Synthesis of 5-chloro-5,8-dideaza analogues of folic acid and aminopterin targeted for colon adenocarcinoma.
Several classical quinazoline analogues of folic acid bearing chloro or methyl substituents at position 5 were evaluated as inhibitors of the growth of four human gastrointestinal adenocarcinoma cell lines in vitro. The preparation of two of these, 5-chloro-5,8-dideazaisofolic acid, 1e, and 5-chloro-5,8-dideazaisoaminopterin, 2a, is reported for the first time. In addition, a new synthetic route to 5-chloro-5,8-dideazaaminopterin, 2b, is described. For compounds having a 2,4-diamino configuration, the presence of chlorine at position 5 afforded superior growth inhibitory potency. However, compound 1e was substantially less effective than its 5-methyl counterpart.
D000230:Adenocarcinoma / Q000188:drug therapy*; D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D011799:Quinazolines; C053406:5-chloro-5,8-dideazaisofolic acid; C053405:5-chloro-5,8-dideazaisoaminopterin; D000630:Aminopterin