Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo.
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.
Reynolds
R C
RC
Organic Chemistry Department, Southern Research Institute, Birmingham, AL 35255, USA. reynolds@sri.org
Johnson
C A
CA
Piper
J R
JR
Sirotnak
F M
FM
D000630:Aminopterin / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D000630:Aminopterin