Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid.
The synthesis of the antifolate 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) has been modified. It is prepared from 2-acetamido-6-formyl-4(3H)-pyrido[2,3-b]pyrimidone and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)] phenylmethyl]-triphenylphosphonium bromide. The synthesis proceeds via a sodium hydride promoted Wittig condensation in 1-methyl-2-pyrrolidone followed by catalytic reduction, mild base hydrolysis, and acid precipitation of the product. Synthesis of DDATHF is achieved in a total of seven steps from commercially available reagents. DDATHF is transported effectively into CCRF-CEM cells and inhibits growth of both human (CEM) and murine (L1210) cells in culture. Studies reported here support the view that methotrexate and DDATHF are transported via a shared transport mechanism.
Boschelli
D H
DH
Department of Chemistry, Lederle Laboratories, Pearl River, New York 10965.
Webber
S
S
Whiteley
J M
JM
Oronsky
A L
AL
Kerwar
S S
SS
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000633:toxicity; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000633:toxicity; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology; D007945:Leukemia, Lymphoid / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000037:antagonists & inhibitors; D051379:Mice; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000633:toxicity
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C045894:lometrexol; D008727:Methotrexate