Improved synthesis and antitumor evaluation of 5,8-dideazaisofolic acid and closely related analogues.
A new synthetic route to 5,8-dideazaisofolic acid (IAHQ) is described which precludes the possibility of contamination due to its 4-amino counterpart 5,8-dideazaisoaminopterin. Substitution of D-glutamic acid in this synthetic scheme gave D-IAHQ. The 9-formyl, 9-methyl, 5-methyl, and 5,9-dimethyl modifications of IAHQ were also prepared. These compounds, together with several structurally related or isomeric analogues, were studied for inhibitory effects upon the growth of four human gastrointestinal adenocarcinoma cell lines in vitro. In general, the compounds having a normal folate configuration at positions 9 and 10 are more active than their reversed bridge isomers. The lack of antitumor activity of D-IAHQ provides indirect evidence concerning the mechanism of action of IAHQ.
D000230:Adenocarcinoma / Q000188:drug therapy; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D011799:Quinazolines / Q000138:chemical synthesis* / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011799:Quinazolines; C035530:5,8-dideazaisofolic acid; D008727:Methotrexate