Improved synthetic routes to 5,8-dideazapteroylglutamates amenable to the formation of poly-gamma-L-glutamyl derivatives.
A variety of quinazoline analogues of folic acid (5,8-dideazafolates) are of interest as potential antineoplastic agents, biochemical probes, and/or affinity ligands for the purification of folate requiring enzymes. Chief among these are 5,8-dideazaisopteroylglutamate, 5,8-dideazaisoPteGlu, (IAHQ), a compound with proven activity against the growth of human colon adenocarcinoma cells in vitro, and 10-formyl-5,8-dideazapteroylglutamic acid, which serves as a substrate for glycinamide ribonucleotide transformylase and is also an effective inhibitor of mammalian thymidylate synthase. New methods for preparing these compounds in excellent purity as determined by high performance liquid chromatography (HPLC) have been developed. In each case the carboxyl groups of L-glutamic acid are protected with t-butyl ester groups, since these can subsequently be removed readily using trifluoroacetic acid without decomposition or racemization of the final product. This approach has proven to be of particular value in the formation of gamma-L-glutamyl derivatives of IAHQ containing 1-3 additional glutamyl residues.
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D005492:Folic Acid / Q000031:analogs & derivatives*; D006801:Humans; D007202:Indicators and Reagents; D011624:Pteroylpolyglutamic Acids / Q000138:chemical synthesis* / Q000633:toxicity; D011799:Quinazolines / Q000138:chemical synthesis* / Q000633:toxicity; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011624:Pteroylpolyglutamic Acids; D011799:Quinazolines; D005492:Folic Acid