Biochemical and chemotherapeutic studies on 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW 301U), a novel lipid-soluble inhibitor of dihydrofolate reductase.
The lipophilic diaminopyridopyrimidine BW 301U (2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine) is as active as methotrexate as an inhibitor of dihydrofolate reductase and mammalian cell growth. This compound was selected from among related pyridopyrimidines and other lipid-soluble diaminoheterocyclic compounds as having the most favorable combination of properties as a potent inhibitor of dihydrofolate reductase with minimal effects on histamine metabolism. In contrast to methotrexate, entry of BW 301U into cells is rapid and is not temperature dependent, indicating passage across cell membranes by diffusion. There is no competition between BW 301U and leucovorin (folinic acid) for uptake into Sarcoma 180 cells in culture. When BW 301U is added to culture medium, deoxyuridine incorporation ceases within the first few min, and this inhibition persists when cells are transferred to drug-free medium. Both leucovorin and thymidine are required to protect cells in culture from the cytotoxicity of BW 301U. The effect on thymidine biosynthesis appears to be indirect since BW 301U is inactive as an inhibitor of thymidylate synthetase. Hypoxanthine and thymidine restore growth by only 50% in cultures containing BW 301U, and complete restoration of growth requires the further addition of adenosine and either uridine or cytidine to the medium. In vivo, BW 301U is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001692:Biological Transport; D002279:Carcinoma 256, Walker / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology; D051379:Mice; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D006637:Histamine N-Methyltransferase; C024530:piritrexim