • Chemistry
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / pharmacology
  • Folic Acid Antagonists / chemical synthesis
  • Folic Acid Antagonists / pharmacology*
  • Lactobacillus casei / drug effects
  • Lactobacillus casei / enzymology
  • Lactobacillus casei / growth & development
  • Leukemia L1210 / enzymology
  • Quinazolines*
  • Streptococcus / enzymology
  • Structure-Activity Relationship
  • Thymidylate Synthase / antagonists & inhibitors


  • Folic Acid Antagonists
  • Quinazolines
  • CB 3717
  • N(10)-(cyanomethyl)-5,8-dideazafolic acid
  • Folic Acid
  • Thymidylate Synthase