title: Folylpolyglutamate synthetase inhibition and cytotoxic effects of methotrexate analogs containing 2,omega-diaminoalkanoic acids.
abstract: The properties of a series of methotrexate analogs containing 2,omega-diaminoalkanoic acids have been investigated. The compounds were potent inhibitors of dihydrofolate reductase but, unlike methotrexate, they were also inhibitors of mammalian folylpolyglutamate synthetases. The potency of synthetase and reductase inhibition increased with increasing length of the 2,omega-diaminoalkanoate moiety. The most cytotoxic compound and the most potent inhibitor of both dihydrofolate reductase (I50 = 2.5 to 4 nM) and folylpolyglutamate synthetase (Ki ca. 4 microM) contained 2,5-diaminopentanoic acid (ornithine). These compounds were 70- to 100-fold less cytotoxic than methotrexate to human leukemia cell lines; however, they retained their potency against sublines resistant to methotrexate via defective transport. Their dual loci of enzyme inhibition and their efficacy against methotrexate transport-defective cell lines indicate that these compounds may be an important new class of antifol.
mesh_terms: D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000032:analysis; D000818:Animals; D002460:Cell Line; D005493:Folic Acid Antagonists; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009952:Ornithine / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D005493:Folic Acid Antagonists; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D009952:Ornithine; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate