Synthesis and Antifolate Evaluation of 10-ethyl-5-methyl-5,10- Dideazaaminopterin and an Alternative Synthesis of 10-ethyl-10- Deazaaminopterin (Edatrexate)

J Med Chem. 1992 Aug 7;35(16):3002-6. doi: 10.1021/jm00094a011.

Abstract

Previous findings suggesting that 5,10-dialkyl-substituted derivatives of 5,10-dideazaaminopterin warranted study as potential antifolates prompted synthesis of 10-ethyl-5-methyl-5,10- dideazaaminopterin (12a). The key step in the synthetic route to 12a was Wittig condensation of the tributylphosphorane derived from 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (7a) with methyl 4-propionylbenzoate. Reaction conditions for the Wittig condensation were developed using the tributylphosphorane prepared from 6-(bromomethyl)-2,4-pteridinediamine (7b) as a model. Each of the respective Wittig products 8a and 8b was obtained in 75-80% yield. Hydrogenation of 8a and 8b at their 9,10-double bond afforded 4-amino-4-deoxy-10-ethyl-5-methyl-5,10-dideazapteroic acid methyl ester (9a) and 4-amino-4-deoxy-10-ethyl-10-deazapteroic acid methyl ester (9b). This route to 9b intersects reported synthetic approaches leading to 10-ethyl-10-deazaaminopterin (10-EDAM, edatrexate), an agent now in advanced clinical trials. Thus the Wittig approach affords an alternative synthetic route to 10-EDAM. Remaining steps were ester hydrolysis of 9a,b to give carboxylic acids 10a,b followed by standard peptide coupling with diethyl L-glutamate to produce diethyl esters 11a,b, which on hydrolysis gave 12a and 10-EDAM (12b), respectively. The relative influx of 12a was enhanced about 3.2-fold over MTX, but as an inhibitor of dihydrofolate reductase (DHFR) from L1210 cells and in the inhibition of L1210 cell growth in vitro, this compound was approximately 20-fold less effective than MTX (DHFR inhibition, Ki = 4.82 +/- 0.60 pM for MTX, 100 pM for 12a; cell growth, IC50 = 3.4 +/- 1.0 nM for MTX, 65 +/- 18 nM for 12a).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminopterin / analogs & derivatives*
  • Aminopterin / chemical synthesis
  • Aminopterin / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Folic Acid Antagonists*
  • Leukemia L1210 / drug therapy
  • Leukemia L1210 / enzymology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Folic Acid Antagonists
  • 10-ethyl-5-methyl-5,10-dideazaaminopterin
  • edatrexate
  • Aminopterin