Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF

Bioorg Med Chem. 2005 May 16;13(10):3587-92. doi: 10.1016/j.bmc.2004.11.050.

Abstract

Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-DDACTHF (1), which incorporate L-glutamine (2) and L-isoglutamine (3) in place of L-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the L-glutamate alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amides / chemistry*
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / pharmacology
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / pharmacology
  • Folic Acid Antagonists / chemical synthesis
  • Folic Acid Antagonists / pharmacology
  • Humans
  • Hydroxymethyl and Formyl Transferases / antagonists & inhibitors
  • Inhibitory Concentration 50
  • Molecular Structure
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Phosphoribosylglycinamide Formyltransferase
  • Purines / antagonists & inhibitors
  • Purines / biosynthesis*
  • Structure-Activity Relationship
  • Tetrahydrofolates* / chemical synthesis
  • Tetrahydrofolates* / chemistry
  • Tetrahydrofolates* / pharmacology
  • Tumor Cells, Cultured

Substances

  • 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid
  • Amides
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Purines
  • Tetrahydrofolates
  • Hydroxymethyl and Formyl Transferases
  • Phosphoribosylglycinamide Formyltransferase
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase