Folate analogues. 32. Synthesis and biological evaluation of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid and related compounds.

Abstract

The chemical synthesis of three close analogues (2-4) of N10-propargyl-5,8-dideazafolate (PDDF) is described. The quinazoline ring of 2 and 4 was constructed from the pivotal intermediate 9 in a novel and unambiguous manner during the final step of the synthesis under very mild conditions. 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolate (DMPDDF) (2) was a strong inhibitor of human and Lactobacillus casei thymidylate synthases, whereas 2-desamino-2-(trifluoromethyl)-N10-propargyl-5,8-didezafolate (3) and 2-desamino-2,3-dimethyl-N10-propargyl-5,8-dideazafolate (4) were only weak inhibitors of this enzyme. DMPDDF exhibited excellent growth inhibition of Manca human lymphoid leukemia and H35 hepatoma cells in culture. The inhibitor activities of 2 were 43- and 65-fold greater than that of PDDF, respectively, in these cell lines. H35R cells that are resistant to methotrexate by virtue of a transport defect were cross resistant to DMPDDF but not to PDDF. H35FF cells which have 70-fold greater amounts of thymidylate synthase compared to H35N cells were 130-fold resistant to DMPDDF. Furthermore, the toxicity of DMPDDF to H35 hepatoma cells could be completely reversed by thymidine, establishing its locus of action as thymidylate synthase. Transport studies in vitro established that DMPDDF effectively inhibits MTX influx into H35 hepatoma cells, whereas PDDF has no effect on MTX transport in this cell line. These data suggest that the greater activity of DMPDDF relative to PDDF is partly due to the ability of the former compound to enter cells via the MTX/reduced folate transport system. Enzyme inhibition data of 4 suggest that the presence of N3H in DMPDDF is essential for binding to thymidylate synthase.

• Authors: S D Patil, C Jones, M G Nair, J Galivan, F Maley, R L Kisliuk, Y Gaumont, D Duch, R Ferone
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 32 Issue 6 Pg. 1284-9 (Jun 1989) ISSN: 0022-2623 [Print] United States
• PMID: 2542557 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Folic Acid Antagonists
• Tetrahydrofolates
• N(10)-propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolic acid
• 2-desamino-2-trifluoromethyl-N(10)-propargyl-5,8-dideazafolic acid
• 2-desamino-2,3-dimethyl-N(10)-propargyl-5,8-dideazafolic acid
• Folic Acid
• Thymidylate Synthase
• ICI 198583

Topics

• Breast Neoplasms (drug therapy)
• Carcinoma, Hepatocellular (drug therapy)
• Chemical Phenomena
• Chemistry
• Fibroblasts (enzymology)
• Folic Acid (analogs & derivatives, chemical synthesis, pharmacology, therapeutic use)
• Folic Acid Antagonists
• Humans
• Lacticaseibacillus casei (drug effects, enzymology)
• Liver Neoplasms
• Lymphoma (drug therapy)
• Molecular Structure
• Streptococcus (drug effects)
• Tetrahydrofolates (pharmacology)
• Thymidylate Synthase (antagonists & inhibitors)
• Tumor Cells, Cultured