New anticancer agents: synthesis of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines).
Reaction of alpha-aminoacetophenone oximes (2) with ethyl 6-amino-4-chloro-5-nitropyridine-2-carbamate (1) gave ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridine-2-carbamate oximes (3), which were hydrolyzed under acidic conditions to give the corresponding ketones (4). Related pyridines substituted with a keto side chain were prepared from 1 and 1,3-diaminopropanone oximes and by oxidation of the side-chain hydroxy group of ethyl 6-amino-4- [[3-(N-methyl-N-phenylamino)-2-hydroxypropyl]amino]-5-nitropyridine-7- carbamates (6). Catalytic hydrogenation of the nitro group of 4 over Raney nickel in a large volume of ethanol gave the 1-deaza-7,8-dihydropteridines (7). Several of the oximes 3 were successfully hydrogenated to give 7 directly. The resulting 1-deaza-7,8-dihydropteridines showed potent cytotoxicity against cultured L1210 cells and significant anticancer activity against lymphocytic leukemia P-388 in mice. These biological activities are attributed to the accumulation of cells at mitosis.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011719:Pyrazines; D011725:Pyridines