title: Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin.
abstract: The chemical synthesis of a series of poly-gamma-glutamyl metabolites of the experimental anticancer drugs 10-deazaaminopterin (10-DAAM) and 10-ethyl-10-deazaaminopterin (10-EDAAM) has been carried out by the solid-phase procedure. The synthetic products were identical with the poly-gamma-glutamyl metabolites of radiolabeled 10-DAAM and 10-EDAAM produced by normal mouse tissues with regard to elution volume from [(diethylamino)ethyl]cellulose columns and susceptibility to hydrolysis by human plasma folylpolyglutamate hydrolase. Poly-gamma-glutamyl metabolites with a glutamate chain length of up to four glutamate residues were detected in the tissues. The antifolate activity was evaluated with methotrexate (MTX) sensitive and MTX-resistant strains of Lactobacillus casei and Streptococcus faecium. In general, inhibitory potency decreases with increasing Glu chain length. However there are two exceptions. Addition of one Glu residue to 10-DAAM enhances its potency for MTX-resistant L. casei and addition of one Glu residue to 10-EDAAM enhances its potency for the MTX-sensitive L. casei. As shown earlier for MTX polyglutamates, polyglutamylation greatly enhances the inhibitory potency of 10-DAAM and 10-EDAAM for L. casei thymidylate synthase. MTX polyglutamates are 15-30 times more inhibitory than the corresponding 10-DAAM derivatives and 30-60 times more inhibitory than the corresponding 10-EDAAM derivatives. Polyglutamylation of 10-DAAM had little influence on its ability to inhibit L. casei dihydrofolate reductase; however, with 10-EDAAM, addition of one or two Glu residues enhanced its inhibitory potency 2.3-fold.
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007780:Lacticaseibacillus casei / Q000187:drug effects; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013291:Streptococcus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D011623:gamma-Glutamyl Hydrolase / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D010455:Peptides; D011099:Polyglutamic Acid; D011623:gamma-Glutamyl Hydrolase; C040210:edatrexate; D000630:Aminopterin; C017178:10-deazaaminopterin; D008727:Methotrexate