title: Comparison of the biological effects of selected 5,8-dideazafolate analogues with their 2-desamino counterparts.
abstract: Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
authors.forename: J B
authors.initials: JB
authors.lastname: Hynes
authors.forename: S A
authors.initials: SA
authors.lastname: Patil
authors.forename: R L
authors.initials: RL
authors.lastname: Hagan
authors.forename: A
authors.initials: A
authors.lastname: Cole
authors.forename: W
authors.initials: W
authors.lastname: Kohler
authors.forename: J H
authors.initials: JH
authors.lastname: Freisheim
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008727:Methotrexate / Q000627:therapeutic use; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; C035530:5,8-dideazaisofolic acid; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase; D008727:Methotrexate