Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo[2.2.2]octane ring in place of the benzene ring

Academic Article

Abstract

  • N-[4-[[2,4-diamino-6-pteridinyl)methyl]amino]bicyclo[2.2.2]octane-1- carbonyl]-L-glutamic acid (1) was synthesized and tested for antifolate activity. N-(4-Aminobicyclo[2.2.2]octane-1-carbonyl-L-glutamic acid dimethyl ester (6), the side chain precursor to subject compound 1, was synthesized readily via reported bicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester (2). The side chain precursor 6 was alkylated by 6-(bromomethyl)-2,4-pteridinediamine (7). Subsequent ester hydrolysis then afforded 1. Antifolate and antitumor evaluation of 1 verses L1210 dihydrofolate reductase (DHFR) and three tumor cell lines (L1210, S180, and HL60) showed it to be ineffective. Although compound 1 was very similar to aminopterin structurally, the bicyclo[2.2.2]octane ring system in place of the phenyl ring in the p-aminobenzoate moiety effectively negates the stoichiometric binding displayed by many classical DHFR inhibitors bearing appropriate aromatic ring systems in the side chain. © 2001 Éditions scientifiques et médicales Elsevier SAS.
  • Digital Object Identifier (doi)

    Author List

  • Reynolds RC; Johnson CA; Piper JR; Sirotnak FM
  • Start Page

  • 237
  • End Page

  • 242
  • Volume

  • 36
  • Issue

  • 3