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.

• Authors: J H Schornagel, P K Chang, L J Sciarini, B A Moroson, E Mini, A R Cashmore, J R Bertino
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 33 Issue 20 Pg. 3251-5 (Oct 15 1984) ISSN: 0006-2952 [Print] England
• PMID: 6487372 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Neoplasm
• Folic Acid Antagonists
• Quinazolines
• Methotrexate

Topics

• Animals
• Cell Line
• DNA, Neoplasm (metabolism)
• Drug Resistance
• Female
• Folic Acid Antagonists (chemical synthesis, pharmacology, toxicity)
• Humans
• Leukemia (drug therapy)
• Methotrexate (pharmacology)
• Mice
• Mice, Inbred Strains
• Quinazolines (chemical synthesis, pharmacology, toxicity)