title: Synthesis and evaluation of 2,4-diaminoquinazoline antifolates with activity against methotrexate-resistant human tumor cells.
abstract: In an attempt to find potent antifolates with selectivity against tumor cells with intrinsic or acquired resistance to methotrexate, eleven nonclassical 2,4-diaminoquinazoline antifolates were synthesized and tested as inhibitors of dihydrofolate reductase from L5178Y cells. Several compounds appeared to be good enzyme inhibitors, with I50 values around 1 nM. Two of the compounds were also good inhibitors of cell growth in vitro. One of these (PKC-32, 9-(2,4-diamino-5-methylquinazoline-6-methylene)aminophenanthren e) appeared to be 100-fold more potent than methotrexate as an inhibitor of growth of a methotrexate-resistant cell line with impaired transport for methotrexate. PKC-32 and PKC-155 were also tested against mouse tumors in vivo. PKC-32 was modestly active in vivo as compared with methotrexate. This drug may be a useful agent in the treatment of methotrexate-resistant tumors.
mesh_terms: D000818:Animals; D002460:Cell Line; D004273:DNA, Neoplasm / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D004273:DNA, Neoplasm; D005493:Folic Acid Antagonists; D011799:Quinazolines; D008727:Methotrexate